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Dragaglobin clears heart failure in diabetes

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

The test was presented here at the Scientific Sessions of the American Heart Association (AHA) 2018 by Editor Stephen Wiviott, MD, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. It was also published online at New England Journal of Medicine.

"What we see in this test is a similar issue to other major trials of sodium glucose (SGLT2) inhibitors – a significant reduction in hospitalization for heart failure and renal events, "Wiviott commented | Medscape Cardiology.

"DECLARE-TIMI 58, however, differs from the other [cardiovascular outcomes] studies in that he enrolled a much wider and healthier population, including 10,000 patients without pre-existing cardiovascular disease but with multiple risk factors, as well as 7,000 patients with pre-existing cardiovascular disease. "

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

"All three SGLT2-inhbitor tests have found a great impact on the endpoint of heart failure and our trial adds to the well-known literature in this regard, but it also extends this benefit to heart failure to the primary diabetic population," Wiviott said.

"If we look at all the tests, empagliflozin showed the greatest benefit to MACE, but that was even less than the benefit of heart failure. I think after the DECLARE-TIMI 58 test we can definitely say today the greatest benefit SGLT2 inhibitors are for the prevention of heart failure and the reduction of major cardiovascular events is limited to patients with existing underlying cardiovascular disease. "

"The DECLARE TIMI-58 test also provides very reassuring safety data without any sign of stroke, amputation or bladder cancer growth," he added.

Major cardiovascular studies (CV) for the newer type 2 diabetes drugs are being conducted to demonstrate safety after a mandate from the US Food and Drug Administration (FDA) in 2008, after concerns about CV damage with older Type 2 drugs diabetes.

So far, however, none of the eight completed CV tests did not identify the excessive CV risk of these drugs and three showed a real benefit.

These included two studies of oral SGLT2 inhibitors: the EMPA-REG OUTCOMES test with hemaglobaline (Jardiance, Boehringer Ingelheim / Lilly) and CANVAS with kanaglysol (Invokana, Janssen). In both studies, all patients had type 2 diabetes and existing cardiovascular disease or had a high risk of cardiovascular disease.

Similarly, in the third study, LEADER, with the enzyme agonist liparound (1 glucagon-like) protein-1 (GLP-1)Victoza, Novo Nordisk), all patients with type 2 diabetes had CV (CVD) or chronic renal insufficiency or were 60 years of age or older with CVD risk factors.

DECLARE now adds to this list of studies showing cardiovascular benefits with new diabetes medicines, although its benefits are limited to the endpoint of heart failure and did not show the same reductions in MACE as other SGLT2 or LEADER inhibitor trials. However, this study included a population of patients with type 2 lower risk diabetes than in previous cardiovascular outcomes.

There is no increase in amputations with dragaglobin in the DECLARATION

For DECLARE-TIMI 58, 17,160 patients with type 2 diabetes who had atherosclerotic CVD or multiple risk factors for cardiovascular disease were randomly assigned to dapagliflozin 10 mg daily or to placebo in addition to the usual treatment.

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

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

Regarding the two efficacy outcomes, MACE decreased numerically in the deafliflozine group, but this finding was not significant. The CV death / CV endpoint was significantly reduced. This was due to a lower rate of hospitalization for heart failure.

A key secondary outcome was a renal complex (≥ 40% reduction in the estimated glomerular filtration rate to <60 mL / min per 1.73 m2 body surface area, new kidney disease or death from renal or CV). This was also significantly reduced with dragaglobin.

Table 1. DECLARE-TIMI 58: Main Results

Variable Dapaglifosin (%) Placebo (%) Risk ratio (95% confidence interval)
CV death / MI / stroke 8.8 9.4 0.93 (0.84 – 1.03)
CV of Death / Nervous Heart Failure 4.9 5.8 0.83 (0.73 – 0.95)
Treatment for heart failure 2.5 3.3 0.73 (0.61 – 0.88)
Biographical death 2.9 2.9 0.98 (0.82 – 1.17)
Complex kidney 4.3 5.6 0.76 (0.67 – 0.87)

After the groups were divided into patients with and without cardiovascular disease, MACE did not significantly decrease with the dapaglifosin in those with established disease but there was no effect on those without established CVD.

Table 2. Results in those with and without CVD (HR for deaglyphlozine)

Variable Risk ratio (95% confidence interval)
CV death / MI / stroke 0.90 (0.79 – 1.02) 1.01 (0.86 – 1.20)
CV of Death / Nervous Heart Failure 0.83 (0.71 – 0.98) 0.84 (0.67 – 1.04)

For adverse reactions, diabetic ketoacidosis was more common with dragaglobin (0.3% vs. 0.1%), as well as genital infections that were interrupted or considered serious (0.9% vs. 0.1 %). Wiviott observed that these are both known side effects of SGLT2 inhibitors.

Commentary: "Our results are also reassuring as we did not see any proposal to increase amputations or strokes with deparaglophosine and this is the largest study of these factors with longer follow-up."

"In the [EMPA-REG OUTCOMES] the cerebral stroke went in the wrong direction, and the CANVAS test with kanaflophylline showed an increased incidence of amputations in the treated group. Because of these observations in previous trials, we evaluated these results very carefully, and we found no evidence of any increase with efavirenz. "

"In the early studies of deparagllozine, there was a small increase in bladder cancer with the drug, so the FDA mandated to monitor it carefully for the DECLARE trial and it turned out that the rate of bladder cancer was actually lower so it is again reassuring and shows that observations in small-number studies are often due to luck, "he added.

Clinical Outcomes in Diabetes: Marine Change in Therapy

Wiviott noted that these newer drugs for type 2 diabetes have slowed down lately in the market. "Currently, cardiologists do not prescribe these drugs often, but now we have many studies showing cardiovascular benefits, I believe their use in the cardiogenic community will also increase in primary and secondary patients with diabetes prevention.

"These studies were initially conducted to show cardiovascular safety, but they did show cardiovascular benefit, which was not expected, so these drugs now turn into cardiovascular agents that also reduce blood sugar and not just diabetic drugs.

"This is a change in the sea and studies are now underway with SGLT2 inhibitors as heart failure and renal preventive therapies in patients without diabetes."

"Research on the mechanism of action has also been launched behind their beneficial effects, which is probably not just due to the reduction in blood sugar," he added. "They affect the sodium / glucose transporter in the kidney, so the patient secretes sodium and glucose into the urine, but it can also have direct cardiac effects," he suggested.

Asked about how to compare the various factors in the class, he said: "I would be sure about using any of these drugs. Instead of competing with the SGLT2 inhibitor to use it, I would recommend that when you treat diabetic patients who have proven cardiovascular and renal benefits would be preferable to older diabetes medicines that have not shown such benefits. "

Reduction of macrovascular and microvascular events: Shifting examples

"I also believe that we are entering a change of example in the treatment of diabetes. All have stabilized so far to lower blood sugar to reduce microvascular complications and there is nothing to differentiate the different categories [newer] but we are now starting to focus on reducing macrovascular complications (eg cardiovascular outcomes). "

Specialist author 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 without established atherosclerotic CVD of all results of the CVLT2 CV inhibitor .

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

"We also see from all the tests together that diabetic patients with underlying cardiovascular disease" taking these factors benefit MACE but that "this phenomenon does not extend to patients without underlying cardiovascular disease."

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

Heart failure is equally or perhaps even more common than major adverse cardiovascular events in patients with diabetes, and heart failure usually has worse results. We also know that we can reduce the cardiovascular outcomes in patients with diabetes working in the lifestyle – weight, blood pressure, etc. – but this does not seem to have the same effect on the risk of heart failure ".

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

To | Medscape Cardiology, Butler added: "The choice between individual SGLT 2 inhibitor drugs is difficult. The benefit from cardiovascular mortality with entafloflozine was very impressive – this is hard to ignore. The benefits of kidney and heart failure seem to overlap with all medicines. There was a slight increase in kanaphylosine amputations. This may have been merely random and has not been observed with other SGLT2 inhibitors. "

"Then we also have GLP-1 agonist drugs, which have proven a clear benefit from serious cardiovascular events but appear to be neutral for the risk of heart failure." I believe we can make an assumption of using both of these categories factors in some cases. "

A more sophisticated view …

Others, however, take a more modest view. One of these is David Nathan, MD, director of the Diabetic Center at Massachusetts General Hospital, Boston, Massachusetts. He commented | Medscape Cardiology: "These SGLT2 inhibitors reduce the risk of hospitalization for heart failure in diabetics with or at increased risk of heart disease but the absolute risk reduction is quite moderate – about 1%." Empagliflozin has shown better results in significantly negative cardiovascular events in patients with established heart disease. "

It also notes that the adverse effects and cost of SGLT2 inhibitors should be taken into account when considering their use.

These drugs increase urinary glucose secretion, leading to urinary tract infections, and we might ask if it is a really expensive diuretic – we will have the same effect with a low dose of furosemide or thiazide diuretic with fewer side effects and a much lower cost ; "

Nathan also noted that the glycemic effects of deparaglove were moderate with a 0.4% reduction in hemoglobin A1c (HbA1c) (reduction of HbA1c from 8.3% to 7.9%) in this trial. "This is not enough to meet the FDA's usual minimum requirements for a new diabetes medicine approval."

"Whether these drugs should be considered more appropriate as treatments for heart failure in diabetic patients instead of glucose-lowering drugs themselves is a not so delicate distinction that needs to be considered," he concluded.

DECLARE-TIMI 58 was funded by Astra Zeneca and Bristol-Myers Squibb. Wiviott reports subsidies 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 on 10 November 2018.

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

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