CHICAGO – dapagliflozin (Farxiga / ForxigaAstraZeneca) showed a non-significant trend toward a reduced rate of major cardiac events (MACE) in patients with type 2 diabetes in the DECLARE-TIMI 58 study.

The study was presented here in the Scientific Sessions 2018 of the American Heart Association (AHA) by lead author Stephen Wiviott, MD, Brigham and Womens Hospital and Harvard Medical School, Boston, Massachusetts. It was also published online on the internet New England Journal of Medicine,

"What we see in this study is a similar topic to other important studies with sodium glucose cotransporter-2 (SGLT2) inhibitors – a significant reduction in hospital insufficiency and kidney disease in heart failure, "commented Wiviott | Medscape cardiology.

"DECLARE-TIMI 58, however, is different from the others [cardiovascular outcomes] Studies that included a much broader and healthier population, including 10,000 patients without pre-existing multiple-risk cardiovascular disease and 7,000 patients with pre-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 could be differentiated between these populations, without this in the primary prevention group and the trend towards a reduction in those with secondary prevention.

"All three SGLT2-Inhbitor studies have found a major impact on the outcome of heart failure, and our study complements well-known literature in this regard, but it also extends the benefits of heart failure to the diabetic population of primary prevention," said Wiviott.

He added, "If we look at all the studies, empagliflozin has shown the greatest benefit for MACE, but it was still less than the benefit in heart failure, and I think that after the DECLARE-TIMI 58 study, we can definitely get the most value SGLT2 inhibitors are used to prevent heart failure and to reduce major cardiovascular events to patients with pre-existing cardiovascular disease. "

"The DECLARE TIMI 58 study also provides very reassuring safety data with no evidence of strokes, amputations or bladder cancer," he added.

The extensive cardiovascular (CV) trials of newer type 2 diabetes drugs are being conducted to demonstrate safety following a mandate from the US Food and Drug Administration (FDA) in 2008, after concerns over CV damage consist of older type 2 diabetes medications.

However, none of the eight completed CV outcome studies have identified an excessive CV risk in the drugs in question, and three have actually shown benefit.

These included two studies on oral SGLT2 inhibitors: the EMPA-REG study OUTCOMES with empagliflozin (Jardiance, Boehringer Ingelheim / Lilly) and CANVAS with Canagliflozin (InvokanaJanssen). In both studies, all patients had type 2 diabetes and existing CVD or were at high risk for CVD.

Also, in the third study, LEADER was evaluated with the once-daily injectable glucagon-like protein-1 (GLP-1) agonist liraglutide (Victoza, Novo Nordisk), all patients with type 2 diabetes had CVD or chronic renal failure, or were 60 years and older with CVD risk factors.

DECLARE now adds this list of studies demonstrating cardiovascular benefit with new diabetes drugs, although the benefit is limited to the endpoint of heart failure and has not shown the same MACE reductions as in the other SGLT2 inhibitor studies or LEADER , However, this study included a lower risk population of patients with type 2 diabetes than in previous cardiovascular outcome studies.

No increase in amputations with dapagliflozin in DECLARE

In 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 receive dapagliflozin 10 mg daily or placebo in addition to standard therapy.

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

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

In terms of the two efficacy results, MACE was numerically reduced in the dapagliflozin group, but this finding was not significant. The endpoint for hospitalization for CV death / heart failure has been significantly reduced. This was caused by lower hospitalization for heart failure.

An important secondary result was renal composite (decrease in estimated glomerular filtration rate by 40% to <60 ml / min per 1.73 m.)2 Body surface, end stage renal disease or death from renal or CV causes). This was also significantly reduced with dapagliflozin.

Table 1. DECLARE-TIMI 58: Main Results

variable Dapagliflozin (%) Placebo (%) Danger ratio (95% confidence interval)
CV death / 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 hospitalization 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 divided into patients with and without established cardiovascular disease, MACE was not significantly reduced in dapagliflozin in patients with established disease, but no effect was seen in subjects with no established CVD effect.

Table 2. Results in subjects with and without CVD (HR for dapagliflozin)

variable Danger ratio (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)

With regard to adverse events, diabetic ketoacidosis occurred more frequently with dapagliflozin (0.3% vs. 0.1%), genital infections led to discontinuation or were considered serious (0.9% vs. 0.1%). Wiviott noted that these are both known side effects of SGLT2 inhibitors.

He commented, "Our results are also reassuring as we have seen no evidence of an increase in amputations or strokes with dapagliflozin, which is the largest study of these drugs with the longest follow-up time."

"In that [EMPA-REG OUTCOMES] In the empiragliflozin study, the stroke was in the wrong direction and in the CANvAS study with canagliflozin, there was an increased incidence of amputations in the treated group. Based on these observations in previous studies, we evaluated these results very carefully and found no signs of an increase with dapagliflozin. "

"In earlier studies with dapagliflozin, there was a minor increase in bladder cancer with the drug, so the FDA called for careful monitoring in the DECLARE trial and found that the rate of bladder cancer in the blood was actually lower was dapagliflozin poor, so it's reassuring to see that observations in studies of low numbers are often random, "he added.

CV Results Studies in Diabetes: Sea Change in Therapy

Wiviott noted that these newer type 2 diabetes drugs have been slow to enter the market. "Currently, cardiologists do not often prescribe these medicines, but now there are several studies showing cardiovascular benefits, and I think their use in cardiology will increase in patients with primary and secondary diabetes prevention.

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

"This is a fundamental change and there are ongoing trials of SGLT2 inhibitors in heart failure and kidney prevention in patients without diabetes."

"Research into the mechanisms of action behind the beneficial effects, which are probably not just due to lowering blood sugar, is being researched on an ongoing basis." "They affect the sodium / glucose transporter in the kidney, so the patient excretes sodium and glucose in the urine, but they can also have direct cardiac effects," he suggested.

When asked how the different compounds in the class are compared, he said, "I would feel confident to use one of these drugs instead of competing on which SGLT2 inhibitor to use, so I would recommend treatment Using one of the medications of diabetes patients A class that has demonstrated cardiovascular and renal benefits would be preferable to older diabetes medications that have not shown such benefits. "

Reduction of macrovascular and microvascular events: a paradigm shift

"I also think we are introducing a paradigm shift in the treatment of diabetes, so far everyone has been focused on lowering blood sugar to reduce microvascular complications, and there was no difference between the different classes of [newer] Diabetes medications, but now we are starting to focus on reducing macrovascular complications (ie, cardiovascular outcomes). "

Designated Panelist Javed Butler, of the University of Mississippi Medical Center, Jackson, Jackson, said DECLARE-TIMI 58 was a well-conducted study that had the highest proportion of diabetics without established atherosclerotic CVD from all studies with SGLT2 inhibitor CV results.

"This study again demonstrates the benefits of SGLT2 inhibitors in diabetics in reducing heart failure risk and kidney problem," he said.

"We also see from all studies that diabetics with underlying cardiovascular disease taking these agents have a benefit for MACE, but that this effect does not affect patients without underlying cardiovascular disease."

Butler emphasized that heart failure is a very important endpoint for diabetes studies.

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

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

To | Medscape Cardiology, Butler added: "The choice between the individual SGLT 2 inhibitor drugs is difficult. The benefit of cardiovascular mortality on empagliflozin was very noticeable – it's hard to ignore. The benefits of kidney and heart failure seem to overlap with all medications. Amputations with canagliflozin increased slightly. This was perhaps just a coincidence and was not observed in other SGLT2 inhibitors. "

"Then there are the GLP-1 agonists, which have shown significant benefit in serious cardiovascular events, but make the heart failure risk seem neutral, and I think we can apply these two classes of drugs to some cases in Germany."

A tougher view …

Others, however, take a more moderate attitude. One of them is David Nathan, MD, director of the Diabetes Center at the Massachusetts General Hospital in Boston, Massachusetts. He commented this | Medscape cardiology"These SGLT2 inhibitors reduce the risk of heart failure in the hospital in diabetics with or at increased risk for heart disease, but the absolute risk reduction is quite low – around 1%." Empagliflozin has shown better effects on serious cardiovascular events in patients with solid heart disease. "

He also points out that the adverse effects and costs of SGLT2 inhibitors must be taken into account when using their products.

"These drugs increase the excretion of glucose in the urine, which leads to urinary tract infections." And we could ask if they are really very expensive diuretics – we would achieve the same effect with a low dose of furosemide or thiazide diuretic with fewer side effects and much lower costs? "

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

"Whether these drugs should be considered as treatments for heart failure in diabetic patients rather than as hypoglycemic drugs in itself is a not-so-subtle difference that needs to be considered," he concluded.

DECLARE-TIMI 58 was 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 to Astra Zeneca.

American Heart Association (AHA) Scientific Meetings 2018. Abstract no. 19485. Presented on 10th November 2018.

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

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