CHICAGO – Treatment with sodium glucose cotransporter-2 (SGLT2) empagliflozin inhibitor (Jardiance, Boehringer Ingelheim / Lilli) is associated with positive effects on the left ventricular structure and function in patients with stable cardiovascular disease (CVD) and type 2 diabetes (T2D), according to new studies.
The results may give some insight into why the previous studies showed a positive correlation between SGLT2 inhibition and heart rate (HF), researchers said.
The randomized EMPA-Heart Cardiolink-6 trial, which involved nearly 100 patients, showed a significantly reduced LV mass in those who received empagliflozin 10 mg / day for 6 months compared to those who received the placebo that was appropriate. The oral medicine is also associated with a significant reduction in systolic blood pressure (BP) and an increase in the level of hematocrit.
"These benefits have been seen in a normotensive population, with a preserved fission fraction, without known cardiac insufficiency and above the standards of care therapy," said the chairman of the author, Subodh Verma, MD, Hospital Sv. Michael and the University of Toronto. a scientific session that later violates the American Heart Association (AHA) Scientific Sessions 2018.
Because of these findings and other results presented at the meeting, "I plan to increase my use of the SGLT2 inhibitor in my patients with type 2 diabetes, especially if they have a history of cardiac insufficiency, and especially if they have a history of coronary heart disease," said discussion speaker Elliott Antman, MD , Brigham and Boston Women's Hospital.
"I encourage you to do this, and I would recommend that we invite our colleagues in general medicine, endocrinology and nephrology to consider this information," Antman added.
SGLT2 inhibition and cardiac insufficiency
At the AHA meeting, the results of the DECLARE-TIMI 58 were also presented. As reported theheart.org | Medscape Cardiologists, patients with CVD and T2D who received the SGLT2 dapagliflozin inhibitor (Farkiga / Forkiga, AstraZeneca) significantly reduced hospitalization for HF. There was also an unimaginative trend towards a reduced rate of major unwanted cardiac events (MACE).
Another SGLT2 inhibitor kanagliflozin (Invokana, Janssen) was evaluated in an earlier study on the assessment of cardiovascular assessment of Canagliflozin (CANVAS), which involved more than 10,000 adults with T2D or who had a CVD risk. The US Food and Drug Administration (FDA) approved a cure for the protection of life last month.
Empagliflozin was first approved by the FDA in 2014 as an additional treatment for nutrition and exercise to improve glycemic control in adults with T2D.
Results presented in the EMPA-REG Outcome study in 2015 showed that 7020 adult participants with T2D and established CVD (about 10% of HF at the beginning) who received empagliphlozin were less likely to die than those who received placebo – The benefits are shown regardless of the cause of death.
In fact, there was a relative risk reduction of 38% in CV mortality and 32% relative decrease in the risk of mortality of all causes, in addition to 14% reduction in MACE and 35% reduction in hospitalization for HF.
In 2016, the FDA allowed the labeling of a drug to require a reduced CV mortality in this population.
In addition, at the Congress of the European Society of Cardiology (ESC) 2016, the EMPA-REG substrate has shown that the patient's status of HF is better than the benefit of a CV.
At the same meeting a year later, the results were presented from another subanalysis, this time in 90% of patients who did not have a basic HF. A relative reduction in the risk of developing HF after the study drug was approximately 29% in the low to medium risk group and about 45% to 50% in high-risk and above-risk groups.
"This trial shows that within the risk spectrum of people who have met the criteria for entering EMPA-REG, a population that already has some risk, you really see a reduction in the risk of heart failure and really need to think about these medicines when we treat our patients with diabetes" , said researcher Javed Butler, MD, University Hospital Stony Brook, New York, at that time. However, he noted that the mechanical reasons for the discovery were based on hypotheses.
For present at the AHA meeting, Verma noted that "there were several mechanisms that work on how these agents work" and affect congestive HF, including natriurese, reduction of interstitial edema, inhibition of the exchange of sodium hydrogen sulphide and improved cardiac bioenergetics.
"But it remains partially unknown if SLT2 inhibitors make it easy to rearrange the reversible heart, an issue that is unacceptable and clinically important," he said.
LV mass "is a strong and independent predictor of major cardiovascular events," including HF. "Moreover, the magnitude of fatty acid regression in correlation with the degree of clinical outcome obtained from the pharmacological and device therapy," he added.
The primary goal of EMPA-HEART was to evaluate the effect of empagliflozine on LV remodeling for 6 months. Secondary outcomes included the identification of pathophysiological mechanisms associated with this type of effect.
The researchers estimated the similarity of 423 patients aged 40 to 80, all of whom had T2D history and established a stable CVD. Exclusion criteria included LV ejection fraction (LVEF) of less than 30% and / or current or recent hypertensive HF.
After turning off, pulling off, screen failure and missing data, 97 participants were included in the final analysis. These patients were randomly assigned to receive empagliflozin (n = 49; 90% men, mean age, 62.2 years, duration of T2D, 11.8 years) or corresponding placebo (n = 48; 96% males, mean age, 63 , 5 years, T2D, 10.1 years). Data on cardiac MRIs and biomarkers were collected at the beginning and at 6 months.
Initially, 25% of each treatment group uses insulin, 96% of each group uses statin, and 82% to 85%, respectively, uses an ACE inhibitor / ARB. In addition, systolic BP was 134 vs. 135 mm Hg, the estimated glomerular filtration rate (eGFR) was 87 vs 88 ml / min at 1.73 m², and LV mass index (LVMI) was 59.3 versus 62.2 g / m².
Primary Outcome Met
The results showed a significantly higher difference in systolic BP after 6 months of treatment with the active drug (mean change, -7.9 mm Hg) than placebo (-0.7 mm Hg, P = .003). There was no significant difference between the groups in the change from diastolic diastolic BP.
The active treatment group also had a higher increase in hematocrit (2.4% versus 0.4%; P = .006).
For the primary outcome, empaggliflozin was associated with a significantly reduced LVMI from baseline in relation to placebo (adjusted difference between groups, -3.35 g / m², 95% CI, -5.9 to -0.81; P = .01).
In the sensitivity analysis of LV mass regression, there were significant differences in LV mass indexed to height (P = .03), to the height1.7 (P = .02), to the height2.7 (P = .01) and weight (P = .005).
In secondary coronary MRI outcomes, the adjusted differences between the active and placebo groups were not significant for LV end-systolic and end-diastolic volumes (P = .36 and .55, respectively).
In addition, "although it is not significant, I think that in this small trial it is noticeable that there has been an increase of 2.2% [LVEF] in the short term ", with a 0.01% decrease in placebo (P = .07), Verma stressed.
Differences between groups in NT-proBNP, troponin I and soluble levels of ST2 are also not significant. These levels "were initially low in this cohort and remained unchanged by empagglipzin during the treatment period," he added.
Undesirable events (AEs) after 6 months of treatment were similar among the groups, with 28 and 27 members of the empagliflozin and placebo group, respectively, reporting at least one AE; and with three and one members, reporting at least one serious AE. The abolition of AE occurred in four and three groups of members, respectively.
There were no reports in any patient of hypoglycaemia, metabolic acidosis, stroke, HF, or hospitalization for HF, myocardial infarction, or death.
"Taking together, the data suggest that empagliflozin improves early and statistically and clinically significant remodeling, which can contribute to the suffering of cardiovascular and cardiac insufficiency observed in the trial analysis of EMPA-REG Outcomes and other SGLT2 inhibitors," said Verma.
To the theheart.org | Medscape Cardiologists, noted that the finding also provides an explanation for future research on the assessment of this class of drugs.
"It provides a large translator bridge for some of the heart failure studies that take place in this area," he said.
An important step
After the presentation, Antman told the audience that "this was a very important mechanistic study".
He noted that SGLT2 inhibitors had previously shown improved glycemic and weight loss rates, delayed albuminuria, delayed eGFR reduction, and reduced hospitalization of HF.
The current trial has been carried out to clarify this other advantage, said Antman, who was not involved in the survey.
"Mass of the left ventricle was significantly reduced in the group of empagliflozines" over a period of 6 months, he said. "This is important because it has been done in a very robust way, it's important to point out that this was done in a low-risk population. Observation in reducing the left ventricular mass was robust and sustained after a series of attempts to adjust."
However, he noticed that, although congratulating the EMPA-HEART investigators, "our work has not been completed. We must continue to evaluate the physiological effects of SGLT2 inhibition and to investigate whether there are direct myocardial effects on bioenergetics or epicardial fat tissue," he said.
"EMPA-HEART is an important step on the way in clinical translation research on the way to our ultimate goal of providing more precise care for our patients."
After the session, Antman said theheart.org | Medscape Cardiologists that Verma presented "the biological credible data associated with the subsequent load and overload associated with the use of empagliflozin of reduced LV mass. I know that higher LV mass is associated with a higher risk of many cardiovascular events, including HF.
"When I combine this observation with the results of the DECLARE-TMI test and recent meta-analysis, I am still inspired to increase the use of SGLT2 inhibitors in patients with type 2 diabetes in general, especially if they have a history of cardiac insufficiency or coronary artery disease," he said.
"Wait and you'll see"
However, for Randall Starling, MD, president of the Association for Heart Insemination of America theheart.org | Medscape Cardiologists to have "more item and wait" in relation to findings.
"This group has watched a small number of patients, followed them and used the most likely best technique for assessing ventricular anatomy," said Starling, who is also a professor at the Lerner College of Medicine Clinical Center and was not involved in the study.
"They in this small cohort report a significant remodeling, which are considered useful in the group that received the SGLT2 inhibitor, so something is happening, and it's generating a hypothesis," he said. "In general, I think the community, including the FDA, feels that changes in ventricular anatomy are a surrogate endpoint that is significant."
That said, "I do not think that this is in any way an observation that changes in practice, but it is a mechanism of insight into what can happen resulting in improvements," Starling said.
He also repeated Antman's phrase that the study showed biological acceptability "and the credibility that this is not an epic phenomenon, that's real."
At this point, "It is extremely startling to hope that one of these drugs is in the treatment portfolio of a patient with a heart failure diabetes," Starling said. "But right now I'm in latency mode – I am waiting for data from large clinical trials with typical outcomes."
"I hope for optimism that this will all take place, but we were disappointed earlier," he said. "So we will wait and see what will happen."
The study was funded by Boehringer Ingelheim. Verma reports that she received voice and / or research support from Abbott, Amgen, AstraZeneca, Baier, Boehringer Ingelheim, Bristol-Miers Skuibb, Eli Lilli, Janssen, Merck, Novartis, Novo Nordisk, Valeant and Sanofi. Antman and Starling did not disclose relevant financial relationships.
American Heart Association (AHA) Scientific Sessions 2018: Summary 19332. Shown on November 11, 2018.