Sodium glucose cotransporter-2 (SGLT2) inhibitor empagliflozin (Jardiance, Boehringer Ingelheim / Lilly) has a beneficial effect on left ventricular (LV) structure and function in patients with stable cardiovascular disease (CVD) and type 2 diabetes (T2D), a new study suggests.
The results could provide insight into why previous studies have shown a positive link between SGLT2 inhibition and heart failure (HF) results, the researchers pointed out.
In a randomized EMPA-Heart Cardiolink-6 trial involving approximately 100 patients, LV was significantly reduced in patients receiving empagliflozin 10 mg / day for 6 months. Oral medications are also associated with a significant decrease in systolic blood pressure (BP) and an increase in hematocrit levels.
Dr. Subodh Verma, a senior researcher at St. Michael's Hospital and the University of Toronto, said, "These benefits have been shown in patients with normal heart failure and have no known heart attack, "He said. The latest scientific session in the American Heart Association (AHA) Science Session 2018.
The results and other results published at this meeting "will increase the use of SGLT2 inhibitors in patients with type 2 diabetes, especially those with a history of heart failure, especially those with coronary heart disease," commented Elliott Antman, MD, Boston Brigham Women's Hospital said in this session.
"I would encourage you to do the same, and we encourage you to consider this information in general medicine, endocrinology and nephrology," Antman added.
SGLT2 inhibition and heart failure
The DECLARE-TIMI 58 test results were also presented at the AHA meeting. Reported by theheart.org | Medscape Cardiology, CVD and T2D patients receiving the SGLT2 inhibitor dapagliflozin (Farxiga / Forxiga, AstraZeneca) greatly reduced the hospitalization of HF. There was also a trend toward no significant decrease in the severity of adverse cardiac events (MACE).
Another SGLT2 inhibitor, canagliflozin (Invokana, Janssen was assessed by the Canadian Centers for Disease Control and Prevention (CANDAS), and more than 10,000 adults were suffering from T2D or at risk for CVD. The US Food and Drug Administration (FDA) approved a drug to protect its resume last month.
Empagliflozin was first approved by the FDA in 2014 as a dietary and augmentative therapy for improved T2D adult blood glucose control.
Results from the EMPA-REG results trial published in 2015 showed that patients receiving empagliflozin among the 7020 adult participants who had established T2D and CVD (approximately 10% of HF from the baseline state) were more likely to die than patients receiving placebo It was shown regardless of the cause of death.
In fact, mortality was relatively low at 38%, relative mortality at 32%, MACE at 14% and HF at 35%.
In 2016, FDA has allowed labeling of this drug in this particular population group to claim reduced CV mortality.
Also at the European Society of Cardiology (ESC) 2016 meeting, submudy of EMPA-REG showed that the drug-induced transplantation effect was not affected by the patient's HF status.
At the same meeting a year later, the results appeared in another sub-analysis, this time in 90% of patients without baseline HF. The relative risk reduction of HF after treatment was 29% in the low and low risk groups and 45% to 50% in the high risk groups.
"This trial actually sees us reducing the risk of heart attack through a risk spectrum of people who meet the entry criteria for the already at-risk population, EMPA-REG, and we are treating patients with diabetes." "Said Dr. Javed Butler, coinvestigator at Stony Brook University Hospital in New York. However, he pointed out that the mechanistic reason for discovery is based on a hypothesis.
An unanswered question
Verma informed attendees at the AHA meeting that "there are several mechanisms that wander about how these agents work and affect congestive heart failure, such as sodium removal, decreased seizure edema, cardiac sodium-hydrogen exchange inhibition, and improved cardiac energy I was crazy.
"However, whether or not SLT2 inhibitors will promote cardiac reverse remodeling is not yet known in part – it is still an unresolved issue and clinically important," he said.
Left ventricular mass is a powerful and independent predictor of major cardiovascular events, including HF. "Also, the magnitude of LV mass regression is related to the degree of clinical outcome benefit seen in pharmacology and device therapy," he added.
The main goal of EMPA-HEART was to assess the effect of empagliflozin on LV reconstitution at 6 months. Secondary outcomes included identification of pathophysiological mechanisms associated with this type of effect.
The researchers evaluated 423 patients aged 40 to 80 years with patients with T2D history and stable CVD. Exclusion criteria included an LV delivery index (LVEF) of less than 30% and / or current or recent hypertensive HF.
Exclusion, withdrawal, screen failure, and missing data, 97 participants were included in the final analysis. These patients were randomly assigned to either empagliflozin (n = 49, male 90%, mean age 62.2 years, T2D duration 11.8 years) or placebo (n = 48, male 96%, mean age 63.5 years, T2D, 10.1 years). Cardiac MRI and biomarker data were collected at baseline and at 6 months.
At baseline, 25% of each treatment group used insulin, 96% of each group used statins, and 82% and 85% used ACE inhibitors / ARB. The systolic blood pressure was 134 vs 135 mmHg, the estimated glomerular filtration rate (eGFR) was 87 vs 88 mL / min per 1.73 m2, and the LV mass index (LVMI) was 59.3 vs 62.2 g / m².
Achieve primary results
Results showed a significant difference in systolic blood pressure at 6 months (median -7.9 mmHg above baseline) of active drug therapy (-0.7 mmHg, blood = .003). There was no significant difference from baseline diastolic blood pressure.
In the active treatment group, hematocrit was increased by 2.4% (0.4%; blood = 0.006).
For the primary outcome, empagliflozin significantly reduced LVMI at baseline compared to placebo (adjusted difference between groups, -3.35 g / m2; 95% CI, -5.9 to -0.81; blood = .01).
In the sensitivity analysis of LV mass regression, the height of LV mass was significantly different according to heightblood = .03), height1.7 (blood = .02), height2.7 (blood = .01), weightsblood = 0.005).
In the case of secondary coronary artery bypass, the adjusted difference between the active and placebo groups was not significant in the volume of left ventricular systolic and diastolic systolic (blood = .36 and .55).
"I think it is noteworthy to admit that there is an increase of 2.2% in this small trial, though it is not important. [LVEF] In the short term, placebo (0.01% decrease)blood = .07), Verma noted.
NT-proBNP, troponin I, and soluble ST2 levels. This figure was "low at baseline in this cohort and not affected by empagliflozin during the treatment period," he added.
Six months post-treatment adverse events (AEs) were reported in 28 and 27 patients, respectively, in the empagliflozin and placebo groups, with more than one AE reported. 3 and 1 reported severe AE, respectively. AE outbreaks occurred in 4 and 3 group members, respectively.
Inpatients with hypoglycemia, metabolic acidosis, stroke, HF or HF, myocardial infarction or death were not reported.
"Combining the data, empagliflozin promotes early and statistically clinically significant remodeling that can contribute to cardiovascular and heart failure observed in EMPA-REG results and other SGLT2 inhibitor clinical trials, Verma said.
on theheart.org | Medscape Cardiology, He also pointed out that this finding provides the rationale for future research to evaluate this drug type.
"This provides a good translation bridge for heart attack research going on in this space," he said.
After the presentation, Antman told attendees, "This was a very important mechanistic study."
He pointed out that SGLT2 inhibitors previously demonstrated improved blood glucose and weight loss, delayed albuminuria, delayed eGFR reduction and HF hospitalization.
Antman, who was not involved in the study, said the current trial was conducted "to explain" the latter's interests.
"There was a significant decrease in left ventricular mass in the empagliflozin group during the 6-month evaluation period," he said. "This is important because it has been done in a very powerful way, it is important to note that this is done in a low-risk population, observations of a reduction in left ventricular mass were solid and endured after several attempts.
But he congratulated the EMPA-HEART investigators, "but our study is not over. We need to continually evaluate the physiological effects of SGLT2 inhibition and investigate whether there is a direct myocardial effect on bioenergetic or epicardial fat tissue "He said.
"EMPA-HEART is an important step in clinical translation research leading to our ultimate goal of providing more accurate care for our patients."
After the session, Antman theheart.org | Medscape Cardiology Verma showed "biologically plausible data." Prognosis and preloading have been associated with the use of empagliflozin and LV mass has decreased. "And I found that the larger LV mass is associated with the higher risk of many cardiovascular events, including HF I know.
"Based on this observation and the results of DECLARE-TMI clinical trials and recent meta-analyzes, I am encouraged to use SGLT2 inhibitors in patients with type 2 diabetes." There is a history of heart failure or coronary artery disease said.
However, Dr. Randall Starling, chairman of the American Heart Association, theheart.org | Medscape Cardiology There is a "more waiting attitude" about the result.
"This group used the best way to observe and track a small number of patients and assess the anatomy of the ventricles," said a Starling researcher who was a professor at the Cleveland Clinic's Lerner School of Medicine and did not participate in the study.
Significant modifications are reported in this small cohort, which appears to be beneficial in the group receiving the SGLT2 inhibitor. So there is a continuing hypothesis, "he said." In general, I think the community, including the FDA, believes that anatomical changes in the ventricles are meaningful agents. "
"It's not an observable change in any way, but it's an insight that things that can happen mechanically can be improved," Starling said.
He also repeated Antman's words that this study showed biologically plausible. "This is not an episode, I believe it's true."
At this point, it is extremely tempting to have one of these drugs in a treatment portfolio for patients with diabetic heart failure. "But now they are in standby mode. We are waiting for large-scale clinical trial data as a typical result. "
"I have hopeful optimism that it will all be unfolded, but we were disappointed before," he said. "So we will wait for what will happen."
This study was supported by Boehringer Ingelheim. Verma has received speaking and / or research support from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Janssen, Merck, Novartis, Novo Nordisk, Valeant and Sanofi. Antman and Starling did not disclose their financial relationship.
American Heart Association (AHA) Science Session 2018: Abstract 19332. Announced November 11, 2018.