CHICAGO – Treatment with the sodium glucose inhibitor of cotransporter-2 (SGLT2) empagliflosine (Jardiance, Boehringer Ingelheim / Lilly) is associated with 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 has shown.
The results could provide an insight into why previous studies have shown a positive association between SGLT2 inhibition and heart failure (HF), researchers said.
The randomized study of EMPA-Heart Cardiolink-6, involving nearly 100 patients, showed a significantly reduced LV mass in those who received emfagliflosin 10 mg per day for 6 months compared to those receiving the appropriate placebo. The oral drug was also associated with significant reduction in systolic blood pressure (BP) and increased hematocrit levels.
"These benefits are visible in the normotensive population, with a preserved fraction of ejaculation, with no known heart failure, in addition to the standard of care therapies," said attendees of the authors of the major author of Subodh Verma, MD, St. Michael and the University of Toronto. late-breaking scientific session here at the American Heart Association (AHA) Scientific Sessions 2018.
Because of these findings and other results presented at the meeting, "I plan to increase the use of SGLT2 inhibitors in my patients with Type 2 diabetes, especially if they have a history of heart failure and especially if they have history of coronary heart disease," said Speaker Elliott Antman, MD , Brigham and the Women's Hospital in Boston.
"I would encourage you to do the same and recommend that we invite our colleagues in general medicine, endocrinology and nephrology to consider this information," added Antman.
SGLT2 inhibition and heart failure
The AHA meeting also presented the results of the research of DECLARE-TIMI 58. As reported theheart.org | Medscape Cardiology, patients with CVD and T2D who received the SGLT2 inhibitor dapagliflozin (Farxiga / Forxiga, AstraZeneca) significantly reduced hospitalization for HF. There is also a slight trend observed at the reduced rate of major adverse events (MACE).
Another SGLT2 inhibitor canagliflozin (Invokana, Janssen) was evaluated in an earlier cardiovascular evaluation of Canagliflozin (CANVAS) that included more than 10,000 adults with T2D or were at risk of CVD. The US Food and Drug Administration (FDA) has approved a cure for CV protection last month.
Empagliflozin was first approved by FDA 2014 as an additional diet therapy and exercise to improve glycemic control in adults with T2D.
The results from the EMPA-REG survey in 2015 show that among 7020 adults with T2D and CVD established (approximately 10% with HF initially), those receiving empagliflozin are less likely to die than those receiving placebo – the benefit shown regardless of the cause of death.
In fact, there was a reduction in the relative risk of mortality from CV and a relative risk reduction of 32% for all cause deaths, with a 14% reduction in MACE and a 35% reduction in hospitalization.
In 2016, the FDA allowed drug labeling to require animal mortality reduction in this population.
Additionally, at the European Cardiology Society (ESC) Congress in 2016, the EMPA-REG subsystem showed that the bioprofit benefit was not influenced by the patient's HF status.
At the same meeting a year later, the results were presented from the second baseline, this time in 90% of patients who did not have a baseline HF. Relative risk reduction in developing HF after receiving the study drug was about 29% in the low to average risk group and about 45% to 50% in "high risk" groups.
"This trial shows us that in the full spectrum of people who have met the requirements for entering EMPA-REG, the population who already has a risk, you really see a reduction in the risk of heart failure, and we should really think about these medicines when we treat our diabetic patient, "said Koordinator Javed Butler, MD, Stony Brook University Hospital, New York at that time. However, he pointed out that the mechanical reasons of the findings are based on hypotheses.
Verma noted that "there were several mechanisms of how these agents work" and that they affect congestive HF, including sodium, reduce interstitial edema, inhibit cardiovascular sodium-hydrogen modification, and enhanced cardiac bioenergy.
"But it remains partially unknown if SLT2 inhibitors facilitate cardiac reversal transformation, which is an issue that is unanswered and clinically important," he said.
LV mass "a strong and independent predictor of major cardiovascular events," including HF. "Further, the magnitude of LV mass regression correlates with the range of clinical outcome used with pharmacological and device therapy," he added.
The primary goal of EMPA-SRCA was to evaluate the effect of empagliflozin on LV remodeling in 6 months. Secondary outcomes include the identification of pathophysiological mechanisms associated with this type of effect.
The researchers estimated that 423 patients were older than 40 to 80 years old, all of whom had T2D history and established stable CVD. Exclusion criteria include LV ejection fraction (LVEF) less than 30% and / or current or recent hypertensive HF.
After the exclusion, withdrawal, screen failure and missing data, 97 participants were included in the final analysis. These patients were randomized to receive empagliflosine (n = 49, 90% male, middle age, 62.2 years, duration of T2D, 11.8 years) or corresponding placebo (n = 48, 96% male, middle age, 63.5 years, T2D, 10.1 years). Heart MRI and biomarker data were collected at the beginning and on month 6.
Initially, 25% of each treatment group used insulin, 96% of each group used statin, and 82% versus 85% used 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 vs 62.2 g / m2.
Primary outcome filled
The results showed a significantly greater 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 in the changes between the basic diastolic warts.
The active treatment group also had a higher hematocrit (2.4% vs. 0.4%; P = .006).
For the primary outcome, empagliflosine was associated with significantly reduced LVMI of baseline compared to placebo (adjusted difference between groups, -3.35 g / m², 95% CI, -5.9 to -0.81; P = .01).
In the LV mass regression sensitivity analysis, 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).
For secondary coronary MRI outcomes, the adjusted differences between the active and placebo groups were not significant for LV endosystolic and endodontic volumes (P = .36 and .55, respectively).
In addition, "although not significant, I think that in this small trial it has been noted that an increase of 2.2% [LVEF] in the short term "vs. 0.01 for the reduction of placebo (P = .07), Verma noted.
The differences between the groups in NT-proBNP, troponin I and soluble ST2 levels were also not significant. These levels were "low at the beginning of this group and remained unchanged with empagliflosine during the treatment period," he added.
Side effects (AE) after 6 months of treatment were similar among groups, with 28 and 27 members of the empagliflosine and placebo groups reported by at least one AE; and three and one members, reporting at least one serious AE. Suspension due to AE occurred in four and three group members.
There were no reports of hypoglycemia, metabolic acidosis, MU in any patient, hospitalization due to HF, myocardial infarction or death.
"Together, data suggest that empagliflozin induces early and statistically and clinically significant remodeling, which may contribute to cardiovascular and cardiovascular disorders noted in the EMPA-REG outcome study and other SGLT2 inhibitors," said Verma.
To theheart.org | Medscape Cardiology, stressed that the results also provide an explanation for future research assessing this class of drugs.
"It provides a great translation bridge for some heart failure studies that are taking place in this area," he said.
An important step
After the presentation, Antman said to the audience that "this is a very important mechanics study".
He noticed that SGLT2 inhibitors previously showed improved glycemic and weight loss measures, postponed albuminuria, delayed eGFR decline, and reduced hospitalization of HF.
The current trial was carried out to "clarify" the latter, said Antman, who was not involved in the research.
"The ventricular weight was significantly reduced in the empagliflosin group" in the six-month evaluation period, he said. "This is important because it is done in a very robust manner, and it is also important to note that this was done at low risk of the population. Observation in lowering left ventricular mass was robust and raised after a series of attempts to adjust."
However, he pointed out that, although congenial to EMPA-HEART investigators, "our work has not been done. We must further assess the physiological effects of SGLT2 inhibition and investigate whether direct effects of myocardium on bioenergy or epicardial fatty tissue are present." He said.
"EMPA-HEART is an important step in the path of clinical translational research on our way to our ultimate goal of providing more accurate care to our patients."
After the meeting, Antman said theheart.org | Medscape Cardiology that Verma presented "biologically credible data that, after loading and overloading, is associated with the use of empagliflosin of reduced LV mass." And I know that LV masses are associated with a higher risk of many cardiovascular events, including HF.
"When I combine observation with the results from the DECLARE-TMI trial and recent meta-analysis, I'm still more inspired by the increased use of SGLT2 inhibitors in type 2 diabetes patients in general, and especially if they have a history of heart failure or coronary artery disease," he said.
"Wait and See"
However, Randall Starling, president of the American Society for Heart Failure, told theheart.org | Medscape Cardiology that "is more than a wait-and-see attitude" about the findings.
"This group looked at a small number of patients, tracked them and used the undoubtedly the best technique for assessing ventricular anatomy," said Starling, who was also a professor at the Cleveland Clinic Lerner Medical School and was not involved in the study.
"They report in this small cohort meaningful remodeling, rated as beneficial in the group that received the SGLT2 inhibitor. So something is happening and that is the hypothesis that it creates," he said. "In general, I think the community, including the FDA, felt that changes in ventricular anatomy were a surrogate end point that makes sense."
He said, "I do not think it's any change in practice that changes in practice, but it's an insight into the mechanism that can happen, which results in improvements," Starling said.
He also echoed Antman's statement that the study showed biological credibility "and the credibility that this is not the phenomenon of Epi, that's really".
At this point, "it is extremely tempting to hope that one of these drugs is in the portfolio of treating a diabetic patient with cardiovascular disease," Starling said. "But for now, I'm in latent mode – I'm waiting for data from major clinical trials with typical outcomes."
"I have optimistic optimism that everyone will fall, but we were disappointed before," he said. "So, we'll wait and see what's going to happen."
The study was funded by Boehringer Ingelheim. Verma reports that Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Janssen, Merck, Novartis, Novo Nordisk, Valeant and Sanofi have been received. Antman and Starling did not find the relevant financial relationships.
American Heart Association (AHA) Scientific Sessions 2018: Abstract 19332 Presented on November 11, 2018.