EMPA-HEART: Empagliflozin May Reduce LV Mass in Patients With CVD, Diabetes

Deborah Brauser

November 13, 2018

CHICAGO — Treatment with the sodium glucose cotransporter-2 (SGLT2) inhibitor empagliflozin (Jardiance, Boehringer Ingelheim/Lilly) is associated with beneficial effects on left ventricular (LV) structure and function in patients with stable cardiovascular disease (CVD) and type 2 diabetes (T2D), new research suggests.

The results might provide some insight into why previous studies have shown a positive association between SGLT2 inhibition and heart failure (HF) outcomes, the investigators note.

The randomized EMPA-Heart Cardiolink-6 trial, which involved almost 100 patients, showed significantly reduced LV mass in those who received empagliflozin 10 mg/day for 6 months compared with those who received matching placebo. The oral drug was also associated with a significant reduction in systolic blood pressure (BP) and with an increase in hematocrit levels.

"These benefits were seen in a normotensive population, with preserved ejection fraction, without known heart failure, and on top of standard of care therapies," lead author Subodh Verma, MD, St. Michael's Hospital and University of Toronto, told attendees at a late-breaking science 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 my 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 a history of coronary heart disease," discussant Elliott Antman, MD, Brigham and Women's Hospital, Boston, said during the session.

"I would encourage you do the same and I would also recommend that we urge our colleagues in general medicine, in endocrinology, and in nephrology to consider this information as well," Antman added.

SGLT2 Inhibition and Heart Failure

Results from the DECLARE-TIMI 58 trial were also presented at the AHA meeting. As reported by theheart.org | Medscape Cardiology, patients with CVD and T2D who received the SGLT2 inhibitor dapagliflozin (Farxiga/Forxiga, AstraZeneca) had significantly reduced hospitalization for HF. There was also a nonsignificant trend toward a reduced rate of major adverse cardiac events (MACE).

Another SGLT2 inhibitor canagliflozin (Invokana, Janssen) was evaluated in the earlier Canagliflozin Cardiovascular Assessment Study (CANVAS), which involved more than 10,000 adults with T2D or who were at risk for CVD. The US Food and Drug Administration (FDA) approved the drug for CV protection last month.

Empagliflozin was first approved by the FDA in 2014 as an adjunct treatment to diet and exercise for improving glycemic control in adults with T2D.

Results presented in 2015 from the EMPA-REG Outcome trial showed that among the 7020 adult participants with T2D and established CVD (about 10% with HF at baseline), those who received empagliflozin were less likely to die than those who received placebo — a benefit that was shown regardless of cause of death.

In fact, there was a 38% relative risk reduction in CV mortality and a 32% relative risk reduction in all-cause mortality, in addition to a 14% reduction in MACE and a 35% reduction in hospitalization for HF.

In 2016, the FDA allowed the drug's labeling to claim reduced CV mortality in this particular population.

In addition, at the European Society of Cardiology (ESC) Congress 2016, a substudy of EMPA-REG showed that the CV benefit from the drug was unaffected by a patient's HF status.

At the same meeting a year later, results were presented from another subanalysis, this time in the 90% of patients who did not have baseline HF. The relative risk reduction in HF development after receiving the study drug was about 29% in the low- to average-risk group and about 45% to 50% in the "high-risk-and-over" groups.

"This trial shows us that across the risk spectrum of people who met the entry criteria for EMPA-REG, a population that already has some risk, you are really seeing a reduction in heart failure risk, and we should really think about these drugs when we are treating our patients with diabetes," coinvestigator Javed Butler, MD, Stony Brook University Hospital, New York, said at the time. However, he noted that mechanistic reasons for the findings were based on hypotheses.

Unanswered Questions

To AHA meeting attendees, Verma noted that "there have been several mechanisms floated as to how these agents work" and affect congestive HF, including natriuresis, reduction in interstitial edema, inhibition of cardiac sodium–hydrogen exchange, and improved cardiac bioenergetics.

"But it remains partly unknown if SLT2 inhibitors facilitate cardiac reverse remodeling, a question that has been unanswered and is clinically important," he said.

LV mass "is a strong and independent predictor of major cardiovascular events," including HF. "Furthermore, the magnitude of LV mass regression correlates with the extent of a clinical outcome benefit seen with pharmacological and device therapies," he added.

The primary objective for EMPA-HEART was to assess the effect of empagliflozin on LV remodeling at 6 months. Secondary outcomes included the identification of pathophysiologic mechanisms associated with this type of effect.

The investigators assessed for eligibility 423 patients 40 to 80 years of age, all of whom had a history of T2D and established, stable CVD. Exclusion criteria included an LV ejection fraction (LVEF) less than 30% and/or current or recent hypertensive HF.

After exclusions, withdrawals, screen fails, 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 matching placebo (n = 48; 96% men; mean age, 63.5 years; duration of T2D, 10.1 years). Cardiac MRI and biomarker data were collected at baseline and at month 6.

At baseline, 25% of each treatment group used insulin, 96% of each group used a statin, and 82% vs 85%, respectively, used an ACE inhibitor/ARB. In addition, systolic BP was 134 vs 135 mm Hg, estimated glomerular filtration rate (eGFR) was 87 vs 88 mL/min per 1.73 m², and LV mass index (LVMI) was 59.3 vs 62.2 g/m².

Primary Outcome Met

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 with placebo (–0.7 mm Hg, P = .003). There was no significant between-group difference in change from baseline diastolic BP.

The active treatment group also had a greater increase in hematocrit (2.4% vs 0.4%; P = .006).

For the primary outcome, empagliflozin was associated with significantly reduced LVMI from baseline compared with placebo (adjusted difference between groups, –3.35 g/m²; 95% CI, –5.9 to –0.81; P = .01).

In sensitivity analyses of LV mass regression, there were significant differences in LV mass indexed to height (P = .03), to height1.7 (P = .02), to height2.7 (P = .01), and to weight (= .005).

For 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 not significant, I think it's notable in this small trial to recognize that there was a 2.2% increase in [LVEF] over the short term" vs a 0.01 decrease in placebo (P = .07), Verma noted.

Between-group differences in NT-proBNP, troponin I, and soluble ST2 levels were also not significant. These levels "were low at baseline in this cohort and remained unaffected by empagliflozin over the period of the treatment," he added.

Adverse events (AEs) after 6 months of treatment were similar between the groups, with 28 and 27 members of the empagliflozin and placebo groups, respectively, reporting at least one AE; and with three and one member, respectively, reporting at least one serious AE. Discontinuation because of an AE occurred in four and three group members, respectively.

There were no reports in any patient of hypoglycemia, metabolic acidosis, stroke, HF or hospitalization for HF, myocardial infarction, or death.

"Taken together, the data suggest that empagliflozin promotes early and statistically and clinically significant remodeling, which may contribute to the cardiovascular and heart failure benefits observed in the EMPA-REG Outcomes trial and other SGLT2 inhibitor trials," Verma said.

To theheart.org | Medscape Cardiology, he noted that the findings also provide the rationale for future research assessing this class of drug.

"It provides a great translational bridge for some of the heart failure studies that are going on in this space," he said.

Important Step

After the presentation, Antman told attendees that "this was a very important mechanistic study."

He noted that SGLT2 inhibitors have previously shown improved glycemia and weight-loss measures, delayed albuminuria, delayed declines in eGFR, and decreased HF hospitalization.

The current trial was conducted "to elucidate" the latter benefit, said Antman, who was not involved with the research.

"Left ventricular mass was significantly reduced in the empagliflozin group" by the 6-month assessment period, he said. "This is important because it was done in a very robust fashion. It's also important to note that this was done in a low-risk population. The observation in the reduction in left ventricular mass was robust and held up after an array of attempts at adjustment."

However, he noted that although he congratulates the EMPA-HEART investigators, "our work is not done. We need to continue to evaluate the physiological effects of SGLT2 inhibition and explore whether there are direct myocardial effects on bioenergetics or on epicardial adipose tissue," he said.

"EMPA-HEART is an important step along our journey in clinical translational research on our way to our ultimate goal of providing more precise care for our patients."

After the session, Antman told theheart.org | Medscape Cardiology that Verma presented "biologically plausible data that afterload and preload are associated with the use of empagliflozin reduced LV mass. And I know that larger LV mass is associated with a higher risk of many cardiovascular events, including HF.

"When I combine that observation with the results from the DECLARE-TMI trial and a recent meta-analysis, I'm even more inspired to increase my use of SGLT2 inhibitors in patients with type 2 diabetes in general, and especially if they have a history of heart failure or coronary artery disease," he said.

"Wait and See"

Randall Starling

However, Randall Starling, MD, president of the Heart Failure Society of America, told theheart.org | Medscape Cardiology that he has "more of a wait-and-see attitude" regarding the findings.

"This group looked at a small number of patients, followed them, and used arguably the best technique to assess ventricular anatomy," said Starling, who is also a professor at the Cleveland Clinic Lerner College of Medicine and was not involved with the research.

"They report in this small cohort meaningful remodeling, judged to be advantageous in the group that received the SGLT2 inhibitor. So there's something going on and it's hypothesis-generating," he said. "In general, I think the community, including the FDA, feels that changes in ventricular anatomy are a surrogate end point that's meaningful."

That said, "I don't think it's in any way a practice-changing observation, but it's one insight into mechanistically what might be happening that is resulting in improvements," Starling noted.

He also echoed Antman's phrase that the study showed biologically plausibility "and credibility that this isn't an epi phenomenon; this is real."

At this point, "it's extremely tempting to hope that one of these drugs is in the portfolio of treatment for a diabetic heart failure patient," Starling said. "But for right now, I'm in the latency mode — waiting for data from large-scale clinical trials with typical outcomes."

"I have hopeful optimism that it will all pan out, but we've been disappointed before," he said. "So we'll wait and see what happens."

The study was funded by Boehringer Ingelheim. Verma reports having 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 have disclosed no relevant financial relationships.

American Heart Association (AHA) Scientific Sessions 2018: Abstract 19332. Presented November 11, 2018.

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