SGLT2 inhibitors ‘changed the landscape’ in HF irrespective of diabetes status
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SGLT2 inhibitors reduce HF in patients with atherosclerotic CVD or risk factors regardless of diabetes status, but more data are needed particularly in HF with preserved ejection fraction, according to a speaker.
“Heart failure in diabetes is not completely understood. ... It is likely a broad systemic disease that includes many of the perturbations that diabetes brings along, whether it be insulin resistance, oxidative stress, inflammation, hypertension, atherosclerosis, all of which leads to not only coronary artery disease on the micro- and macrovascular level, but also fibrosis that reduces compliance and eventually can lead to diastolic and systolic dysfunction and clinical heart failure,” Benjamin M. Scirica, MD, MPH, FESC, FACC, FAHA, senior investigator of the TIMI Study Group in the cardiovascular division at Brigham and Women’s Hospital and associate professor of medicine at Harvard Medical School, said during the presentation at the virtual Heart in Diabetes CME Conference.
These factors can make HF difficult to treat, Scirica said. HF is a heterogenous disease with ejection fractions that can span from very low, reduced EF to completely preserved or hyperdynamic HF. Over the last 20 years, a lot of work has been done in the area of treating HF with reduced EF, whereas study of HF with preserved EF has yet to result in any meaningful treatments for risk reduction.
“That is particularly important because patients with diabetes have a lot of heart failure with preserved ejection fraction,” Scirica said.
Clinical risk factors
SGLT2 inhibitors may play a role in modifying HF, as they promote natriuresis and promote glucosuria. This can lead to improvements in glucose and weight loss, in addition to tubule-glomerular feedback improvements, BP lowering, volume overload reductions and renal function improvements, Scirica said. In addition, SGLT2 inhibitors may have a direct impact on the cardiomyocyte and may decrease sympathetic nervous tone, which can lead to lower volume and BP without increasing heart rate.
A major focus on SGLT2 inhibitors in CV outcomes trials has been seen since 2015, with empagliflozin (Jardiance, Boehringer Ingelheim) in the EMPA-REG OUTCOME trial, canagliflozin (Invokana, Janssen) in the CANVAS trial and dapagliflozin (Farxiga, AstraZeneca) in the DECLARE-TIMI-58 trial.
All of these trials included patients with established ASCVD or multiple CV risk factors. For both groups, there was a consistent 30% to 35% reduction in HF hospitalization. Even with this evidence of benefit, participants were not selected for HF, as there were few patients with HF at baseline. Since data were not well collected regarding EF and prior HF, several questions remained regarding patient selection for treatment.
Scirica and colleagues worked on developing a method to risk stratify patients with diabetes that was clinically useful and easy to use, he said. To do so, he and his colleagues used data from patients from the placebo group in the SAVOR-TIMI 53 trial. The independent risk indicators that achieved statistical significance were prior HF, atrial fibrillation, CAD, and reduced estimated glomerular filtration rate and evidence of macroalbuminuria. When categorized by risk score, there was a stepwise increase in HF hospitalization as risk increased. This was also validated with data from patients in the placebo arm in the DECLARE-TIMI 58 trial.
This risk stratification score was similarly analyzed with data from the EMPA-REG OUTCOME trial and resulted in consistent results, according to Scirica.
“This is a very important external validation of our studies from [SAVOR-TIMI 53] and DECLARE-TIMI 58,” Scirica said.
Biomarkers for risk stratification
The prognostic implications of biomarkers have also been assessed in patients with type 2 diabetes who have a high CV risk. Scirica and his team analyzed this with data from the SAVOR-TIMI 53 trial and looked at N-terminal pro-B-type natriuretic peptide, high-sensitivity troponin T and high-sensitivity C-reactive protein. With increasing quartiles, there was a stepwise increase in the risk for HF hospitalization compared with lower quartiles, especially with NT-proBNP and high-sensitivity troponin T.
“We have found that biomarkers offer even a more impressive risk stratification tool than even clinical markers,” Scirica said. “As we learn more about these, hopefully they’ll be incorporated in standard risk stratification tools.”
In another study, researchers found that having an elevated high-sensitivity troponin T level even in stable patients is associated with a higher risk for HF and other CV outcomes.
“It seems to be a greater predictor to have elevated risk than clinical history,” Scirica said. “Evidence of cardiac injury is very important in diabetes in terms of predicting outcome.”
The DAPA-HF trial has shown that dapagliflozin has a dramatic effect on patients with HF regardless of diabetes status. A subsequent study assessing data from this trial found that the degree of glycemia had no impact on the benefit of dapagliflozin compared with placebo in patients with HFrEF.
Dapagliflozin also reduced the risk for recurrent events, which is important for patients with diabetes since they often have a higher risk for recurrent HF, Scirica said.
“SGLT2 inhibitors really have changed the landscape not only in diabetes, but now heart failure,” Scirica said. “There are other studies that are ongoing in heart failure, especially in preserved ejection [fraction] that will further inform us, but we really do now have agents that reduce incident and recurrent heart failure. That reduction seems to be greatest in those patients who are at highest risk, whether it’s by ejection fraction or clinical risk score. We’ll have to see about other measures. Now we just want to see how the data are going to be in heart failure with preserved ejection fraction to see if we’ll have a potential agent in that group as well.”
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Scirica BM. Heart failure risk stratification and efficacy of SGLT2 inhibitors in patients with T2DM. Presented at: Heart in Diabetes CME Conference; Aug. 21-24, 2020 (virtual).
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