Clinical trial and meta-analysis find diabetes drugs could benefit all heart failure patients
Researchers from Brigham and Women’s Hospital, a founding member of the Mass General Brigham Health System, presented new evidence that drugs originally developed to treat type 2 diabetes can benefit a wide range of patients with heart failure. In a Hot Line session on Saturday at the ESC 2022 Congress in Barcelona, and in simultaneous publications in The New England Journal of Medicine and The Lancet, physician-scientists from Brigham, in collaboration with a team from the University of Glasgow, presented research from the largest trial to date of heart failure patients with a slightly reduced or preserved ejection fraction. They showed that dapagliflozin, which had previously been shown to benefit heart failure patients with reduced ejection fraction, is likely to also reduce cardiovascular deaths and hospitalizations in patients with heart failure. slightly reduced or preserved ejection fraction – a population of millions of patients who have had a limited ejection fraction. therapeutic options. A meta-analysis that included two clinical trials further strengthened the evidence that this class of drugs can offer protection to a wide range of patients with heart failure.
Scott Solomon, MD, of Brigham’s Division of Cardiovascular Medicine, presented results from the DELIVER trial, a randomized, placebo-controlled trial of dapagliflozin in heart failure patients with mildly reduced ejection fraction or preserved, funded by AstraZeneca.
“In the largest and most inclusive trial in heart failure with mildly reduced or preserved ejection fraction, we found that treatment with the SGLT2 inhibitor dapagliflozin can benefit patients across the spectrum. specter of heart failure,” Solomon said. “These results make SGLT2 inhibitors a fundamental treatment for patients with heart failure, regardless of ejection fraction, to help prevent hospitalization and morbidity, prolong survival and improve related quality of life. to health. These are the outcomes that matter most to patients and clinicians – so patients feel better and live longer.
Muthiah Vaduganathan, MD MPH, also of Brigham’s Division of Cardiovascular Medicine, presented the results of a prespecified meta-analysis of DELIVER and EMPEROR-Preserved, a large-scale clinical trial of empagliflozin, funded by Boehringer Ingelheim and Eli Lilly.
“Our meta-analysis, encompassing over 12,000 patients, provides a summary of the totality of evidence and drives home the message that when it comes to heart failure, there is therapy for everyone” , Vaduganathan said. “These trials included patients across a wide range of ages, races, functional classes, gender, and medical history, but regardless of individual characteristics, they consistently benefited from this treatment.”
Dapagliflozin is an inhibitor of the sodium-glucose co-transporter-2 (SGLT2) – a class of drugs that cause the body to excrete sugar in the urine. In addition to controlling blood sugar in diabetic patients, SGLT-2 inhibitors have been shown to provide significant benefits for cardiovascular and kidney disease. The DELIVER trial was designed to determine whether dapagliflozin would reduce cardiovascular morbidity and mortality in patients with heart failure with mildly reduced or preserved ejection fraction. The trial was conducted at 353 sites in 20 countries. The trial enrolled patients aged 40 or older with symptomatic heart failure with an ejection fraction greater than 40%, including mildly reduced ejection fraction and preserved ejection fraction, as well as patients who previously had a reduced ejection fraction that improved to greater than 40%, both in outpatient and inpatient settings. Over 6,000 participants were randomized to receive dapagliflozin or placebo and followed for a median of 2.3 years. The primary endpoint was a composite endpoint of cardiovascular death or worsening heart failure.
Dapagliflozin significantly reduced the composite primary endpoint by 18%. Worsening of heart failure occurred in 368 participants (11.8%) in the dapagliflozin group compared with 455 participants (14.5%) in the placebo group. Cardiovascular deaths in these groups occurred in 231 (7.4%) and 261 (8.3%) participants, respectively. Key secondary outcomes were also significantly reduced, including total heart failure hospitalizations and total symptom burden.
The meta-analysis, led by Vaduganathan and colleagues, used data from DELIVER and EMPEROR-Preserved, with a composite of cardiovascular death or first hospitalization for heart failure. The team found that SGLT2 inhibitors reduced the risk of a primary outcome by 20%. The effects were consistent across all subgroups across age, gender, race, body mass index, systolic blood pressure, history of various medical conditions and more. Vaduganathan and colleagues further incorporated data from additional clinical trials with SGLT2 inhibitors, including those performed with dapagliflozin and empagliflozin in patients with reduced ejection fraction, and in patients with a clinical trial of sotagliflozin, an SGLT1/2 inhibitor. The totality of evidence with all of these data suggests that patients across the spectrum of heart failure benefit from this class of drugs, regardless of ejection fraction or care setting.
The authors note that the work has some limitations. Less than 5% of patients enrolled in DELIVER were black, symptom assessment limited by the COVID pandemic after March 2020, and trial subgroups were undernourished. However, the results were consistent across the predefined subgroups.
“There are more than 64 million people worldwide affected by heart failure, half of whom have a slightly reduced or preserved ejection fraction,” Solomon said. “Our goal is to rigorously and scientifically evaluate potential treatments so that we can provide the best evidence-based care to help them live longer, healthier lives.”
Disclosures: Disclosure forms provided by authors are available with the full text of the published article on NEJM.org. Vaduganathan has received a research grant or served on advisory boards for American Regent, Amgen, AstraZeneca, Bayer, Baxter Healthcare, Boehringer Ingelheim, Cytokinetics, Lexicon Pharmaceuticals, Novartis, Pharmacosmos, Relypsa, Roche Diagnostics, and Sanofi; has received speaker fees from AstraZeneca, Novartis and Roche Diagnostics; and participates in clinical trial committees for studies sponsored by Galmed, Novartis, Bayer, Occlutech and Impulse Dynamics.
Funding: DELIVER: funded by AstraZeneca; DELIVER ClinicalTrials.gov number, NCT03619213.
- Solomon SD, McMurray JJV, Claggett B, et al. Dapagliflozin in heart failure with a slightly reduced or preserved ejection fraction. N Engl J Med. DOI 2022: 10.1056/NEJMoa2206286
- Vaduganathan M, Docherty KF, et al. SGLT-2 inhibitors in patients with heart failure: a comprehensive meta-analysis of five randomized controlled trials. The Lancet. DOI 2022: 10.1016/S0140-6736(22)01429-5