Pooled analysis of SGLT1/2i data may be just the beginning

A pooled analysis of patient-level data from two trials, SCORED and SOLOIST-WHF, found that an investigational sodium–glucose cotransporter 1/2 (SGLT1/SGLT2) inhibitor significantly reduced cardiovascular adverse events in patients with diabetes and across the full spectrum of heart failure (HF)—from ejection fractions ranging from close to 20% to more than 65%.

“Treatment with sotagliflozin robustly and significantly reduced cardiovascular adverse events across the full spectrum of patients with HF, including patients who have HF with preserved ejection fraction (HFpEF), for which no effective treatment is currently available,” Deepak L. Bhatt, MD, MPH, executive director of interventional cardiovascular programs at Brigham and Women’s Hospital Heart & Vascular Center, professor of medicine at Harvard Medical School, and principal investigator for the study said in a prepared statement. “The benefit for patients with HFpEF is striking—this is the first trial to find a significant benefit in this population. We believe that these results merit a recommendation that patients who have both diabetes and HFpEF should be treated with sotagliflozin or another medication in its class.”

Sotagliflozin is an investigational drug and is an inhibitor of both SGLT1 and SGLT2, which may explain the striking results, Bhatt said. “It may be that there is a mechanistic reason that inhibition of SGLT1 is more beneficial in HFpEF, but that is a question for mechanistic investigations.”

Bhatt reported results of the meta-analysis at a late-breaking clinical trials session at ACC.21. At a press briefing following the presentation, BreakingMED asked if he believed already approved SGLT2i would also demonstrate benefit across the full spectrum of heart failure.

He noted that results of EMPEROR-Preserved, a trial of empagliflozin in HFpEF, are currently slated for presentation at the European Society of Cardiology in late August.

But right now, Bhatt said “SGLT2 inhibitors as a class should be used much more broadly than they are today. And as far as which one at this point in time, they all have great data… excellent data supporting safety, and also efficacy across really the range of patients with diabetes. So most patients with diabetes, barring contraindication or access issues, I think, should be on an SGLT2 inhibitor. This is especially true if they have chronic kidney disease, or if they have HF, certainly HF with reduced ejection fraction (HFrEF), but also, HFpEF as well, in part based on the data I just presented, but also in part because a lot of those patients with diabetes likely do have some degree of chronic kidney disease, some degree of diminished glomerular filtration rates (GFR) and/or albuminuria… So, there are a variety of reasons that they should be on the agent… I do feel that the results that I’ve shown here… likely do apply as a class to the entire SGLT2 inhibitor portfolio of drugs.”

Taken together, the SCORED and SOLOIST-WHF trials not only presented the full-spectrum of heart failure, from HFrEF to HFpEF, but also looked at sotagliflozin treatment in the outpatient setting (SCORED) and in “the vulnerable period of an admission for worsening heart failure” (SOLOIST-WHF).

By the numbers:

  • The SCORED trial evaluated whether sotagliflozin prevented cardiovascular events, including deaths due to a heart attack or stroke and hospitalizations or urgent visits for HF in patients who had both diabetes and chronic kidney disease.
  • 10,584 patients were randomly assigned to treatment with either sotagliflozin or a placebo.
  • At 16 months’ follow-up, sotagliflozin reduced cardiovascular events by 26% compared with placebo.
  • The SOLOIST-WHF trial evaluated whether sotagliflozin prevented cardiovascular deaths and hospitalizations or urgent visits for HF in patients who had diabetes and worsening HF.
  • 1,222 patients were randomly assigned to treatment with either sotagliflozin or a placebo.
  • At a median of 9 months’ follow-up, sotagliflozin reduced cardiovascular deaths and hospitalizations or urgent visits for HF by 33% compared with placebo.

There were 11,784 patients in the pooled analysis of the two trials, and sotagliflozin reduced the combined endpoint of cardiovascular death, hospitalization for HF, and urgent HF visit by 28% (HR 0.72 (95% CI 0.63-0.82; P=0.000002). “Treatment patient years to avoid one endpoint event was 31,” Bhatt said.

In the subgroup of 4,500 patients with a history of HF, the results were also impressive: “Among patients with an ejection fraction of 40% or less, sotagliflozin treatment reduced risk by 22% in both the entire cohort and in the HF group. For patients with an ejection fraction of 40% to 50%, sotagliflozin reduced risk in the entire cohort by 39% and in the HF group by 43%. For patients with HFpEF, the medication reduced risk by 30% in the entire cohort and by 33% in the HF group. All results were statistically significant and were similar for men and women.”

The results in women with HFpEF were particularly impressive, said discussant Ileana L. Piña, MD, MPH, a heart failure specialist at Central Michigan University in Mount Pleasant, Michigan. “You know, this could be a blockbuster drug to give to our patients who often are women, and are older. So first of all, I congratulate you, this is the right age group. This is the definition of HFpEF in women as well. And the fact that the results are positive in women is very encouraging.”

A limitation of the study is that the results apply only to patients with HF who also have diabetes, Bhatt said. The researchers had intended to also analyze the effect of sotagliflozin in patients with HF who did not have diabetes; however, this analysis was not performed because both the SCORED and SOLOIST-WHF trials were terminated early due to loss of funding at the onset of the Covid-19 pandemic.

  1. Pooled analysis of trials of an investigational SGLT1/2 inhibitor in patients with diabetes and chronic kidney disease or worsening heart failure found a reduction in risk of the combined endpoint of cardiovascular death, heart failure hosptialization, or worsening heart failure, irrespective of LVEF.

  2. Be aware that this report describes findings from studies of an investigational agent as well as off-label indications for approved agents.

Peggy Peck, Editor-in-Chief, BreakingMED™

The SCORED and SOLIST-WHF trials were initially funded by Sanofi and subsequently by Lexicon Pharmaceuticals

Bhatt disclosed the following relationships -Advisory Board: Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, Janssen, Level Ex, Medscape Cardiology, MyoKardia, Novo Nordisk, PhaseBio, PLxPharma, RegadoBiosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care, TobeSoft; Chair: American Heart Association Quality Oversight Committee; Data Monitoring Committees: BaimInstitute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic (including for theExCEEDtrial, funded by Edwards), ContegoMedical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo), Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Vice-Chair, ACC Accreditation Committee), BaimInstitute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD(CME steering committees), MJH Life Sciences, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair). Bhatt also disclosed research funding from Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cardax, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Lexicon, Lilly, Medtronic, MyoKardia, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLxPharma, Regeneron, Roche, Sanofi, Synaptic, The Medicines Company; Royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); Site Co-Investigator: Abbott, Biotronik, Boston Scientific, CSI, St. Jude Medical (now Abbott), Svelte; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Merck, and Takeda.

Piña, MD, MPH, has disclosed serving as an advisor or consultant for Relypsa.

O’Connor reported personal fees from Dey, L.P. Merck, Bayer, and Bristol Myers Squibb Foundation.

Cat ID: 102

Topic ID: 74,102,730,102,103,305,446,914,12,187,307,127,411,192,669,918,925,168