A pair of trials of a novel inhibitor of sodium-glucose cotransporter 1 and 2 (SGLT1/2i) offer the first tantalizing hint of a treatment that appears to demonstrate efficacy not only for reduced ejection fraction heart failure (HFrEF) but also for preserved ejection fraction heart failure (HFpEF).
If that apparent benefit can be confirmed in other trials, it would be a true game changer, since there currently is no approved therapy for HFpEF.
Findings from the trial of the novel agent sotagliflozin in 1,222 type 2 diabetes mellitus patients who were recently hospitalized for worsening heart failure found that treating just 4 patients for 1 year (NNT) would avoid one combined endpoint event (cardiovascular death, hospitalization for heart failure, or urgent visits for heart failure) — and, that benefit held true for both HFrEF and HFpEF patients.
That finding emerged from the SOLOIST-WHF trial, which was one of two sotagliflozin trials reported by Deepak L. Bhatt, MD, MPH, executive director of interventional cardiovascular programs at Brigham and Women’s Hospital Heart & Vascular Center and professor of medicine at Harvard Medical School, as late breaking clinical trials at the American Heart Association’s virtual Scientific Sessions 2020. Both trials were also simultaneously published online by The New England Journal of Medicine.
But there are issues, including the fact that both of the trials, “Effect of Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening Heart Failure (SOLOIST-WHF)” and “Cardiovascular and Renal Events in Patients with Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk (SCORED),” were halted early when the study funder pulled out, citing Covid-19 as the reason. That left the investigators without funds to complete planned analyses.
“Owing to concerns about the potential for an inadequate number of events, the primary end point was changed to total number of events in an attempt to preserve statistical power. The change to a heart failure-related end point was made at a time when there was evidence that SGLT2 inhibitors as a class reduced heart failure, although sotagliflozin, with SGLT1/2 activity, had not been tested in this regard. The change may have biased the findings toward benefit of the trial drug,” Bhatt and colleagues wrote. “The power to show a difference between the trial groups was not recalculated with the change of the end point; the trial remained adequately powered for the initial and revised primary end points but not for secondary end points, such as death from cardiovascular causes and progression of kidney disease. The trial design had called for adjudication of events, but this was not completed; therefore, investigator-defined end-point events were used for all analyses. Approximately 31% of adjudicated heart-failure hospitalizations or urgent visits were not confirmed to be primary events, leading to overestimation of the number of events. Furthermore, hospitalization for reasons other than heart failure would remove patients from the risk of a primary end-point event, although fewer total hospitalizations in the sotagliflozin group than in the placebo group (1,923 versus 2,094) spanning fewer total patient-years (104 versus 119) suggest the absence of bias favoring sotagliflozin with respect to the primary end point.”
Nonetheless, Bhatt noted that there are other trials currently underway that are investigating two SGLT2i agents — dapagliflozin and empagliflozin — for treatment of HFpEF, “and, although I haven’t seen the data, I believe those, too, will find a benefit for SGLT2 in HFpEF,” he said.
In SOLOIST and SCORED, HFpEF was defined as LVEF of more than 50% and HFrEF was defined as LVEF of less than 40%.
Another distinctive finding from the sotagliflozin trials was a reduction in the rate of myocardial infarction and stroke, “which is a first,” Bhatt said.
SCORED enrolled 10,584 patients who had TD2, “chronic kidney disease (estimated glomerular filtration rate, 25 to 60 ml per minute per 1.73 m2 of body-surface area), and risks for cardiovascular disease.” They were evenly randomized to sotagliflozin or placebo. The primary endpoint, which was changed when the funder pulled out, was total number of deaths from cardiovascular causes, HF hospitalization, or urgent HF visit.
Among the findings of the SCORED trial:
- Rate of primary endpoint was 5.6 events per 100 patient-years in the sotagliflozin arm versus 7.5 events per 100 patient-years in the placebo arm (P<o.001).
- CV death rate per 100 patient years: 2.2 in sotagliflozin versus 2.5 in controls (P=0.35).
- “Diarrhea, genital mycotic infections, volume depletion, and diabetic ketoacidosis were more common with sotagliflozin than with placebo.”
Among the findings in the SOLOIST trial:
- Primary endpoint event rate per 100 patient years was 51.0 versus 75.3, favoring sotagliflozin (P <0.001).
- CV death rate was 10.6 versus 12.5 (HR 0.84, 95% CI 0.58-1.22; P=0.36).
- All-cause mortality rate 13.5 in the sotagliflozin group and 16.3 in the placebo group (HR: 0.82; 95% CI, 0.59 to 1.14).
In concluding, Bhatt said that his take away from SOLOIST and SCORED was that this was the “first time that this has been seen in a prospective trial, looking at preserved ejection fraction and finding consistent benefit there — and also in patients with chronic kidney disease across the full range of protein leakage in the urine; prior trials had focused on patients with chronic kidney disease with large amounts of protein being excluded in the urine. Here, we looked at patients even with very small amounts and still found consistent benefit. And finally, the lower rate of heart attack and stroke with sotagliflozin suggests an additional early anti-atherosclerotic or perhaps anti-ischemic effect of SGLT2 or 1 inhibition, and this should be explored further in future trials.”
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Be aware that this activity presents information about a drug that is not yet FDA approved.
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Two trials of a novel SGLT1/2 inhibitor suggest that the agent may have benefit for treatment of HFrEF and HFpEF and may also have anti-atherosclerotic or anti-ischemic effects.
Peggy Peck, Editor-in-Chief, BreakingMED™
SOLOIST-WHF and SCORED were initially sponsored by Sanofi and then by Lexicon.
Bhatt disclosed the following relationships – Advisory Board: Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, Level Ex, Medscape Cardiology, MyoKardia, PhaseBio, PLx Pharma, Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care, TobeSoft; Chair: American Heart Association Quality Oversight Committee; Data Monitoring Committees: Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (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), Baim Institute 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); Research Funding: Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cardax, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Idorsia, Ironwood, Ischemix, Lexicon, Lilly, Medtronic, MyoKardia, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi, Synaptic, The Medicines Company; Royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); Site Co-Investigator: Biotronik, Boston Scientific, CSI, St. Jude Medical (now Abbott), Svelte; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Merck, Novo Nordisk, Takeda.
SOLOIST-WHF was initially sponsored by Sanofi and then by Lexicon.
Cat ID: 232
Topic ID: 74,232,232,3,446,914,12,13,187,192,669,918,925,231
