Sotagliflozin Scores Wins in SCORED and SOLOIST-WHF Trials

Two new studies provide a boost to the use of sotagliflozin (Zynquista; Sanofi Aventis/Lexicon) in two very distinct patient populations, adding more data to the evolving sodium-glucose cotransporter 2 (SGLT2) inhibitor story.

The SCORED and SOLOIST-WHF trials, both presented this week at the virtual American Heart Association 2020 Scientific Sessions and published simultaneously in the New England Journal of Medicine, showed that sotagliflozin reduced the risk of hospitalizations for heart failure (HF) in diabetic patients with chronic kidney disease (CKD) and decompensated HF, respectively, and this benefit was largely evident after just a few months.  

In the SOLOIST-WHF study, which was prematurely stopped after losing funding from the study sponsor amid the ongoing COVID-19 pandemic, investigators pushed the use of SGLT2 inhibitors further upstream by starting treatment in patients hospitalized with acute HF or within 3 days of discharge. Reporting outcomes on 1,222 patients—they had initially planned to enroll roughly 4,000 patients—investigators showed that use of sotagliflozin significantly lowered the risk of death from cardiovascular causes and hospitalizations or urgent visits for HF.

“The first question was whether this was really a safe thing to do,” lead SOLOIST-WHF investigator Deepak Bhatt, MD, MPH (Brigham and Women’s Hospital, Boston, MA), told TCTMD. Patients who present with acute decompensated heart failure undergo diuresis, and kidney function is likely to fluctuate because of the diuretics and other medications. “The second goal was to see if it was efficacious as no trial had really done this before in an adequately powered study,” he added. “What we found was a large, significant reduction in heart failure.”

The first question was whether this was really a safe thing to do. Deepak Bhatt

Right now, there are a lot of data supporting use of SGLT2 inhibitors in stable HF—either treating patients who already have it or preventing it—but SOLOIST-WHF is the next evolution, said Bhatt. The findings are “potentially practice changing,” he said, particularly the demonstration of safety with starting sotagliflozin in the decompensated HF setting. He suspects the benefit can likely be extrapolated to other SGLT2 inhibitors.

To TCTMD, Carlos Santos-Gallego, MD (Icahn School of Medicine at Mount Sinai, New York, NY), who wasn’t involved in the study, said the focus on patients with acute HF in SOLOIST-WHF is a welcome addition given the lack of data in this population, calling it a “paradigm-changing” study. “It really shows us that the earlier, the better,” he said, when it comes to initiating treatment for patients following acute HF.

Santos-Gallego noted that sotagliflozin is a unique drug in that it is a dual inhibitor of SGLT1, the primary transporter for glucose absorption in the gut, and SGLT2, which is expressed in the kidney where it reabsorbs glucose. Technically speaking, while he is comfortable starting SGLT2 inhibitor therapy in decompensated HF patients at the time of discharge, there are still no data showing the other SGLT2 inhibitors, which don’t act on SGLT1, provide the same benefit—other trials, like EMPULSE with empagliflozin, are coming. Nonetheless, he believes there is a real benefit to acting early once the acute HF patient is stabilized.

“For the majority of patients in HF admitted to hospital and who have responded well to diuretics, I would be comfortable prescribing the SGLT2 inhibitors,” said Santos-Gallego. He likened SOLOIST-WHF to PIONEER, which took sacubitril-valsartan (Entresto; Novartis), originally tested in chronic HF patients in PARADIGM-HF, and moved it into the decompensated patient population. On the whole, the data show that HF patients once stabilized should be treated as early as possible. “It’s a concept we want to hammer,” he said. “Not only for SGLT2 inhibitors, but all types of drugs. Do not delay the initiation of any of the four pillars of [HF] therapy.”

Jane Wilcox, MD (Northwestern University Feinberg School of Medicine, Chicago, IL), who discussed the trials during the late-breaking session, said both trials adds more evidence to “SGLT2 inhibitor story” where the aggregate data favors early treatment in HF patients with diabetes and chronic kidney disease.      

SOLOIST-WHF     

The SOLOIST-WHF study included patients with diabetes aged 18 to 85 years hospitalized for heart failure and receiving IV diuretic therapy. Patients were stabilized in hospital before randomization to treatment with sotagliflozin or placebo, with criteria for stability including no need for oxygen, systolic blood pressure of 100 mm Hg or greater, no need for intravenous inotropic or vasodilator therapy, and transitioning from IV to oral diuretic therapy.

After a median follow-up of 9.2 months, there were 245 primary endpoint events in the 608 patients randomized to sotagliflozin compared with 355 events in 614 patients assigned to placebo. This translated into 51.0 primary endpoint events per 100 patient-years in the sotagliflozin arm versus 76.3 per 100 patient-years in the placebo arm (HR 0.67; 95% CI 0.52-0.85). The benefit was driven by a reduction in hospitalization and urgent visits for heart failure (HR 0.64; 95% CI 0.49-0.83).

Do not delay the initiation of any of the four pillars of [HF] therapy. Carlos Santos-Gallego

Subodh Verma, MD, PhD (University of Toronto/St. Michael’s Hospital, Canada), another of the SOLOIST-WHF investigators, said the trial provides data for use of SGLT2 inhibitors in a patient population where none previously existed. DAPA-HF and EMPEROR-Reduced both included patients with stable, ambulatory HF.

“In the context of somebody who has had a worsening heart failure admission, you can actually see a marked benefit,” said Verma, referring to the treatment approach in SOLOIST-WHF. “I think it’s a game changer. It says: use it upstream.” For Verma, even though the trial had to prematurely halt enrollment—and Sanofi severed their partnership with Lexicon last year, placing the drug’s future in limbo—the result demonstrates how powerful the SGLT2 inhibitors are in the context of HF.

That treatment benefit occurred early, within a month of randomization, and was evident in those with preserved and reduced ejection fractions. When investigators looked at patients stratified by EF, they observed a significant reduction in the risk of the primary endpoint in those with EFs less than 50% (HR 0.72; 95% CI 0.56-0.94) and in those with higher EFs (HR 0.48; 95% CI 0.27-0.86).

The treatment benefit in those with heart failure with preserved ejection fraction (HFpEF) is the first time a treatment effect with an SGLT2 inhibitor has been demonstrated in this patient population, said Bhatt. Investigators caution, however, that early stoppage of SOLOLIST-WHF, along with the relatively small numbers of patients with HFpEF, make drawing firm conclusions difficult at this time. Verma noted that trials testing two SGLT2 inhibitors in patients with HFpEF, dapagliflozin in DELIVER and empagliflozin in EMPEROR-Preserved, are currently underway. 

“The field of cardiology, all of us, are excited by the fact we might finally have a treatment for HFpEF,” Santos-Gallego told TCTMD.

However, he also expressed caution interpreting these “promising” results. With the small sample size—the HFpEF patients made up only 20% of the SOLOIST-WHF trial—there are wide confidence intervals around the treatment effect so the results should be confirmed in larger studies. There are important nuances to the coming trials, he said, noting that EMPEROR-Preserved will include patients with chronic HF, a different population than the acute HF patient in SOLOIST-WHF. Event rates in chronic HF might be much lower, so it may be more challenging to show a benefit in these trials.

Follow-up Reduced With Funding Loss

With SCORED, which also lost funding that led to curtailed follow-up, investigators focused on patients with diabetes and chronic kidney disease, with and without albuminuria, and at least one major cardiovascular risk factor. The two original coprimary endpoints were a classic MACE endpoint (death from cardiovascular causes, nonfatal MI, or nonfatal stroke), designed to assess the safety of the diabetes drug, as well the composite of cardiovascular death and hospitalizations for HF. Due to the early trial stoppage and fewer than planned events, the primary endpoint was changed to deaths from cardiovascular causes, hospitalizations for HF, and urgent visits for HF.

I think it’s a game changer. It says: use it upstream. Subodh Verma

After a median follow-up of 16 months, there were 5.6 and 7.5 primary endpoint events per 100 patient-years in the sotagliflozin- and placebo-treated patients, respectively (HR 0.74; 95% CI 0.63-0.88). With respect to hospitalizations and urgent visits for HF, there were 3.5 and 5.1 events per 100 patient-years in the sotagliflozin- and placebo-treated patients, respectively (HR 0.67; 95% 0.55-0.82). There was no difference in cardiovascular mortality.

For the original co-primary endpoint, there was a 23% reduction in the relative risk of cardiovascular death, nonfatal MI, or nonfatal stroke, including significant reductions in MI and stroke. Bhatt said SCORED is the first trial to demonstrate a reduction in stroke with an SGLT2 inhibitor, noting there was some initial controversy surrounding higher stroke numbers with empagliflozin—a finding later deemed to be a spurious finding—in EMPA-REG OUTCOMES.

“With that part, I think we were a little bit hurt by COVID and the sponsor pulling funding from the trial, because the study [follow-up] wasn’t long enough, in my opinion, to show the full benefit of the drug in terms of MACE,” said Bhatt. “But it was significantly reduced, and I think it’s a real finding. Other SGLT2 inhibitors have shown signals in some of the trials, not consistently, of a reduction in MI. I think there’s probably something to it.”

This early anti-ischemic benefit of sotagliflozin needs to be explored further, he added.

In her discussion, Wilcox said the cardiovascular benefit of SGLT2 inhibitors in the early trials of type 2 diabetes was driven by a reduction in HF hospitalizations, but that SCORED adds a new wrinkle by suggesting sotagliflozin may influence ischemic and HF events, said Wilcox. Like Bhatt and Santos-Gallego, Wilcox said these benefits need to be confirmed in future trials.

Finally, given its dual action on SGLT1 and SGLT2, sotagliflozin significantly reduced HbA1c levels in SCORED patients with estimated glomerular filtrations rates (eGFR) < 30 mL/min/1.73 m2 and those with less impairment.

Verma, who wasn’t involved in SCORED, noted that one of the issues with SGLT2 inhibitors is that while efficacy for reducing HF events is preserved in patients with low eGFR, the ability to lower HbA1c levels is impaired. “There seems to be a greater HbA1c reduction at low levels of eGFR in [SCORED and SOLOIST] compared with what we’ve seen with conventional SGLT2 inhibitors, per se,” he said. “The SGLT1 is found in the GI tract and that might be a nonrenal mechanism in which blood glucose is regulated at low levels of eGFR.”

Last year, the US Food and Drug Administration declined to approve sotagliflozin as an add-on to insulin in type 1 diabetes, although it is approved in Europe for such patients. It is not approved for the treatment of type 2 diabetes.