The Prospect of SGLT1/2i in Heart Failure: Cardiologists Await FDA Decision on Sotagliflozin

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As the May 27, 2023, PDUFA date approaches, the heart failure community awaits the US Food and Drug Administration’s decision regarding the New Drug Application (NDA) for sotagliflozin (Zynquista) as a treatment for heart failure.¹

A novel agent, boasting SGLT1 and SGLT2 inhibition, the unique mechanism of action of sotagliflozin is paralleled by its unconventional journey as a potential agent for heart failure.

In 2015, Sanofi announced it would be entering into a collaboration and license agreement with Lexicon Pharmaceuticals for the development and commercialization of sotagliflozin. The relationship would be terminated in 2019 following the receipt of a Complete Response Letter from the FDA for their NDA for sotagliflozin, which sought an indication as a treatment in adults for type 1 diabetes in combination with insulin.^2,3,4

The twists in the journey did not end in 2019, with the phase 3 heart failure program fraught with unexpected hurdles. Although both demonstrated statistically significant benefits and were used as part of the most recent NDA for heart failure, which was filed in July 2022, the phase 3 SOLOIST-WHF and SCORED were stopped early due to loss during the COVID-19 pandemic.^5,6

With a primary endpoint of total cardiovascular death, hospitalization for heart failure, or urgent visit for heart failure, the SOLOIST-WHF trial enrolled 1222 patients and randomized them in a 1:1 ratio to once-daily 400 mg sotagliflozin against placebo therapy. For inclusion in SOLOIST-WHF, participants were required to have type 2 diabetes and have recently been hospitalized for worsening heart failure. Results of the study suggested use was associated with a statistically significant reduction in the primary endpoint, with the rate of primary endpoint events being 70 and 98 per 100 patient-years, respectively, for the sotagliflozin and placebo arms of the trial (Hazard ratio [HR], 0.67 [95% confidence interval [CI], 0.52-0.85]; P = .0009). Further analysis indicated significance was achieved by 28 days of follow-up.⁵

Sharing the same primary endpoint as SOLOIST-WHF, the SCORED trial enrolled a population of 10,584 patients with type 2 diabetes. For inclusion in SCORED, patients were required to have type 2 diabetes, chronic kidney disease and risks for cardiovascular disease Results of the study indicated a primary endpoint event occurred among 11.3% of those using sotagliflozin and 14.4% of those receiving placebo (HR, 0.74 [95% CI, 0.63-0.88]; P = .0004), with this difference achieving statistical significance by 95 days. Of note, the trial’s original primary endpoint was first occurrence of major adverse cardiovascular events and this was changed as a result of the trial being stopped early due to loss of funding during COVID-19. For this endpoint, use was associated with a 16% reduction in risk relative to placebo therapy (HR, 0.84 [95% CI, 0.72-0.99]; P = .035).⁶

Since the initial presentation at the American Heart Association 2020 Scientific Sessions, the full studies have been published in the New England Journal of Medicine and a multitude of subgroups analyses have provided further insight into a potential role for sotagliflozin in real-world care, including a cost-effectiveness analysis based on SOLOIST-WHF data presented at International Society for Pharmacoeconomics and Outcomes Research 2023 annual meeting.^5,6,7

In the July 2022 release announcing the submission of their NDA for sotagliflozin, Lexicon Pharmaceuticals noted it would be pursuing 2 specific indications for the SGLT1/2 inhibitor. The desired labeling would indicate the agent to:¹

• Reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure visit in adults with heart failure, including those with acute or worsening heart failure.
• Reduce the risk of cardiovascular death, hospitalization for heart failure, urgent heart failure visit, nonfatal myocardial infarction, and nonfatal stroke in adults with type 2 diabetes mellitus, chronic kidney disease, and other cardiovascular risk factors, including a history of heart failure.

Leading up to the FDA’s potential decision, HCPLive Cardiology reached out to a group of clinicians for their view of the ideal role for sotagliflozin as well as what hesitancies they could foresee clinicians having related to prescribing the agent, if approved. This group includes Stephen Greene, MD, advanced heart failure specialist at the Duke University School of Medicine, Ankeet S. Bhatt, MD, MBA, cardiologist and research scientist at Kaiser Permanente Northern California, Muthiah Vaduganathan, MD, MPH, codirector of the Center for Cardiometabolic Implementation Science at Brigham and Women’s Hospital, Emmanuel Finet, MD, staff physician in the Section of Heart Failure and Transplantation Medicine at the Cleveland Clinic, and Deepak L. Bhatt, MD, MPH, principal investigator of the SOLOIST-WHF and SCORED trials and the director of Mount Sinai Heart.

^{L to R: Deepak Bhatt, MD, MPH; Ankeet Bhatt, MD, MBA; Muthiah Vaduganathan, MD, MPH; Stephen Greene, MD; and J Emmanuel Finet, MD
Credit: Mount Sinai; Twitter; Brigham and Women's Hospital; Cleveland Clinic; Duke University School of Medicine}

HCPLive: Based on the phase 3 trial data, what do you think the ideal role of sotagliflozin might be if approved?

Greene: SOLOIST-WHF provides very compelling data for the efficacy and safety of sotagliflozin in patients with HF, across the spectrum of ejection fraction. But the natural question is whether SGLT1 inhibition adds to effect of SGLT2 inhibition alone in the treatment of HF. For purposes of preventing HF and improving HF outcomes, I think the totality of evidence from meta-analyses and review of the individual trials suggests that dual SGLT1/SGLT2 inhibition and single SGLT2 inhibition are likely similarly effective.

Yet, there are some interesting findings from the sotagliflozin trial data to suggest that dual SGLT inhibition may offer added benefits on reducing risk of MI and stroke, at least in patients with comorbid type 2 diabetes. There also seems to be some biologic plausibility to potentially back this up. So, there is a hypothesis that sotagliflozin could be ideal for HF patients who are at very high risk of ASCVD events and/or have a strong history of ASCVD, but really the only way to definitively address this would be comparative trials between sotagliflozin and other SGLT2 inhibitors.

AS Bhatt: The development program for SGLT2 inhibtion has been impressive to date and the success of this therapy in improving outcomes across of wide range of populations, including heart failure, has been exciting for the field. It may have a role in the worsening heart failure population, but I do think both empagliflozin and dapagliflozin have established evidence in this space. Based on SCORED, sotagliflozin may have some role in treating high risk diabetic patients with chronic kidney disease but without albuminuria, a population that is distinct from that treated in the chronic kidney disease trials of other SGLT2 inhibition. Overall, we’ll need to learn more about the incremental effects of SGLT1 inhibition in addition to SGLT2 inhibition which will help the community understand where it might provide and important incremental benefit.

Vaduganathan: While the pivotal trial, SOLOIST-WHF, was stopped early due to loss of funding, the robust efficacy signal coupled with consistency across the SGLT2 inhibitor class from adjacent trials adds confidence with regards to the role of sotagliflozin in heart failure. Implementation of sotagliflozin, if approved, should mirror the target population of SOLOIST-WHF, those high-risk individuals who are actively hospitalized or who have had a recent worsening heart failure event.

Vaduganathan: While the pivotal trial, SOLOIST-WHF, was stopped early due to loss of funding, the robust efficacy signal coupled with consistency across the SGLT2 inhibitor class from adjacent trials adds confidence with regards to the role of sotagliflozin in heart failure. Implementation of sotagliflozin, if approved, should mirror the target population of SOLOIST-WHF, those high-risk individuals who are actively hospitalized or who have had a recent worsening heart failure event.

Finet: Independently of the inclusion criteria of the SOLOIST-WHF and SCORED trials, present data seem to indicate that as a class, SGLT2 inhibitors indeed reduce cardiovascular mortality in high-risk populations (heart failure, diabetes, chronic kidney disease, etc). I believe the role of sotagliflozin will be like that of dapagliflozin or empagliflozin: to overall reduce cardiovascular risk.

DL Bhatt: I think ultimately, the specific answer to your question will depend on the labeling of the drug. However, I believe the data from SOLOIST, and for that matter SCORED, really supports the use of sotagliflozin in patients who come in with acute decompensated heart failure and have been stabilized. It is beneficial to initiate treatment relatively early and prior to their discharge. The data from SOLOIST supports this, and it also showed benefits when the drug was started a few days after discharge. Additionally, it demonstrated benefits in patients at high cardiovascular risk who were outpatients, as observed in the context of SCORED.

Based on the data, I believe it provides benefits across the full spectrum of patients, regardless of whether they are at risk for heart failure, have heart failure, or have been admitted for heart failure, with benefit in both reduced ejection fraction and preserved ejection fraction. As you may recall, SOLOIST was the first trial to show a significant benefit in HFpEF for any drug and this includes the other SGLT2 inhibitors as well.

I hope that the labeling reflects this data and allows for its use, but we will have to wait and see what the label exactly contains. To answer your question, my personal belief is that SGLT2 inhibitors should be initiated in the hospital for patients admitted with heart failure, assuming there are no contraindications. I strongly support this approach based on the strong evidence from the SOLOIST trial. Whether sotagliflozin specifically or another SGLT2 inhibitor should be used will depend on the labeling, cost, and formulary decisions. But, based on the data from SOLOIST, I highly endorse the approach of starting SGLT2 inhibitors in the hospital once a patient has been initially stabilized and there are no contraindications.

HCPLive: What are some hesitancies you might or could foresee others having around prescribing this agent?

Greene: There is seemingly always hesitancy with use of any novel therapy. We have seen this time and time again in the heart failure and cardiorenalmetabolic spaces where early adoption is slow, despite strong clinical trial evidence and guideline recommendations. We are just now starting to see clinicians become increasingly familiar with dapagliflozin and empagliflozin, which have already been commercially available for years, so those agents certainly have a head start on developing clinician and patient recognition.

But regardless, approval of a 3rd SGLT inhibitor as a treatment for heart failure would be a great milestone for the heart failure community. This means that patients and clinicians now have 3 highly efficacious and safe drugs to pick from and this can only better allow every eligible patient with HF has access to medication. This is in contrast with ARNI, where there is only one formulation. For purposes of implementation, having 3 options is always better than 1 or 2, and may increase competition within industry and other stakeholders. This hopefully will further improve patient access to medication.

AS Bhatt: Overall, the trials have shown this therapy to have a largely favorable safety profile. Given the mechanism of action of SGLT1 inhibition, there appears to be a greater risk of diarrhea with therapy. While this shouldn’t generally preclude population level use, this may be a concern for patients in terms of desire to take this therapy or its impact on lifestyle. Whether folks with diarrhea and relative volume depletion are at any greater risk for euglycemic diabetic ketoacidosis hasn’t been shown, but should be a consideration for long-term pharmacovigilance programs. Otherwise, the evidence to data supports the relative safety of this therapy.

Vaduganathan: The incremental therapeutic effects afforded by the SGLT1 inhibition component of sotagliflozin have yet to be clarified when compared with conventional SGLT2 specific inhibitors as head-to-head trials are lacking. That said, sotagliflozin might have a specific role in management of diabetes in patients with HF and CKD, as the gut-mediated glycemic effects persist even at low eGFR (which is in contrast with conventional SGLT2 inhibitors that lose these glycemic effects in this eGFR range). There will be side effects (namely diarrhea) which will be unique to sotagliflozin which we will need to educate patients and the broader community about.

Finet: High cost, variable insurance coverage, polypharmacy, urinary tract and genital yeast infections, and concerns of hypoglycemia are some of the hurdles that will need to be overcome or tolerated when prescribing these medications; decision-making will need to be individualized on the basis of risk and the expected benefit for each patient.

DL Bhatt: Well, sotagliflozin appears to be at least as good as any of the SGLT2 inhibitor drugs that are currently available. Whether the fact that it's an SGLT1/2 inhibitor and also inhibits SGLT1 adds additional benefits is something doctors will have to determine by looking at the data. From the SCORED trial, we do know that sotagliflozin not only reduces heart failure hospitalizations, which seems to be a class effect of all SGLT2 inhibitors, but it also shows a significant reduction in the major adverse cardiovascular events endpoint, including myocardial infarction (MI) and stroke, compared to the placebo.

While there is a mixed bag when looking at the class of SGLT2 inhibitors in terms of reducing stroke in previous standalone trials, some have shown a reduction in MI and others haven't. However, the large, significant reductions in heart failure and major adverse cardiovascular events observed in the SOLOIST trial may be attributed to the added benefit of SGLT1 inhibition. Although, in fairness, it is possible that the other SGLT2 inhibitors would have shown similar results if they were tested in a population similar to that of the SOLOIST trial, with an appropriate sample size and study design.

Therefore, without a head-to-head comparison, it is speculative to say exactly what SGLT1 inhibition is adding. However, looking at the populations in SCORED, where all patients had diabetes, some degree of chronic kidney disease, and additional cardiovascular risk factors, they experienced a reduction in major adverse cardiovascular events. This wasn't clear in other chronic kidney disease trials involving different SGLT2 inhibitors. So, it may not necessarily be the population alone. Ultimately, without a head-to-head trial, it is difficult to say whether sotagliflozin has an advantage over other SGLT2 inhibitors. However, the reduction in major adverse cardiovascular events, particularly in stroke, may be a distinguishing feature of SGLT1 inhibition.

Another potential benefit of SGLT1 inhibition is in patients with diminished kidney function in terms of glycemic control. SGLT1 inhibition may provide better glycemic control compared to more conventional SGLT2 inhibitors as the glomerular filtration rate (GFR) decreases. Sotagliflozin, due to its kidney-independent effects on glycemic control, seems to maintain good glycemic control even with decreasing GFR.

It's worth mentioning that the company has filed for a heart failure indication for the drug rather than a glycemic control indication. So, while what I'm saying is scientifically true, it may not be immediately clinically relevant if the label does not include the use of the drug for diabetes. However, I believe sotagliflozin could be a highly effective addition to the armamentarium of heart failure drugs available. I won't delve into comparisons of one SGLT2 inhibitor being better than another, but I think the bigger issue lies in the underutilization of SGLT2 inhibitors as a class. If doctors choose to start sotagliflozin in appropriate patients, that is commendable. However, if they decide to start another SGLT2 inhibitor due to formulary availability or cost advantages, I would encourage them to go ahead and do so. Again, I believe the primary concern is the lack of use of any SGLT2 inhibitors as a class.

Editor’s note: These transcripts have been edited for grammar and clarity.

References:

1. Lexicon Pharmaceuticals, Inc. Lexicon announces FDA acceptance of New Drug Application for Sotagliflozin to treat heart failure. Lexicon Pharmaceuticals, Inc. July 27, 2019. Accessed May 26, 2023. https://www.globenewswire.com/news-release/2022/07/27/2486783/0/en/Lexicon-Announces-FDA-Acceptance-of-New-Drug-Application-for-Sotagliflozin-to-Treat-Heart-Failure.html.
2. Sanofi and Lexicon Pharmaceuticals to collaborate on Sotagliflozin, an investigational new oral medicine for people with diabetes. Sanofi. November 6, 2015. Accessed May 26, 2023. https://www.news.sanofi.us/2015-11-06-Sanofi-and-Lexicon-Pharmaceuticals-To-Collaborate-on-Sotagliflozin-an-Investigational-New-Oral-Medicine-for-People-with-Diabetes.
3. FDA issues complete response letter for Zynquista(TM) (sotagliflozin). Sanofi. March 22, 2019. Accessed May 26, 2023. https://www.sanofi.com/en/media-room/press-releases/2019/2019-03-22-18-15-00-1759502.
4. Lexicon Pharmaceuticals, Inc. Lexicon Pharmaceuticals announces termination of Alliance and Settlement with Sanofi. Lexicon Pharmaceuticals, Inc. September 10, 2019. Accessed May 26, 2023. https://www.globenewswire.com/news-release/2019/09/10/1913802/0/en/Lexicon-Pharmaceuticals-Announces-Termination-of-Alliance-and-Settlement-With-Sanofi.html.
5. Effect of Sotagliflozin on cardiovascular events in patients with type 2 diabetes post worsening heart failure. American College of Cardiology. November 16, 2020. Accessed May 26, 2023. https://www.acc.org/Latest-in-Cardiology/Clinical-Trials/2020/11/11/22/00/SOLOIST-WHF.
6. Effect of Sotagliflozin on cardiovascular and renal events in patients with type 2 diabetes and moderate renal impairment who are at cardiovascular risk. American College of Cardiology. November 16, 2020. Accessed May 26, 2023. https://www.acc.org/Latest-in-Cardiology/Clinical-Trials/2020/11/11/22/02/SCORED.
7. Campbell P. Analysis suggests Sotagliflozin is cost-effective in patients with worsening heart failure. HCP Live. May 23, 2023. Accessed May 26, 2023. https://www.hcplive.com/view/analysis-suggests-sotagliflozin-is-cost-effective-in-patients-with-worsening-heart-failure.