Dr Deepak Bhatt Discusses SCORED, SOLOIST Trial Results

Both trials move forward the safety and efficacy of sodium glucose co-transporter 2 inhibitors in the field, said 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. Bhatt's talk was presented at the American Diabetes Association's (ADA) 81st Scientific Sessions.

Transcript:

Can you discuss the significance of the new SCORED results presented at the ADA, particularly with regard to stroke?

So we're talking about the drug sotagliflozin. The key things to know about the drug are that it's a sodium glucose co-transporter 2 (SGLT2) inhibitor, which works in the kidneys, of course, enhancing glucose elimination. But in addition, it's an SGLT1 inhibitor. So where that works is in the gut, thereby decreasing postprandial glucose elevations. That's a non-kidney-related effect. The reason that's relevant is that in patients that have marked decrease in their glomerular filtration rate (GFR), SGLT2 inhibitors still do provide clinical benefit, but they're not so effective for glycemic control in patients with diabetes. Potentially, this drug because of its SGLT1 mechanism would provide good glycemic control, even in that patient with diabetes with a lowish GFR. Indeed, we saw that in the SCORED trial, that even low GFR patients seemed to derive good glycemic control.

What the sotagliflozin compound was studied in was then 2 large randomized clinical trials, SOLOIST and SCORED. Both were previously published in the New England Journal of Medicine and had been presented as lead breakers at American Heart Association (AHA) [meeting]. SOLOIST, to quickly recap, consisted of patients with worsening heart failure, and diabetes, but worsening heart failure, admitted to the hospital with that heart failure. SCORED consisted of outpatients with diabetes with chronic kidney disease (CKD). One was basically an inpatient, one was an outpatient trial. Diabetes was required for both trials. But again, SOLOIST is acute decompensated. heart failure. SCORED is stable CKD. Both trials were very positive for sotagliflozin versus placebo. The primary end point was cardiovascular death, hospitalization for heart failure, or heart failure visits. That was significantly reduced in the SOLOIST trial. That benefit kicked in, and it was statistically significant by 28 days, so very early benefit. In SCORED, even though that was a stable outpatient population, the benefit kicked in there too, with heart failure-related events significantly reduced by about 3 months or so.

But what was perhaps quite striking in SCORED was that there was also a significant reduction in total myocardial infarctions and total strokes. Here as well, that benefit became significant by about 3 months. So a very early benefit on atherosclerotic endpoints. Now, potentially, that has to do with the study population, that is diabetes, CKD, enough statistical power to see that early benefit. But potentially, that could be the SGLT1 because other trials of SGLT2 inhibitors to date, have not found a significant reduction in stroke, and they've been sort of mixed with respect to reductions in myocardial infarction. Then potentially, this approach is sotagliflozin is providing protection against heart failure, against ischemic events, and also some degree of kidney protection.

Can you discuss the SOLOIST results? Taken with results from SCORED, what do they tell us about options for patients with diabetes and chronic kidney disease?

I think some of the lessons of what we've learned from this program, sotagliflozin's program, the SOLOIST and SCORED trials, specifically, I think are class effects. That is, I think, the safety of initiating SGLT2 inhibitors in patients with a recent admission for heart failure, starting the medicine in house, I think we've proven the safety of that. Now, obviously, you have to make sure the patient is stabilized from their heart failure. We didn't start it on day 1. But once the patient is off inotropes, intravenous diuretics, oxygen, and is being transitioned to their outpatient regimen and heading towards discharge there, that sort of patient we showed can safely be started on an SGLT2 inhibitor barring contraindications with careful monitoring, and again, waiting until they're stabilized. But that I believe, is a lesson that is applicable to the class of SGLT2 inhibitors.

We also showed a significant benefit and I presented some of these data here at the ADA across the full range of ejection fraction. Data were pooled from both SOLOIST and SCORED, including heart failure with preserved ejection fraction, where we found a significant benefit of sotagliflozin versus placebo. Really the first time any drug has been shown to have a statistically robust benefit in reducing heart failure with preserved ejection fraction, and interesting also [it was] a benefit that was consistent in men and women. Of course, older women being at particular risk for heart failure with preserved ejection fraction, a particularly thorny situation to treat, again with, well, recently some approved drugs, but really none with great robust data supporting them until now.

I think this is a message that is likely generalizable to the SGLT2 inhibitor class. But we'll find out soon, because at the European Society of Cardiology, it's been announced now that EMPEROR-Preserved will be presented. We'll see if empagliflozin also is effective in heart failure with preserved ejection fraction. The data for dapagliflozin should follow thereafter, later on in the year or so. We'll see if it's a class effect or not. My prediction is it's a class effect and SGLT2 inhibitors work in heart failure with preserved ejection fraction just as they work in heart failure with reduced ejection fraction. But there's a chance that they might be negative, in which case I'd say, 'Okay, I was wrong, it looks like it's an SGLT1 inhibitor effect that has led to this benefit in heart failure with preserved ejection fraction that we're seeing in SOLOIST and SCORED.' But again, my gut feeling is that the ongoing other trials of heart failure with preserved ejection fraction with SGLT2 inhibitors will indeed be robustly positive, but we'll find out soon.

In terms of contributions to the field, I think both trials really move forward both the safety and efficacy of SGLT2 inhibitors, and then potentially for this specific drug, sotagliflzin and it potentially has some effect on glycemic control in low GFR patients and effects on early atherosclerotic events, stroke and myocardial infarction, that may be specific to the SGLT1 pathway. The fate of the drug will depend on how the FDA opines. The initial feedback is publicly disclosed. It's been quite positive. We just have to see if the company, the small company that's trying to get it through the FDA and find a partner is successful in those steps and actually commercializing the drugs. I certainly hope they are, I think would be a useful addition to the clinical armamentarium but we'll see how all that plays out.