SCORED/SOLOIST: Dual inhibitor provides benefits in type 2 diabetes and heart failure, CKD
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The dual SGLT1/SGLT2 inhibitor sotagliflozin is effective at reducing risk for heart failure, myocardial infarction and stroke while also slowing progression of chronic kidney disease, according to findings from two large clinical trials.
In the SOLOIST trial, sotagliflozin (approved in the European Union as Zynquista and developed by Lexicon) reduced the risk for cardiovascular death, hospitalization for heart failure (HF) and urgent HF visits by 33% among adults with diabetes and acute decompensated HF, with an early benefit observed by 1 month. In SCORED, the risk for CV death, hospitalization for HF and urgent HF visits was reduced 26% among adults with diabetes and CKD, with a significant benefit by about 3 months.
As Healio previously reported, in a pooled meta-analysis from the two trials, sotagliflozin led to a lower risk for CV death, hospitalization for HF and urgent HF visits compared with placebo (HR = 0.72; 95% CI, 0.63-0.82; P = .000002). The agent also reduced risk for CV death, HF hospitalization and urgent HF visits across all ranges of ejection fraction, with benefits observed for both men and women.
“From a patient’s perspective, SGLT inhibition is an important intervention and one that can be employed safely as long as patients are selected with some caution in terms of not starting it in hypotensive patients or patients that were obviously volume depleted,” Deepak L. Bhatt, MD, MPH, executive director of interventional cardiovascular programs at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, told Healio. “In patients who were stabilized at discharge, SGLT inhibition does seem like a safe and effective approach.”
Sotagliflozin improves outcomes in HFpEF, women
Researchers conducted two parallel trials with sotagliflozin. In the SOLOIST trial, 1,222 adults with diabetes hospitalized for worsening HF were randomly assigned to 200 mg sotagliflozin (with a target dose of 400 mg) or placebo for a median follow-up time of 9 months.
Participants in the sotagliflozin group had a reduced risk for total CV death, hospitalization for HF and urgent HF visits compared with placebo (HR = 0.67; 95% CI, 0.52-0.85; P = .009).
Similar findings were observed in the SCORED trial, in which 10,584 adults with diabetes and CKD were randomly assigned to 200 mg sotagliflozin (with a target dose of 400 mg) or placebo for a median follow-up of 16 months.
SCORED participants randomly assigned to sotagliflozin had a lower risk for total CV death, hospitalization for HF and urgent HF visits compared with placebo (HR = 0.74; 95% CI, 0.63-0.88; P = .0004). The sotagliflozin group also had a lower risk for total CV death, nonfatal MI and nonfatal stroke compared with placebo (HR = 0.77; 95% CI, 0.65-0.91; P = .002).
In meta-analysis of SCORED and SOLOIST data, sotagliflozin lowered the risk for total CV death, HF hospitalization and urgent HF visits for adults with HF with reduced ejection fraction (HFrEF) of less than 40% (HR = 0.78; 95% CI, 0.63-0.96; P = .02), those with HF with midrange EF (HFmrEF) of 40% to 50% (HR = 0.61; 95% CI, 0.4-0.94; P = .02) and adults with HF with preserved EF (HFpEF) of 50% or greater (HR = 0.63; 95% CI, 0.45-0.89; P = .009).
The meta-analysis also revealed further benefits for women. The risk for total CV death, hospitalized HF and urgent HF visits was reduced by 29% in all women with ejection fraction of 50% or greater (HR = 0.71; 95% CI, 0.54-0.94) and 35% in women with a history of HF and ejection fraction of 50% or greater (HR = 0.65; 95% CI, 0.46-0.92).
“It is interesting that in the women with HFpEF, it is a significant benefit,” Bhatt said during a presentation. “HFpEF had no trials that showed a significant benefit until SOLOIST did, and then this pooled analysis builds upon that finding. Furthermore, in older women, in particular, HFpEF is an especially challenging issue to treat, but it does appear that there is now a therapy that is effective.”
Sotagliflozin also resulted in increased days alive out of the hospital, according to an analysis of 1,222 older adults with type 2 diabetes and HFrEF or HFpEF participating in SOLOIST. As Healio previously reported, 16.3% of patients taking sotagliflozin were hospitalized more than once compared with 22.1% with placebo. The days alive out of hospital rate was higher for those taking sotagliflozin compared with placebo (RR = 1.03; 95% CI, 1-1.06), mostly due to a decline in the rate of days dead (RR = 0.71; 95% CI, 0.52-0.99).
Sotagliflozin slows kidney disease progression
Sotagliflozin reduced the risk for CV events among SCORED participants with an estimated glomerular filtration rate between 25 mL/min/1.73 m2 and 60 mL/min/1.73 m2 and no requirement for micro- or macro-albuminuria. In addition to CV benefits, sotagliflozin led to reductions in HbA1c for people with both moderate and severe eGFR subgroups. In adults with CKD, sotagliflozin preserved eGFR, slowing the decline in kidney disease after the acute effect in the first 4 weeks of the trial (P < .0001).
The primary renal outcome was the first sustained decrease of 50% or more in eGFR, chronic dialysis, renal transplant or a sustained eGFR of less than 15 mL/min/1.73 m2. There was no statistically significant benefit in renal outcomes with sotagliflozin. Julia B. Lewis, MD, professor of medicine in the division of nephrology at Vanderbilt University, said statistical significance was not observed because the SCORED trial ended early after 16 months due to a loss of funding. Over 16 months, the maximum loss of eGFR is about 13 mL/min/1.73 m2. Lewis noted any participant enrolled in the trial with an eGFR of 28 mL/min/1.73 m2 or greater is unlikely to decrease by 50% within a 16-month period.
“Furthermore, albuminuria is the single most predictor of progression of renal disease, and with a baseline median urine albumin to creatinine ratio of 74 [mg/g] in the SCORED trial, few subjects would have been expected to be fast progressors,” Lewis said.
Lewis noted other trials, such as DAPA-CKD, showed renal benefits of SGLT2 inhibitors in diabetic and nondiabetic kidney disease. However, she said, if DAPA-CKD had ended early at 16 months, no significant renal benefits would have been observed.
More research to come
The data from SCORED/SOLOIST revealed novel findings in adults with diabetes and either acute decompensated HF or CKD. In addition to the benefits found for women, Bhatt noted the pooled data from SOLOIST and SCORED was the first to show a therapy had a significant effect on adults with HFpEF.
Lawrence A. Leiter, MD, FRCPC, FACP, FACE, FAHA, FACC, director of the lipid clinic, associate director of the clinical nutrition and risk factor modification center, and associate scientist in the Li Ka Shing Knowledge Institute at St. Michael’s Hospital in Toronto, said a dual SGLT1/SGLT2 inhibitor may provide added benefits compared with only SGLT2 inhibitors, although comparator studies need to be conducted.
“Both in SCORED and in other trials, sotagliflozin has the advantage of lowering glucose even in patients with significant renal impairment,” Leiter said during a Q&A session. “As endocrinologists, we continue to believe glucose control is important, especially with regard to the microvascular complications.”
In a commentary at the end of the presentation, Javed Butler, MD, MPH, MBA, the Patrick H. Lehan Chair in Cardiovascular Research, and professor and chairman of the department of medicine at the University of Mississippi Medical Center, said more research is needed in several areas, including whether SGLT1 inhibitors offer incremental CV benefit, if there is an effect of drug class, whether the benefits in HFpEF will be replicated in larger studies, what the renal outcomes would be if endpoints are standardized, and more.
“Many questions were answered, and many questions were raised by this research,” Butler said. “We have ongoing studies in further patients with CKD, HFpEF, post-MI patients, acute HF patients, and we will continue to learn further.”
References:
- Bhatt DL, et al. N Engl J Med. 2021;doi:10.1056/NEJMoa2030183.
- Bhatt DL, et al. N Engl J Med. 2021;doi:10.1056/NEJMoa2030186.
- Szarek M, et al. Ann Intern Med. 2021;doi:10.7326/M21-0651.
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Bhatt DL, et al. 3-CT-SY24. Presented at: American Diabetes Association Scientific Sessions; June 25-29, 2021 (virtual meeting).
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