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Bhatt DL et al. 3-CT-SY24. Presented at: Scientific Sessions of the American Diabetes Association; 25-29 June 2021 (virtual meeting).
Disclosure:
Bhatt reports that in his role as director of studies for SOLOIST and SCORED, he has received research grants from Sanofi and Lexicon. Butler reports that he has financial relationships with Abbot, Adrenomed, Amgen, Array, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squib, CVRx, G3 Pharmaceutical, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk has, Relypsa, Roche, V-Wave Limited and Vifor. Leiter reports that he has received scholarships, research support, lectureship, and honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Esperion, Kowa, Lexicon, Merck, Novartis, Novo Nordisk, Sanofi, Servier, and The Medicines Company. and is a member of the SOLOIST / SCORED Executive Committee. Lewis reports that she served on the Executive Committee of the SCORED process. Please refer to the study for all relevant financial information from the other authors.
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The dual SGLT1 / SGLT2 inhibitor sotagliflozin effectively reduces the risk of heart failure, myocardial infarction and stroke while slowing the progression of chronic kidney disease, according to the results of two large clinical studies.
In the SOLOIST study, sotagliflozin (approved in the European Union as Zynquista and developed by Lexicon) reduced the risk of cardiovascular death, hospitalization for heart failure (HR), and urgent HR visits in adults with diabetes and acutely decompensated HR by 33%, with an early benefit observed from 1 month. In SCORED, the risk of cardiovascular death, hospitalization for HI, and urgent HF visits in adults with diabetes and CKD was reduced by 26%, with a significant benefit of approximately 3 months.
Women with an EF of 50% or higher with or without a history of HF were at lower risk for risk for total cardiovascular death, hospitalized HR, and urgent HR visits With Sotagliflozin Therapy versus placebo. The data were provided by Bhatt DL et al. 3-CT-SY24. Presented at: Scientific Sessions of the American Diabetes Association; 25-29 June 2021 (virtual meeting).
As Healio previously reported, in a pooled meta-analysis from the two studies, sotagliflozin resulted in a lower risk of cardiovascular death, hospitalization for HF, and urgent HF visits compared to placebo (HR = 0.72; 95% CI 0.63- 0.82; P = 0.000002)). The drug also reduced the risk of cardiovascular death, HF hospital admissions, and urgent HF visits in all areas of the ejection fraction, with benefits seen for both men and women.
Deepak L. Bhatt
“From the patient’s point of view, SGLT inhibition is an important intervention and one that can be used safely, as long as patients are selected with caution so as not to begin with hypotensive patients or those with apparent volume depletion.” 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 appears to be a safer and more effective approach.”
Sotagliflozin improves results in HFpEF, women
The researchers conducted two parallel studies with sotagliflozin. In the SOLOIST study, 1,222 adults with diabetes who were hospitalized for worsening HI were randomized to 200 mg sotagliflozin (with a target dose of 400 mg) or placebo for a median follow-up of 9 months.
Participants in the sotagliflozin group had a reduced risk of total cardiovascular death, hospitalization for HF, and urgent HF visits compared to placebo compared to placebo (HR = 0.67; 95% CI, 0.52-0, 85; P = 0.009).
Similar results were seen in the SCORED study, in which 10,584 adults with diabetes and CRF were randomly assigned 200 mg sotagliflozin (with a target dose of 400 mg) or placebo for a median follow-up of 16 months.
SCORED participants who were randomly assigned to sotagliflozin had a lower risk of total cardiovascular death, hospitalization for HI, and urgent HF visits compared to placebo compared to placebo (HR = 0.74; 95% CI , 0.63-0.88; P = 0.0004). The sotagliflozin group also had a lower risk of total cardiovascular death, non-fatal MI, and non-fatal stroke compared to placebo (HR = 0.77; 95% CI 0.65-0.91; P = 0.002) .
In the meta-analysis of the SCORED and SOLOIST data, sotagliflozin reduced the risk of total cardiovascular death, HI hospitalization, and urgent HF visits in adults with HI with reduced ejection fraction (HFrEF) of less than 40% (HR = 0.78 ; 95% CI, 0.63-0.96; P = 0.02), those with HF with medium EF (HFmrEF) of 40% to 50% (HR = 0.61; 95% CI, 0.4- 0.94; P = 0.02) and adults with HF with retained EF (HFpEF) of 50% or more (HR = 0.63; 95% CI, 0.45-0.89; P = 0.009).
The meta-analysis also revealed other benefits for women. The risk of total cardiovascular death, hospitalization, and urgent HR visits was 29% (HR = 0.71; 95% CI, 0.54-0.94) and 35 for all women with an ejection fraction of 50% or more % in women with a history of reduced HR and ejection fraction of 50% or more (HR = 0.65; 95% CI, 0.46-0.92).
“It is interesting that this is a significant benefit in the women with HFpEF,” said Bhatt during a presentation. “Until SOLOIST, HFpEF had no studies that showed a significant benefit, and then this pooled analysis builds on that result. In addition, HFpEF is a particularly difficult issue to treat, especially in older women, but it appears that there is now an effective therapy. ”
According to an analysis of 1,222 older adults with type 2 diabetes and HFrEF or HFpEF who participated in SOLOIST, sotagliflozin also resulted in an increased number of days outside the hospital. As Healio previously reported, 16.3% of patients taking sotagliflozin were hospitalized more than once compared with 22.1% taking placebo. The number of days of survival outside the hospital was higher for patients taking sotagliflozin than for placebo (RR = 1.03; 95% CI, 1-1.06), mainly due to a decrease in the number of deaths (RR = 0.71; 95% CI, 0.52-0.99).
Sotagliflozin slows the progression of kidney disease
Sotagliflozin reduced the risk of cardiovascular events in SCORED participants with an estimated glomerular filtration rate between 25 ml / min / 1.73 m2 and 60 ml / min / 1.73 m2 and without the need for micro- or macroalbuminuria. In addition to the cardiovascular benefits, sotagliflozin reduced HbA1c levels in those with moderate and severe eGFR subgroups. In adults with CKD, sotagliflozin preserved the eGFR and slowed the rate of renal disease regression after the acute effect for the first 4 weeks of the study (P <0.0001).
Julia B. Lewis
The primary renal endpoint was the first sustained decrease in eGFR of 50% or more, chronic dialysis, kidney transplant, or a sustained eGFR of less than 15 ml / min / 1.73 m2. There was no statistically significant advantage in the renal endpoints with sotagliflozin. Julya B. Lewis, MD, A professor of medicine in the Department of Nephrology at Vanderbilt University, said statistical significance was not observed because the SCORED study ended early after 16 months due to a loss of funding. Over 16 months, the maximum eGFR loss is around 13 ml / min / 1.73 m2. Lewis noted that any participant enrolled in the study with an eGFR of 28 ml / min / 1.73 m2 or greater is unlikely to decrease 50% in 16 months.
“In addition, albuminuria is the most important predictor of kidney disease progression and has a median albumin-creatinine ratio at baseline of 74 [mg/g] in the SCORED study, few subjects would have been expected to make rapid progress, ”said Lewis.
Lewis noted that other studies like DAPA-CKD showed renal benefits of SGLT2 inhibitors in diabetic and nondiabetic kidney disease. However, if DAPA-CKD had been prematurely terminated after 16 months, no significant kidney benefit would have been observed.
Further research follows
The SCORED / SOLOIST data showed new evidence in adults with diabetes and either acute decompensated HF or CKD. In addition to the benefits noted for women, Bhatt noted that the pooled data from SOLOIST and SCORED were the first to show that 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 at the Li Ka Shing Knowledge Institute at St. Michael’s Hospital in Toronto, said that a dual SGLT1 / SGLT2 inhibitor compared to only SGLT2 inhibitors, although comparative studies need to be carried out.
Lawrence A. Head
“In both SCORED and other studies, sotagliflozin has the advantage of lowering blood sugar even in patients with significant renal impairment,” said Leiter during a question-and-answer session. “As endocrinologists, we continue to believe that glucose control is important, especially with regard to microvascular complications.”
In a comment at the end of the presentation Javed servant, MD, MPH, MBA, Patrick H. Lehan Chair in Cardiovascular Research and professor and chair of the medical faculty at the University of Mississippi Medical Center, said more research is needed in several areas, including whether SGLT1 inhibitors offer an incremental CV benefit, though whether the benefit of HFpEF is replicated in larger studies, what renal outcomes would look like if endpoints were standardized, and more, has a drug class effect.
Javed Butler
“Many questions have been answered and many questions have been raised through this research,” said Butler. “We have ongoing studies with other patients with CKD, HFpEF, post-MI patients, acute HF patients and we will continue to learn.”
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