A Review of the Potential Role of Sotagliflozin: A Dual SGLT2 and SGLT1 Inhibitor—in the Treatment of Heart Failure

Abstract

Objective: This review provides an overview of the pharmacology, efficacy, and safety of sotagliflozin, a dual inhibitor of sodium-glucose cotransporters 1 and 2 (SGLT1 and SGLT2), to reduce the risk of cardiovascular death and hospitalization in those with heart failure. Data sources: A search of Embase via Elsevier, PubMed, Web of Science—All Databases, and The Cochrane Library for clinical trials in CENTRAL, as well as the MedRxiv and BioRxiv pre-print servers, was conducted from inception through December 1, 2023. Search terms included sotagliflozin, lx 4211, lp 802034, sar 439954, and (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol. Study selection and data extraction: Published phase 1, phase 2, and phase 3 clinical trials, meta-analyses, and systematic reviews. Studies were included if they were published in English and evaluated sotagliflozin pharmacology, pharmacokinetics, efficacy, or safety. Data synthesis: The Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure (SOLOIST-WHF) and Sotagliflozin on Cardiovascular and Renal Events in Patients with Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk (SCORED) phase 3 trials compared sotagliflozin with placebo in patients with type 2 diabetes mellitus. In both the SCORED and SOLOIST-WHF trials, treatment with sotagliflozin resulted in a statistically significant reduction in the primary composite outcome of death from cardiovascular causes, hospitalizations due to heart failure (HF), and urgent visits for HF. Conclusions: Dual SGLT1 and SGLT2 inhibition with sotagliflozin is efficacious in reducing myocardial infarction (MI), stroke, and HF hospitalizations and urgent visits in the SCORED and SOLOIST-WHF trials. However, its impact on reducing cardiovascular mortality remains uncertain due to premature study discontinuation. Owing to these factors and lack of generalizability, further studies are needed to establish its role in renal protection and cardiovascular mortality in broader populations. At this time, more evidence is warranted to definitively establish sotagliflozin in HF.

Introduction

Approximately 6.7 million adults in the United States have heart failure (HF), with prevalence expected to grow to 8.5 million by 2030. ¹ Heart failure is a life-limiting illness with significant impact on quality of life, morbidity and mortality, and health care costs. ¹ Optimizing guideline-directed medical therapy (GDMT) is essential to reduce the risk of HF hospitalization and death. Based on recent evidence, sodium-glucose cotransporter inhibitors (SGLTis) have become a key pillar of HF GDMT regardless of ejection fraction (EF).^2-8

The SGLTis were initially developed as antihyperglycemic medications. Given the benefits of SGLTis in slowing progression of chronic kidney disease (CKD) and improving cardiovascular (CV) outcomes in patients with HF, several agents have now been approved for additional indications regardless of diabetes diagnosis. Empagliflozin and dapagliflozin were the first SGLT2i to be Food and Drug Administration (FDA)-approved for use in patients with HF to reduce the risk of CV death and hospitalization for HF.^9,10 Approval for these indications was based on large, randomized controlled trials across a spectrum of EFs demonstrating the benefit of treatment with dapagliflozin and empagliflozin in reducing the composite outcome of risk for HF hospitalizations and CV death. These outcomes were driven by reductions in HF hospitalization, with less substantial effects observed with CV death.^4-7 Sotagliflozin (Inpefa) was FDA approved in May 2023 for use to reduce the risk of CV mortality, hospitalization for heart failure (HHF), and urgent HF visits in adults with HF. ¹¹ Other SGLTis including canagliflozin, bexagliflozin, and ertugliflozin have not been investigated as agents to reduce HF morbidity and mortality in the absence of type 2 diabetes mellitus (T2DM). Sotagliflozin differs from other SGLTis in that it is a dual inhibitor of SGLT2 and SGLT1. Although the SGLT2 inhibitors have not been directly compared against one another in clinical trials, nonselective agents such as sotagliflozin may have more substantial impacts on HF outcomes.^12,13 This is believed to be due to differences in the anatomical location and roles of SGLT1 and SGLT2. There are a variety of hypotheses which seek to explain the additional benefits of SGLT1 inhibition in cardiac tissues on the course of heart failure. The SGLT1 upregulation is associated with cardiomyopathy through increased formation of reactive oxygen species. ¹⁴ The SGLT1 inhibition may decrease HF risk through beneficial effects on weight through increased glucagon-like-peptide-1 (GLP1) and gastric inhibitory peptide (GIP). ¹⁴

This review will provide an overview of sotagliflozin and discuss its pharmacology, clinical efficacy, safety, and potential role in therapy for use in HF.

Data Selection

A search of Embase via Elsevier, PubMed, Web of Science—All Databases, and The Cochrane Library for clinical trials in CENTRAL, as well as the MedRxiv and BioRxiv pre-print servers, was conducted from inception through December 1, 2023. Search terms included sotagliflozin, lx 4211, lp 802034, sar 439954, and (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol (Appendix). Published phase 1, phase 2, and phase 3 clinical trials, meta-analysis, and systematic reviews were included for review. In addition, studies published in English evaluating sotagliflozin pharmacology, pharmacokinetics, efficacy, or safety were included. Animal studies, phase 2, and phase 3 studies where diabetes management was the primary or secondary outcome were excluded. The literature review resulted in 1216 articles, from which 6 were included in this review: 1 phase 1, 4 phase 2, and 2 phase 3 trials.

Clinical Pharmacology

Mechanism of Action

Sotagliflozin is a dual SGLT1 and SGLT2 inhibitor.^11,15 All SGLTis function by inhibiting both isoforms of SGLT—SGLT1 and SGLT2. Available agents vary greatly in selectivity for SGTL2 over SGLT1 (Table 1).^16,17 Differences in selectivity theoretically impact tolerability and CV outcomes. ¹⁴

Table 1.

Selectivity and Indications of SGLTi.

Agent	Selectivity for SGLT2/SGLT2i	FDA-approved indications
Empagliflozin	2500x 16	T2DM, HF, CKD 9
Ertugliflozin	2500 16	T2DM 18
Bexagliflozin	2435x 17	T2DM 19
Dapagliflozin	1200x 16	T2DM, HF, CKD 10
Canagliflozin	250x 16	T2DM 20
Sotagliflozin	20x 16	HF, CVRR a , 11

Abbreviations: T2DM: type 2 diabetes mellitus, HF: heart failure; CKD: chronic kidney disease; CVRR: cardiovascular risk reduction.

^aCVRR: risk reduction of cardiovascular mortality, hospitalization for heart failure, and urgent heart failure visits in adults with type 2 diabetes, chronic kidney disease, and other cardiovascular risk factors.

Although SGLT2 receptors are primarily located in the kidneys, SGLT1 is found in multiple extrarenal tissues including the brush border of the small intestine, skeletal muscle, heart, and brain capillaries.^14,21 The SGLT1 expression is approximately 10× higher in the heart than in the kidneys. ²¹ The SGLTis inhibit renal reabsorption of glucose by increasing the threshold for glucose reabsorption, leading to increased glycosuria. The SGLT2 is the primary sodium-glucose cotransporter responsible for renal glucose reabsorption (~97%), whereas SGLT1 plays a much smaller role (~3%). ¹⁴ In the small intestines, SGLT1 delays glucose reabsorption and decreases postprandial glucose (PPG).^11,15 The impact of SGLT1 inhibition in the heart is not fully elucidated. Available data suggest that SGLT1 inhibition through genetic mutation is protective against HF development, suggesting that differences in selectivity for SGLT1 may impact the cardioprotective effects of SGLTis (Table 1). It is hypothesized that the cardioprotective mechanism of SGLT2 inhibition is multifaceted, with renal protective effects playing a significant role. ²² Renal protection, achieved through a reduction in intraglomerular pressure via afferent arteriolar constriction, indirectly enhances cardiac function. ²² In addition, mitigating renal stress can indirectly improve cardiac function by decreasing afferent sympathetic nervous system activation, inflammation, and reactive oxygen species production. ²² The SGLT2 inhibition is noted to have potential in prevention of cardiac remodeling by targeting the mammalian target of rapamycin pathway, which was seen to reduce left ventricular wall stress, in turn improving cardiac function. ²²

Pharmacokinetics

Summary of sotagliflozin pharmacokinetics can be found in Table 2, including absorption, distribution, metabolism, and elimination. When administered with a high-caloric meal compared with fasting conditions, C_max and area under the concentration time curve from time 0 to infinity (AUC_0-inf) increased by 149% and 50%, respectively. ¹¹ Therefore, sotagliflozin should be taken ≤ 1 hour before the first meal of the day. ¹¹ Sotagliflozin is extensively metabolized to sotagliflozin 3-O-glucuronide via the UDP-glucuronosyltransferase 1A9 (UGT1A9) enzyme and to a lesser extent, cytochrome P450 3A4 (CYP3A4). ¹¹ Both sotagliflozin and its metabolite are primarily renally eliminated, with 57% recovered in the urine and 37% in the feces. In addition, sotagliflozin undergoes enterohepatic circulation. The terminal half-life (T_1/2) of sotagliflozin ranges between 21 and 35 hours and 19 and 26 hours for sotagliflozin 3-O glucuronide following a dose of 200–400 mg. ¹¹ Steady state is estimated to be approximately 5 days after daily dosing. ¹¹

Table 2.

Pharmacokinetics Characteristics of Sotagliflozin.^11,15.

Characteristic	Sotagliflozin
Absorption
Absolute bioavailability	25%
Tmax	1.25-4 hours
Food effect	Taken not more than 1 hour before first meal of the day to maximize plasma exposure
Distribution
Vd	9000 L
Protein binding	Sotagliflozin—>93% protein bound Sotagliflozin 3-O-glucoronide—>93% protein bound
Metabolism	Primary—glucuronidation by UGT1A9 Secondary—CYP3A4 Major metabolite—sotagliflozin 3-O-glucoronide
Elimination
Half-life	Sotagliflozin—21 hours Sotagliflozin 3-O-glucoronide—19-26 hours
Urine	57%
Feces	37%
Mean oral clearance (CL/F)	260-370 L/h

Abbreviations: T_max, time to maximum concentration; Vd, volume of distribution; UGT1A9, UDP-glucuronosyltransferase family 1 member A9; CYP3A4, cytochrome P3A4; CL/F; meal oral clearance.

A single dose of 400 mg of sotagliflozin was 70% higher in those with mild renal impairment (eGFR 60-<90 mL/min/1.73 m²) and 170% higher in moderate renal impairment (eGFR 30-<60 mL/min/1.73 m²). ¹¹ There was a 3-fold increase in AUC in those with a Child-Pugh B score and a 6-fold increase with a Child-Pugh C score. ¹¹

Drug Interactions

The major metabolite of sotagliflozin is sotagliflozin 3-O-glucuronide, which can inhibit CYP3A4 and CYP2D6 while inducing CYP3A4. ¹¹ In addition, sotagliflozin can inhibit p-glycoprotein (P-gp) and the breast cancer resistance protein (BCRP). ¹¹ Sotagliflozin is a substrate of the organic anion transporter (OAT) 3, OAT polypeptides (OATP) 1B1, and OATP 1B3. ¹¹

Coadministration of sotagliflozin with hydrochlorothiazide, ramipril, metformin, mefenamic acid, and oral contraceptives do not result in clinically significant drug interactions. ¹¹ Exposure of digoxin may increase when coadministered with sotagliflozin; therefore, it is recommended to closely monitor digoxin levels during coadministration. ¹¹ Conversely, lithium concentrations decreased when coadministered with sotagliflozin, necessitating close monitoring of lithium during coadministration. ¹¹ Glucuronidation by UGT1A9 is a major metabolic pathway for sotagliflozin. Rifampin, an inducer of urindine 5’-diphospho-glucuronosyltransferase (UGT), has been shown to decrease the exposure of sotagliflozin when coadministered, leading to decreased efficacy. ¹¹

Clinical Trials

Phase 2 Trials

In phase 2 trials, of patients with T1 and T2DM, sotagliflozin was effective in reducing hemoglobin A_1c (HbA_1c), fasting plasma glucose (FBG), PPG, weight, and insulin requirements. Tolerability was largely similar to previously studied SGLT2i, with the exception of reports of GI upset. In trials of patients with T1DM, there were 2 reports of diabetic ketoacidosis (DKA), which were believed to be pump-related rather than study-drug related. These beneficial effects led to its investigation as an agent for T2DM in phase 3 clinical trials.^15,23-25

Phase 3 Trials

Sotagliflozin on Cardiovascular and Renal Events in Patients with Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk

The Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients with Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk (SCORED) Trial was a phase 3, randomized controlled trial investigating the CV effects of sotagliflozin compared with placebo in patients with T2DM, elevated CV risk, and CKD. ²⁶ Patients age ≥18 years old with a diagnosis of T2DM, CKD (GFR = 25-60 mL/min/1.73 m²), and elevated CV risk were eligible for inclusion. ²⁶ Patients were considered to have elevated CV risk if they had at least 1 major CV risk factor and were ≥18 years old or if they were ≥55 years old with ≥2 minor CV risk factors. ²⁶ Major risk factors included reduced EF (≤40%), left ventricular hypertrophy (LVH), elevated C-reactive protein (CRP) or brain natriuretic (BNP), and urine albumin-creatinine ratio (UACR) ≥300 mg/g. ²⁶ Minor risk factors included body mass index (BMI) ≥35 kg/m², dyslipidemia despite statin therapy, tobacco smoking, coronary artery calcium score between 100 and 300, hypertension despite antihypertensive therapy, and UACR between 30 and 300 mg/g. ²⁶ Participants were randomly assigned to receive placebo or sotagliflozin initiated at a dose of 200 mg once daily and increased to 400 mg once daily if tolerated. ²⁶ Preplanned coprimary endpoints were the first occurrence of a major adverse cardiovascular event (MACE) and first occurrence of death from CV causes or hospitalization for HF. ²⁶ Owing to loss of funding, the trial was shortened and the primary endpoint was adjusted to the total number of deaths from CV causes, HHF, and urgent visits for HF. ²⁶

A total of 10 584 participants were treated for a mean duration of 14.2 months. ²⁶ Participants were mostly white males with a median age of 69 years. ²⁶ Approximately 30% had a diagnosis of HF. Most patients with HF had an EF >50% (nearly 16%). Approximately 9.7% and 5.5% of patients with HF had an EF <40% and between 40% and 50%, respectively. ²³ The average EF was 60% in each group. Most patients were treated with a renin-angiotensin-aldosterone system (RAAS) inhibitor (88.9%), primarily an angiotensin-converting enzyme (ACE) or angiotensin receptor blocker (ARB) (87%). ²⁶ Approximately 15% were treated with a mineralocorticoid receptor antagonist (MRA) and 63% with a beta-blocker. ²⁶ Rates of treatments are not reported separately for HF by left ventricular ejection fraction (LVEF). Diabetes treatments in SCORED reflected standard of care at the time of the study; few patients were treated with a GLP1-receptor agonist (RA) (~6.0%). ²⁶

A total of 400 primary outcome events occurred in the sotagliflozin group, compared with 530 in the placebo group. Compared with placebo, treatment with sotagliflozin resulted in a statistically significant reduction in the primary composite outcome of death from CV causes, hospitalizations and urgent visits for HF (5.6 events/100 patient years vs 7.5 events/100 patient years; hazard ratio [HR] = 0.74, 95% confidence interval [CI] = 0.63-0.88, P < 0.001). ²⁶ A statistically significant reduction in HF hospitalization and urgent visits for HF was observed in the treatment group. ²⁶ No statistically significant difference in other secondary endpoints was observed, including deaths from CV causes. ²⁶ In subgroup analyses, GLP1-RA use impacted the primary outcome. ²⁶ A reduction in risk of the primary outcome occurred in patients not taking a GLP1-RA (HR = 0.75, 95% CI = 0.64-0.88), but not in those who were prescribed this class of medication (HR = 0.68, 95% CI = 0.33-1.40). ²⁶ Although definitive conclusions cannot be drawn from the subgroup analyses, differences in outcome based on GLP1-RA use are pertinent considering the established CV benefit of GLP1-RAs and recent data demonstrating the benefits of GLP1-RAs in patients with heart failure with preserved ejection fraction (HFpEF) and obesity. ²⁷

Owing to loss of funding, the intended follow-up duration was shortened, potentially impacting the ability to capture a significant number of events. Furthermore, adjustments were made to the primary endpoint, potentially affecting the study’s power to detect outcome differences. Owing to inability to complete event adjudication, investigator-defined endpoints were used, resulting in an overestimation of events.

SOLOIST-WHF

The SOLOIST-WHF trial was a phase 3 randomized placebo-controlled trial designed to evaluate the efficacy and safety of sotagliflozin after worsening heart failure, regardless of EF. ²⁸ It included patients 18 to 85 years of age with T2DM who were admitted to the hospital or had an urgent care or emergency department visit for worsening HF with evidence of volume overload. Patients also had to be receiving intravenous loop diuretics and had to have an HF diagnosis at least 3 months prior, have prior history of using oral loop diuretics. Patients with heart failure with reduced ejection fraction (HFrEF), defined as an EF of ≤40%, were required to be on background beta-blocker and RAAS inhibitors. Eligible participants who achieved clinical and hemodynamic stability were randomized to receive a starting dose of sotagliflozin 200 mg daily or placebo before or within 3 days after hospital discharge, with a max dose of 400 mg daily. ²⁸ Study enrollment was terminated early due to loss of funding and this led to a change in the original primary endpoint, modified to a total number of deaths from CV causes, HF hospitalizations, or urgent care encounters for HF. ²

A total of 1222 patients were included in the intent-to-treat analysis with a median follow-up of 9.2 months in the treatment arm. ²⁸ A majority of patients in the treatment arm were white and male with a mean age of 69 years. ²⁸ The median EF was 35% and a majority (79%) had an EF less than 50%, with about 59% of patients having HFrEF. Approximately 91% of trial participants had the New York Heart Association (NYHA) functional class of 2 to 3. ²⁸ With regard to baseline GDMT, approximately 82% of patients were on angiotensin-converting-enzyme inhibitor (ACEi) or ARB, 15% were on sacubitril-valsartan, 66% were on an MRA, and 93% were on a beta-blocker. About half of the patients in the sotagliflozin initiated therapy after discharge and the median time to initiation was 2 days post-discharge. ²⁸ There was a total of 600 primary endpoint events that occurred and the study did not meet the prespecified power calculation. There were 51% of patients in the sotagliflozin group compared with 76.3% in the placebo group that experienced CV death, HF hospitalizations, and urgent visits for HF (P < 0.001, HR = 0.67, 95% CI = 0.52-0.85). ²⁸ The CV mortality alone was not found to be statistically significant between the 2 groups (P = 0.36, HR = 0.84, 95% CI = 0.58-1.22). ²⁸ Overall, sotagliflozin was effective in preventing HF hospitalizations and urgent visits among clinically stable patients with T2DM after worsening HF. ²⁸ A post-hoc analysis of SOLOIST-WHF demonstrated that starting sotagliflozin soon before or at discharge was associated with reduced HF-related events at 30 and 90 days, and reduced all-cause mortality at 90 days, further underscoring the importance of avoiding delays in starting GDMT for HFrEF. ²⁹ However, the benefit of starting sotagliflozin during ADHF has yet to be explored. ⁸

Safety

In a dose finding study (n = 36), sotagliflozin was associated with gastrointestinal AEs, headaches, dysuria, and vulvovaginal pruritis. ¹⁵ Within the SCORED trial, the most common AEs that were statistically significant when compared with placebo were diarrhea (8.5% vs 6.0%, P < 0.001), DKA (0.6% vs 0.3%, P < 0.02), genital mycotic infections (2.4% vs 0.9%, P < 0.001), and volume depletion (5.3% vs 4.0%, P = 0.003). ²⁶ Similar AEs were reported within the SOLOIST-WHF trial. ²⁸ Compared with placebo, hypotension, diarrhea, genital mycotic infections, urinary tract infections, and hypoglycemia were more common within the sotagliflozin group. ²⁸ There were less incidences of acute kidney injury (AKI) within the sotagliflozin group. ²⁸ Although other AEs were reported, similar rates occurred between the 2 groups. ²⁸ Study discontinuation rates were 5.6% and 5.4% for the sotagliflozin and placebo group, respectively, in the SOLOIST trial, and 5.0% and 4.5% in the SCORED trial.^26,28 There was a small increase in serum creatinine and decrease in estimated glomerular filtration rate (eGRF) with initiation of sotagliflozin. ¹¹ These changes were noted within the first 4 weeks following initiation but stabilized regardless of baseline kidney function. ¹¹

Dosing and Administration

Sotagliflozin is available as 200 and 400 mg film coated tablet. ¹¹ The recommended starting dose is 200 mg tablet once daily, titrated every 2 weeks to 400 mg tablet once daily as tolerated. ¹¹ Sotagliflozin should be taken no more than 1 hour before the first meal of the day. ¹¹ Tablets should be swallowed whole and should not be crushed, chewed, or cut. ¹¹ In the SOLOIST-WHF study, 40% of sotagliflozin-treated patients were aged 65 to 74 years, and 29% were ≥ 75 years old.^11,28 Similarly, in the SCORED study, 47% were aged 65 to 74 years and 23% were ≥75 years old.^11,26 Although no overall efficacy differences were found between older and younger patients, it cannot be ruled out that some older individuals may have greater sensitivity in responses. ¹¹

No dose adjustments is recommended in patient with renal impairment; however, sotagliflozin was not studied in those with eGFR <25 mL/min/1.73 m² or on dialysis. ¹¹ In addition, sotagliflozin therapy was discontinued in those with eGFR <15 mL/min/1.73 m² or on chronic dialysis. ¹¹ No dose adjustment is recommended in those with mild hepatic impairment (Child-Pugh A), but a 3-fold to 6-fold increase in exposure was noted in those with moderate (Child-Pugh B) to severe (Child-Pugh C) hepatic impairment compared with patients without hepatic dysfunction. ¹¹

Warnings and Precautions

Those with T1DM should be informed that the use of sotagliflozin can increase the risk of life-threatening DKA, whereas T2DM is a risk factor for fatal ketoacidosis. ¹¹ Patients should also be monitored for precipitating factors for DKA. ¹¹

Symptoms of hypotension or acute but transient changes in serum creatinine caused by intravascular volume depletion are other potential AEs of sotagliflozin. ¹¹ Those with impaired renal function, eGFR <60 mL/min/1.73 m², elderly patients, or on loop diuretics should undergo close monitoring and assessment prior to initiating sotagliflozin. ¹¹

Serious urinary tract infections (UTIs), include urosepsis and pyelonephritis, have been reported with the use of SGTL2 inhibitors, including sotagliflozin.^11,30 A history of genital mycotic infections increases the likelihood of genital mycotic infection with sotagliflozin use. ¹¹ Fournier’s gangrene (FG), a serious and life-threatening necrotizing infection affecting the perineum, was also reported in postmarketing surveillance in diabetic patients with SGLTis.^11,30,31 Patients on sotagliflozin who present with pain, erythema, or swelling of the genital or perineal areas, signs and symptoms of infection, should be assessed immediately. Sotagliflozin and other SGLTis should not be retrialed in the case of FG.

Sotagliflozin when used in conjunction with insulin and insulin secretagogues can increase the risk of hypoglycemia. ¹¹ Lower dose of insulin or insulin secretagogues may be required to prevent hypoglycemia. ¹¹

Monitoring glucose level with 1,5-anhydroglucitol (1,5-AG) assay or via a urine glucose test is not recommended as it is unreliable in measuring glucose levels in those taking SGLT2 inhibitors due to its mechanism of action. ¹¹

Application to Clinical Practice

In clinical trials, sotagliflozin was shown to have an impact on select CV outcomes in patients with T2DM and CKD or HF. Although sotagliflozin significantly reduced HF hospitalizations and urgent visits in the SCORED and SOLOIST-WHF trials, its impact on reducing CV mortality in patients with T2DM and HF remains uncertain due to premature study discontinuation, subsequent study endpoint modifications, and limited applicability to the broader HF population.^26,28 Based on available clinical trial data, sotagliflozin may therefore be considered in patients with T2DM and chronic NYHA class II to III HF to reduce hospitalizations. However, results from the SOLOIST-WHF trial may not be generalizable to patients without T2DM due to study inclusion or with preserved ejection fraction (HFpEF) as only 21% of patients had an EF >50%. ²⁸ In contrast, other SGLTis, namely dapagliflozin and empagliflozin, have been studied across the EF spectrum in broader populations without T2DM across the EF spectrum. Table 3 reviews the landmark trials of comparable SGLT2 inhibitors in heart failure. Results from the ongoing Sotagliflozin in Patients HFpEF Patients without Diabetes (SOTA-P-CARDIA) trial will hopefully provide more insight on the role of sotagliflozin in HFpEF without DM (NCT 05562063). ³² The lack of clarity regarding sotagliflozin’s impact on renal outcomes also limits its adoption over other SGLT2is in a patient population who often suffers from multiple comorbidities such as CKD.

Table 3.

Summary of Phase 3 Landmark Trial Outcomes of SGLT2 Inhibitors in Heart Failure.

Trial	SGLT2i	HF population a	Primary composite endpoint	Primary endpoint, incidence rate in SGLT2i vs placebo groups; HR (95% CI)	CV mortality, incidence rate in SGLT2i vs placebo groups; HR (95% CI)
DAPA-HF 4	Dapagliflozin	EF ≤40% regardless of T2DM status	Hospitalization or urgent visit for HF, HF hospitalization, urgent HF visit, CV death	16.3% vs 21.2%; 0.74 (0.65-0.85)	9.6% vs 11.5%; 0.82 (0.69-0.98)
DELIVER 5	Dapagliflozin	EF >40% regardless of T2DM status		16.4% vs 19.5%; 0.82 (0.73-0.92)	7.4% vs 8.3%; 0.88 (0.74-1.05)
EMPEROR-Reduced 7	Empagliflozin	EF ≤40% regardless of T2DM status	HF hospitalization, CV death	19.4% vs 24.7%; 0.75 (0.65-0.86)	10.0% vs. 10.8%; 0.92 (0.75-1.12)
EMPEROR-Preserved 6	Empagliflozin	EF >40% regardless of T2DM status		13.8% vs 17.1%; 0.79 (0.69-0.90)	7.3% vs 8.2%; 0.91 (0.76-1.09)

Abbreviations: CV, cardiovascular; EF, ejection fraction; HF, heart failure; HR, hazard ratio; T2DM, type 2 diabetes mellitus.

^aAll studies included adults age 18 years or older and a New York Heart Association functional class of 2 to4.

In addition, although the average wholesale price of sotagliflozin is comparable to that of canagliflozin, dapagliflozin, and empagliflozin, its adverse effect profile differs substantially from these agents and has been associated with higher rates of severe hypoglycemia and diarrhea.^18-20,33 The potential for diarrhea may exacerbate the gastrointestinal distress caused by other preferred antidiabetic medications such as metformin and GLP1-receptor agonists and may make it challenging to manage volume status in HF. ³³

Conclusions

As clinicians work to initiate GDMT in HF, there are several factors that may make sotagliflozin less desirable than other SGLTi. Although the underlying rationale for dual SGLT inhibition may be promising from a mechanistic standpoint, it is difficult to determine the clinical significance of sotagliflozin in reducing adverse CV and renal outcomes in patients with HF, regardless of T2DM status and in patients with HFpEF. Sotagliflozin also carries an additional risk of diarrhea, an unfavorable consequence of dual SGLT2 inhibition. Given the availability of other SGLTis with stronger evidence for CV risk reduction and renal protection as well as better tolerability, in the absence of robust clinical trial data, sotagliflozin is not the ideal SGLTi for HF at this time.

Appendix

PubMed—run 12/01/2023

sotagliflozin OR inpefa^® OR zynquista^® OR “lx 4211” OR lx4211 OR “(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol” OR “(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol”[Supplementary Concept]

The Cochrane Library for clinical trials in CENTRAL—run 12/01/2023

sotagliflozin OR inpefa^® OR zynquista^® OR “lx 4211” OR lx4211 OR “(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol”

Embase via Elsevier—run 12/01/2023

“sotagliflozin”/exp OR sotagliflozin OR inpefa^® OR zynquista^® OR “(2s,3r,4r,5s,6r)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2h-pyran-3,4,5-triol” OR “2 [4 chloro 3 (4 ethoxybenzyl) phenyl] 6 (methylthio) tetrahydro 2h pyran 3, 4, 5 triol” OR “lp 802034” OR lp802034 OR “lx 4211” OR lx4211 OR “sar 439954” OR sar439954

Web of Science—All Databases—run 12/01/2023

sotagliflozin OR inpefa^® OR zynquista^® OR “lp 802034” OR lp802034 OR “lx 4211” OR lx4211 OR “sar 439954” OR sar439954 OR “(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol”