Meta‐analysis of sotagliflozin, a dual sodium‐glucose‐cotransporter 1/2 inhibitor, for heart failure in type 2 diabetes

Abstract

Sodium‐glucose co‐transporters (SGLTs) mediate sodium and glucose transport across cell membranes. SGLT2 inhibitors have a recognized place within heart failure (HF) guidelines. We evaluated the effect of sotagliflozin on HF and cardiovascular outcomes in participants with type 2 diabetes. Scopus, Medline, Embase and Central were searched from inception until 2 June 2023. Randomized controlled trials evaluating sotagliflozin in type 2 diabetes participants and reporting HF events were selected. Major adverse cardiovascular events (MACE) and systolic blood pressure were evaluated. The Cochrane risk of bias tool (RoB 2.0) was used. Pooled mean difference (MD), relative risk (RR), 95% confidence intervals and the number needed to treat (NNT) were estimated (PROSPERO: CRD42023432732). We selected nine studies (n = 15 320 participants: n = 8040 intervention and n = 7280 control). The median follow‐up was 13.4 months (Q1 = 13, Q3 = 21). One study recruited participants with HF at baseline. After a follow‐up of >52 weeks, sotagliflozin significantly reduced the risk of HF [n = 8 studies; RR = 0.66 (0.64, 0.69)], stroke [n = 6 studies; RR = 0.75 (0.58, 0.97)] and MACE [n = 8 studies; RR = 0.73 (0.66, 0.81)]. The NNT was 20 and 26 for HF and MACE, respectively. Sotagliflozin lowered systolic blood pressure [n = 7; MD = −2.38 mmHg (−2.79, −1.97)]. No dose‐dependent effect was identified for HF [200 mg: RR = 0.38 (0.16, 0.89), 400 mg: RR = 0.57 (0.39, 0.85), P‐value = 0.22]. The high risk of bias was a limitation of this review. Sotagliflozin reduced HF and cardiovascular events in type 2 diabetes participants. Research exploring its effects in HF and comparisons with SGLT2 inhibitors is warranted to determine if dual SGLT inhibition surpasses selective inhibition.

Introduction

Heart failure (HF), characterized by the inability of the heart to pump blood efficiently, ¹ affects 64 million people worldwide and significantly burdens healthcare systems. ² Despite advancements in the treatment of HF, there remains a critical need for novel therapeutic approaches to improve patient outcomes. ³ Sodium‐glucose co‐transporter 2 (SGLT2) inhibitors have emerged as a novel therapeutic approach in the management of HF. ³ The rationale for investigating SGLT inhibitors for HF stems from the dysregulation of glucose and sodium homeostasis observed in this condition and the maladaptive compensatory mechanisms that can lead to further disease progression.

Inhibition of SGLT2, predominantly expressed in the renal proximal tubules, reduces glucose reabsorption, leading to glycosuria. In addition to glucose‐lowering effects, SGLT2 inhibition exerts favourable cardiovascular effects by inducing osmotic diuresis, resulting in reduced plasma volume, and decreasing intravascular filling pressures. ⁴ This volume reduction is accompanied by decreased cardiac preload and afterload. Furthermore, SGLT2 inhibition attenuates myocardial fibrosis, reduces oxidative stress and improves myocardial energetics. ⁵ , ⁶ , ⁷ Additionally, they modulate the renin‐angiotensin‐aldosterone system and reduce sympathetic nervous system activity.

Sodium‐glucose co‐transporter 1 (SGLT1) inhibition provides additional benefits by delaying the absorption of glucose in the intestines. This may lead to higher levels of the natural hormone glucagon‐like peptide‐1 (GLP‐1), resulting in improved cardiovascular outcomes. ⁸ This improvement may be more pronounced with dual SGLT1/2 inhibitors compared with selective SGLT2 inhibitors ⁹ and attributed to enhanced functioning of cardiac energy production, ion regulation, promotion of autophagy and changes in the regulation of adipokines. ⁹ , ¹⁰

Sotagliflozin, a dual SGLT1/2 inhibitor, is a new therapy licensed by the Food and Drug Administration (FDA) for the management of HF, including HF with preserved ejection fraction and HF with reduced ejection fraction, in May 2023. ¹¹ Developed initially as a glucose‐lowering therapy, sotagliflozin inhibits SGLT1 in the intestine, thereby reducing glucose absorption, and SGLT2 in the kidneys, leading to increased urinary glucose excretion. The SOLOIST‐WHF trial ¹² demonstrated that sotagliflozin significantly reduced the risk of cardiovascular death, HF hospitalization and urgent HF visits in patients with worsening HF and in patients with type 2 diabetes mellitus (T2DM). ¹² Similarly, the SCORED trial ¹³ showed that sotagliflozin reduced the risk of cardiovascular death and hospitalization for HF in patients with chronic kidney disease and T2DM. ¹³ These effects align with the improved HF outcomes observed with SGLT2 inhibitors. ¹⁴

This systematic review aimed to evaluate the effects of sotagliflozin on HF outcomes in participants with T2DM. The primary outcome was to establish the effect of sotagliflozin on HF events. The secondary outcomes were to determine the impact of sotagliflozin on weight, systolic blood pressure (SBP) and major adverse cardiovascular events (MACE).

Methods

Data source and search strategy

Medline, Embase, Scopus and Central databases were searched from database inception until 2 June 2023 to identify relevant literature for this review. The search strategy, verified by a medical librarian, included the terms ‘sotagliflozin’, ‘type 2 diabetes mellitus’ and ‘randomized controlled trials’ (Appendix S1). This review adhered to the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) statement ¹⁵ and was registered with the International Prospective Register of Systematic Reviews (PROSPERO registration number: CRD42023432732).

Eligibility criteria

Phase II or III randomized controlled trials (RCTs) that recruited T2DM participants and reported on HF events were included in this review. The intervention of the RCTs was sotagliflozin or LX4211, compared with placebo or an SGLT2 inhibitor. If reports of the same trial were published at different endpoints, the reports referring to the longest follow‐up were included in this review. RCTs without a comparator—those that recruited participants aged under 18 years or under the legal age of majority (whichever was greater)—were excluded. Conference abstracts, preclinical studies, reviews and records not written in English were also excluded.

Data screening and extraction

All records identified by the search strategy were screened using the web‐based tool Rayyan ¹⁶ by two reviewers (M. A. B. and J. K.). Screening was undertaken by title and abstract initially and then by full text. In both stages, a third reviewer (R. M.) adjudicated disagreements. Data extraction was also performed in duplicate by two reviewers (R. M. and D. B. B.) and adjudicated by a third (P. S.), using a pilot‐tested extraction form that followed the population, intervention, comparator, outcome and study design format. Data were preferentially extracted from the published peer‐reviewed reports; however, if unavailable, the clinical trials registry was used.

Risk of bias (ROB) and certainty of evidence

The Cochrane risk of bias 2 (RoB 2) tool ¹⁷ was used to assess the quality of evidence in the included RCTs, according to the Cochrane Handbook for Systematic Reviews of Interventions. ¹⁸ Two independent reviewers (J. K. and R. T.) evaluated the ROB, and a third (R. M.) resolved discrepancies. ROB plots were created using the RobVis tool. ¹⁹ The certainty of the evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. ²⁰ Two reviewers (P. S. and D. B. B.) evaluated the certainty of the evidence independently, utilizing the GRADE profiler software (Version 3.6). ²¹ Any disagreements were resolved by a third reviewer (M. A. B.). RCTs without significant limitations were categorized as ‘high quality’. If limitations were present in terms of ROB, imprecision, inconsistency of results, indirectness of evidence or publication bias assessments, the quality was downgraded by one level (moderate quality) or two levels (low quality). The quality of the evidence was upgraded by one or two levels if a large effect size was observed. The scoring rubric used to assess the evidence was based on the GRADE handbook ²⁰ (Appendix S2).

Data analysis

The primary outcome was the risk of cardiac failure events, defined as the composite of HF, left ventricular failure, acute left ventricular failure, cardiac failure, cardiac failure acute, HF congestive and cardiac failure congestive. A detailed description of the definitions used by each RCT can be found in Appendix S3. The secondary outcomes were risk of myocardial infarction (MI), cardiovascular death and MACE (classical 3‐point composite of stroke, MI and cardiovascular death), as well as change in SBP (least squares means in mmHg) and weight (least squares means in kg) from baseline. Change in glycated haemoglobin (HbA1c) (least squares means in percentage) was also assessed.

Data synthesis and statistical analysis

The R project was employed to undertake the meta‐analyses using the package ‘meta’. A random‐effects model was used, with the effect measures modified using the Knapp–Hartung adjustment to reduce the potential for bias arising from within‐ and between‐study heterogeneity. The relative risk (RR) and corresponding 95% confidence interval (CI) were estimated for categorical outcomes using the Mantel and Haenszel approach and the Paule–Mandel method for establishing the τ ². The mean difference (MD) and corresponding 95% CI were estimated for continuous outcomes using the Hedges approach. The τ ² was calculated using the DerSimonian–Laird method.

Heterogeneity was investigated using the χ ² test on Cochrane's Q statistic, τ ² and I ². ¹⁸ It was determined to be insignificant, low, moderate or high if the I ² was 0%–25%, 25%–50%, 50%–75% and >75%, respectively. Publication bias was assessed by visually inspecting funnel plots of the examined outcomes. A significance level of ≤0.05 was used to determine statistical significance.

If outcome data were available for different doses or timeframes, the data corresponding to the highest dose and/or longest timeframe were chosen. Where outcome data were available for both active comparator and placebo, data corresponding to the placebo were used in the meta‐analysis to ensure homogeneity across all study comparators.

Deviations from protocol

Only two ¹² , ²² of the included studies examined the change in ejection fraction, and the reporting was inconsistent, limiting the potential for a comprehensive analysis. A narrative description of the findings related to this outcome can be found in Appendix S4. Furthermore, a subgroup analysis according to comparator was not achievable due to a lack of data. One study ²² used an active comparator without providing a comparison against a placebo. It was also the only study with a follow‐up duration of <52 weeks. It was thus excluded from the meta‐analysis to ensure the homogeneity of the data. MD was used instead of standardized mean difference (SMD) as the effect measure for continuous data to improve interpretation.

Results

A total of 676 records were identified from the search after record deduplication. A total of 630 reports were excluded at the abstract screening stage. Forty‐six full texts were reviewed, nine of which fulfilled our eligibility criteria and were included in this systematic review (Figure 1).

Figure 1.

PRISMA flow chart illustrating the study selection process for inclusion in this review.

Study characteristics

All included studies ¹² , ¹³ , ²² , ²³ , ²⁴ , ²⁵ , ²⁶ , ²⁷ , ²⁸ were double‐blinded RCTs (Table 1). Eight RCTs ¹² , ¹³ , ²³ , ²⁴ , ²⁵ , ²⁶ , ²⁷ , ²⁸ (89%) were phase 3 trials; one was phase 2 ²² (11%). The intervention was sotagliflozin monotherapy in seven RCTs ¹² , ¹³ , ²² , ²⁵ , ²⁶ , ²⁷ , ²⁸ (78%). One RCT ²⁴ (11%) administered to both the sotagliflozin and placebo arms metformin and a sulfonylurea. One RCT ²³ (11%) administered to both the sotagliflozin and placebo arms insulin glargine (with or without oral antidiabetic drugs).

Table 1.

Characteristics of studies included in this review, including details on administered interventions.

Study	Intervention			Control
	Dose (mg)	Sample size	Follow‐up (weeks)	Comparator	Sample size	Follow‐up (weeks)
NCT03315143 (SCORED‐CKD) 13	200/400	5292	125.6	Placebo	5292	128.6
NCT03521934 (SOLOIST‐WHF) 12	200/400	608	92.1	Placebo	614	93.9
NCT03242252 (SOTA‐CKD3) 27	200	263	58	Placebo	260	54
	400	264	60
NCT03242018 (SOTA‐CKD4) 26	200	92	55.3	Placebo	93	56.3
	400	92	56.1
NCT03066830 (SOTA‐SU) 24	400 a	253	79	Placebo a	254	79
NCT03332771 (SOTA‐GLIM) 25	200	160	52	Placebo	159	52
	400	318		Glimepiride b	318
NCT03285594 (SOTA‐INS) 23	200 c	141	54.7	Placebo c	144	55.7
	400 c	286	54.6
NCT03386344 (SOTA‐BONE) 28	200	125	104	Placebo	126	106
	400	125	104
NCT03462069 (Posch et al.) 22	400	21	8	Empagliflozin 25 mg	20	8

^a Metformin and sulfonylurea were administered as part of the intervention and control.

^b Titrated up to 6 mg.

^c Insulin glargine (with or without oral antidiabetic drugs) was administered as part of the intervention and control.

Five (56%) ¹² , ¹³ , ²⁶ , ²⁷ , ²⁸ studies used placebo only as the comparator; one (11%) study ²⁵ had two comparator arms: a placebo and a glimepiride arm; and one (11%) study ²² used empagliflozin as the comparator. One (11%) was a single‐centre study, ²² and eight ¹² , ¹³ , ²³ , ²⁴ , ²⁵ , ²⁶ , ²⁷ , ²⁸ (89%) were multi‐centre. The number of countries where the trial sites were located ranged from 4 to 44, including Europe (n = 9), Asia (n = 6), North America (n = 8), South America (n = 4), Africa (n = 1) and Oceania (n = 3) (Appendix S5). The duration, defined as the duration of time during which the outcome was assessed, ranged from 8 ²² to 130 ¹³ weeks. The median follow‐up was 58 weeks. Five (56%) RCTs included a dose‐finding component, ²³ , ²⁵ , ²⁶ , ²⁷ , ²⁸ evaluating the 200 and 400 mg doses.

Population characteristics

The pooled sample size of the included RCTs ¹² , ¹³ , ²² , ²³ , ²⁴ , ²⁵ , ²⁶ , ²⁷ , ²⁸ was 15 320 participants: 8040 (52.5%) in the sotagliflozin cohort and 7280 (47.5%) in the comparator cohort. There were no significant differences in the baseline variables between the intervention and control groups (Appendix S6, Table S1). Overall, 6779 (44%) of the participants were female: 3516 in the intervention group and 3263 in the control group. The age of the participants ranged from 58.6 to 69.6 years old in the intervention cohort and 59.8 to 70 years old in the comparator cohort. In the intervention group, 6640 (83%) participants were Caucasian, 376 (4.7%) were Black or African American and 433 (5.4%) were Asian (Appendix S6, Table S2). In the control cohort, 6049 (83%) were Caucasian, 379 (5.2%) were Black or African American and 539 (7.4%) were Asian.

Baseline HbA1c levels for the intervention and control groups ranged from 7.2% to 8.76% and 7.2% to 9.7%, respectively. Five of the studies reported estimated glomerular filtration rate (eGFR) at baseline. This ranged from 23.8 to 86.6 in the intervention group and 24.1 to 88.6 in the control group. ¹² , ¹³ , ²² , ²⁶ , ²⁷ Five studies reported the participants' use of renin‐angiotensin‐aldosterone system inhibitors. ¹² , ¹³ , ²² , ²⁶ , ²⁷ The proportion ranged from 69.6% to 100% in the intervention group and 82.8% to 100% in the control group. Four studies ¹² , ¹³ , ²⁶ , ²⁷ reported the participants' use of beta‐blockers, which ranged from 54.2% to 92.8% in the intervention cohort and 49.5% to 91.4% in the control cohort. Five studies ¹² , ¹³ , ²² , ²⁶ , ²⁷ reported the baseline body mass index (BMI) of the participants, which ranged from 30.3 to 32.4 kg/m² in the intervention group and 28.9 to 32.5 kg/m² in the control group. The average baseline values for SBP were comparable between the intervention and control groups.

ROB

The ROB assessment for composite HF events is summarized in Figure 2. Eight studies ¹² , ¹³ , ²³ , ²⁴ , ²⁵ , ²⁶ , ²⁷ , ²⁸ (89%) demonstrated a low ROB in relation to the randomization process. This was primarily attributed to the utilization of central interactive response technology for randomization. One study ²² did not provide explicit information about the randomization procedure, thereby raising some concerns about the potential for bias. All studies had a minimal risk of straying from the intended intervention.

Figure 2.

‘Traffic light’ plot of the domain‐level judgements for composite heart failure and bar plots of the distribution of risk‐of‐bias judgements within each bias domain.

Four studies ¹² , ²⁴ , ²⁶ , ²⁷ (44%) were identified as having a high ROB attributable to >5% of the missing data. Among these, two studies (22%) ²⁴ , ²⁶ imputed missing data as placebo allocation, deemed to introduce bias as it may not preserve the original treatment assignment. In contrast, five studies (55%) ¹³ , ²³ , ²⁵ , ²⁷ , ²⁸ utilized imputation by considering missing data as non‐responders to intervention, which was deemed acceptable. Bhatt et al. (2021) ¹³ and Bhatt et al. (2021) ¹² (22%) provided a missingness table, performed sensitivity analyses and discussed the potential impact of imputation on their findings, which were not considered to introduce bias.

GRADE

The summary of findings for the primary outcome of this review is provided in Table 2. The composite HF outcome was of moderate certainty. No publication bias was detected (Appendix S6, Figure S1).

Table 2.

Summary of findings for primary outcome composite heart failure.

Sotagliflozin compared with placebo in heart failure
Outcomes	No. of participants (studies)	Certainty of the evidence (GRADE)	Relative effect (95% CI)	Anticipated absolute effects
				Risk with placebo	Risk difference with sotagliflozin
Composite heart failure	14 158 (8 RCTs)	⨁⨁⨁◯ Moderate a , b	RR 0.66 (0.64, 0.69)	152 per 1000	52 fewer per 1000 (55 fewer to 47 fewer)

Note: The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). GRADE Working Group grades of evidence: high certainty = ⨁⨁⨁⨁: we are very confident that the true effect lies close to the estimate of the effect; moderate certainty = ⨁⨁⨁◯: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different; low certainty = ⨁⨁◯◯: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect; and very low certainty = ⨁◯◯◯: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of the effect.

Abbreviations: CI; confidence interval; GRADE, Grading of Recommendations, Assessment, Development, and Evaluation; RCTs, randomized controlled trials; RR, relative risk.

^a Fifty per cent of the studies received an overall ‘high’ risk of bias rating.

^b I ² = 0%.

Composite cardiac failure

Eight RCTs (89%) ¹² , ¹³ , ²³ , ²⁴ , ²⁵ , ²⁶ , ²⁷ , ²⁸ reported on the number of cardiac failure events (n = 14 158: n = 7227 sotagliflozin and n = 6931 placebo). All studies had a follow‐up duration of >52 weeks. The pooled risk ratio (RR) was 0.66 (95% CI: 0.64, 0.69). No heterogeneity was identified (I ² = 0%; Figure 3). No significant dose‐dependent response (Appendix S7, Figure S1) was identified (P‐value = 0.22). For the 200 mg group, the pooled RR was 0.38 (95% CI: 0.16, 0.89), whereas for the 400 mg group, it was 0.57 (95% CI: 0.39, 0.85). No statistical difference (P‐value = 0.99) was identified according to the ROB (Appendix S7, Figure S2). The number needed to treat for an additional beneficial outcome was 20.

Figure 3.

Forest plot for the risk of composite cardiac failure events of sotagliflozin compared with placebo. CI, confidence interval; RR, relative risk.

MACE

Eight ¹² , ¹³ , ²³ , ²⁴ , ²⁵ , ²⁶ , ²⁷ , ²⁸ RCTs (89%) reported on MACE (n = 14 159: n = 7228 sotagliflozin and n = 6931 placebo). The pooled RR was 0.73 (95% CI: 0.66, 0.81). No heterogeneity was identified (Appendix S7, Figure S3). No statistically significant differences were identified according to dose [200 mg: RR = 0.53 (0.05, 6.03), 400 mg: RR = 0.87 (0.44, 174), P‐value = 0.30] (Appendix S7, Figure S4). The number needed to treat for an additional beneficial outcome was 26.

A further analysis (Appendix S7, Figures S5–S10 and Table S1) was undertaken according to the individual MACE components to determine if any divergent trends would be identified. No significant reductions in the risk of MI [RR = 0.84 (95% CI: 0.64, 1.11)] and cardiovascular disease (CVD) death [RR = 0.90 (95% CI: 0.67, 1.21)] were identified; however, a reduction in stroke events was found [RR = 0.75 (95% CI: 0.58, 0.97)].

SBP

Seven ¹³ , ²³ , ²⁴ , ²⁵ , ²⁶ , ²⁷ , ²⁸ RCTs (78%) reported SBP as an outcome (n = 12 956: n = 6629 sotagliflozin and n = 6327 placebo). The pooled MD was −2.38 mmHg (−2.79, −1.97). No heterogeneity was observed (I ² = 0%) (Appendix S7, Figure S11). No significant statistical significance was identified by dose (Appendix S7, Figure S12) or duration of intervention (Appendix S7, Figure S13 and Tables S2 and S3).

Weight and glycaemic control

Seven ¹³ , ²³ , ²⁴ , ²⁵ , ²⁶ , ²⁷ , ²⁸ RCTs (78%) examined the change in body weight from baseline (n = 12 956: n = 6629 sotagliflozin and n = 6327 placebo) (Appendix S7, Figures S14–S16). The pooled MD was −1.17 kg (95% CI: −1.28, −1.07). No heterogeneity was identified (I ² = 0%). No statistically significant differences were found based on the dose or the duration of the intervention. Additionally, sotagliflozin was effective in reducing HbA1c [MD = −0.45% (95% CI: −0.67, −0.24)] (Appendix S7, Figures S17 and S18 and Table S2).

Adverse events

All RCTs ¹² , ¹³ , ²² , ²³ , ²⁴ , ²⁵ , ²⁶ , ²⁷ , ²⁸ reported data on serious adverse events (n = 15 320: n = 8040 intervention and n = 7280 control): 1750 (21.8%) in the intervention group versus 1882 (25.9%) in the comparator group. Non‐serious adverse events were also reported by all RCTs: 1453 (18.1%) in the intervention group and 1346 (18.5%) in the control group (Appendix S7, Table S4).

Discussion

This systematic review and meta‐analysis of nine RCTs ¹² , ¹³ , ²² , ²³ , ²⁴ , ²⁵ , ²⁶ , ²⁷ , ²⁸ evaluated sotagliflozin on HF outcomes in participants with T2DM. The results demonstrated a reduction in the risk of composite HF events, stroke and MACE by 34%, 25% and 27%, respectively. Significant reductions in weight and SBP were also noted.

These results are consistent with findings from landmark clinical trials of SGLT2 inhibitors in HF, EMPEROR‐Reduced ²⁹ and DAPA‐HF, ³⁰ which demonstrated a reduction in the risk of cardiovascular death and HF of 31% and 25%, respectively. SGLT1/2 inhibition was superior to selective SGLT2 inhibition, according to a frequentist meta‐analysis, which demonstrated a decreased hazard rate of MI and stroke with SGLT1/2 inhibitors. ⁹ The superior cardiovascular benefits may be related to SGLT1 inhibition by both direct and indirect pathways (Figure 4).

Figure 4.

Simplified diagrammatic illustration of the heart benefits related to SGLT1 inhibition by both direct and indirect pathways. Direct: SGLT1 inhibition may reduce the hyperglycaemia‐induced generation of reactive oxygen species (ROS) in myocardial cells, matrix metalloproteinases (MMP) in cardiac fibroblasts and toxic calcium accumulation in myocardial cells. Indirect: Antihypertensive, diuretic and natriuretic effects by increased renal glucose excretion and weight‐loss properties by an increase in glucagon‐like peptide‐1 (GLP‐1) and short‐chain fatty acids (SCFA). BP, blood pressure; SGLT, sodium‐glucose co‐transporter. Created by BioRender®.

Furthermore, the results reported in this study reflect those of a previous meta‐analysis conducted by Avgerinos et al. ³¹ They showed that sotagliflozin reduced the incidence of HF by 32% [odds ratio (OR) = 0.68, 95% CI: 0.58, 0.79] and of MI by 28% (OR = 0.72, 95% CI: 0.54, 0.97). They did not, however, identify a significant difference in the incidence of stroke (OR = 0.73, 95% CI: 0.52, 1.01). Moreover, the primary outcome of our meta‐analysis was HF events, whereas for the meta‐analysis by Avgerinos et al., it was a change in HbA1c. ³¹ This enabled us to perform a GRADE assessment on the HF outcome and supplement our evaluations of sotagliflozin's effects on HF events with a certainty of evidence grade. As the impact of sotagliflozin on cardiac events was our main focus, we undertook additional analyses, determining that the number needed to treat was 20 and 26 for HF and MACE, respectively. We also identified that the effects of sotagliflozin on HF events, MI, stroke, cardiovascular death and MACE were not dose dependent. Lastly, our analysis indicated a significantly lower risk of MACE in the sotagliflozin cohort (RR = 0.73, 95% CI: 0.66, 0.81). The primary benefit of evaluating MACE, in addition to its individual components, was to increase the statistical power of the analysis, allowing for the detection of differences that may not reach significance when assessing individual endpoints. ³²

SGLT1 is expressed in the small intestine, late proximal tubule of the kidneys, heart, pancreatic alpha cells, liver, lung and skeletal muscle. ³³ In healthy individuals, SGLT1 expression is limited. In contrast, in those with uncontrolled T2DM or patients on SGLT2 inhibitors, SGLT1 transporters become up‐regulated. ³⁴ Cardiac SGLT1 up‐regulation has also been noted in the hearts of diabetic patients, as well as patients with end‐stage cardiomyopathy secondary to T2DM and T2DM mouse models. ³⁵ This is hypothesized to be due to free fatty acid‐induced insulin resistance. ³⁶ Furthermore, SGLT1 mediates the cardiac insulin‐dependent inotropic effects. ³⁷

SGLT1 has been implicated in hyperglycaemia‐induced generation of reactive oxygen species in myocardial cells and is believed to play a crucial role in raised ischaemic cell death observed in both HF and ischaemia/reperfusion injuries. ³⁴ Additionally, it has been suggested that SGLT1 worsens ischaemic cardiac outcomes by being responsible for sodium influx in myocardial and cerebral neuronal cells, leading to the toxic accumulation of calcium. ³⁴ Furthermore, SGLT1 inhibition may protect against the development of diabetic cardiomyopathy by inhibiting the hyperglycaemia‐induced expression of matrix metalloproteinases in cardiac fibroblasts. ³⁸ It can also reduce the availability of glucose substrates in cardiac myocytes, leading to a decline in the inotropic effects. ³⁷ Therefore, the need for dual SGLT1 and SGLT2 inhibition for the optimized treatment of cardiac pathologies becomes apparent.

The ability of sotagliflozin to induce weight loss and lower blood pressure may contribute to its overall cardiovascular benefits, similar to SGLT2 inhibitors, ¹³ , ¹⁴ , ³⁹ as excessive body weight and hypertension are common comorbidities in patients with HF. ⁴⁰ The antihypertensive properties of sotagliflozin stem from its effects on the kidneys. During normal conditions, the kidney's proximal convoluted tubule reabsorbs 80%–90% of the filtered glucose through SGLT2, with the remaining glucose being reabsorbed downstream by SGLT1. ⁴¹ When SGLT2 is inhibited, just 30%–40% of the filtered glucose is excreted in the urine, ⁴¹ as SGLT1 is capable of functioning in a compensatory capacity and reabsorbing up to 40% of glucose that failed to be reabsorbed upstream. ⁴² Thus, with dual SGLT1/2 inhibition, a higher proportion of glucose is excreted in the urine, resulting in a superior diuretic and natriuretic effect compared with selective SGLT2 inhibition. ⁴³ Consequently, blood pressure is reduced, which enhances preload and afterload and optimizes ventricular load conditions. ⁴³

The weight‐loss properties of sotagliflozin are also noteworthy. Inhibiting SGLT1 in the small intestine reduces glucose and galactose absorption and leads to calorie wasting. ⁴⁴ , ⁴⁵ It also reduced the gastric inhibitory peptide release ⁴⁶ and improved GLP‐1 and peptide YY, ⁴⁷ which were shown to be beneficial in managing weight. ⁴⁶ Overall, it delays intestinal glucose absorption postprandially, which is a recognized cardiovascular risk. ⁴⁸ Additionally, higher availability of glucose in the intestines can become available for the gut microbiota, enhancing the production of short‐chain fatty acids, which may potentiate prolonged GLP‐1 secretion and have an active role in the pathophysiology of HF. ⁴⁹ , ⁵⁰

Overall, the most likely modification of underlying pathophysiology in HF is attributed to a multifaceted interplay of factors affecting the heart, kidneys, vasculature and the entire body. ⁵¹ Direct cardiac benefits ³⁴ , ³⁸ , ⁵¹ encompass enhanced energy metabolism, reduced inflammation, improved cardiac remodelling, decreased ischaemia/reperfusion injury, improved autophagy and lysosomal degradation, Na⁺/H⁺ exchange inhibition, decreased oxidative stress and reduced epicardial fat mass. Renal ⁴¹ , ⁴² , ⁵¹ advantages include elevated natriuresis/diuresis, glucosuria leading to decreased blood glucose, reduced hyperuricaemia, Na⁺/H⁺ exchange inhibition and improved energy metabolism. Direct benefits to the vasculature ¹³ , ⁴³ , ⁵¹ are attributed to decreased inflammation and blood pressure, increased pro‐vascular progenitor cells and improved vascular function. Overall systemic benefits ¹³ , ⁴⁵ , ⁴⁶ , ⁴⁹ involve increased weight loss, sympathetic nervous system inhibition and elevated erythropoietin. Collectively, these factors work together to modify the fundamental pathophysiology of HF. ⁵¹

Sotagliflozin was approved by the FDA as an HF treatment in May 2023. ¹¹ The outcomes of this study suggest that sotagliflozin is as effective, if not more effective, than the SGLT2 inhibitors currently in practice. Nonetheless, it is imperative to address financial considerations prior to the widespread implementation of a new intervention. Patients with type 2 diabetes on sotagliflozin as part of the SOLOIST‐WHF trial ¹² gained an average of 0.51 quality‐adjusted life years (QALYs). Over the patients' lifetime, this would be equivalent to 4.43 QALYs, an addition of 0.39 QALYs, for an incremental cost‐effectiveness ratio (ICER) of $75 510 per QALY gained. ⁵² For comparison and contextualization, in a simulated cohort based on the DAPA‐HF trial, ³⁰ adding dapagliflozin to guideline‐directed therapy improved quality‐adjusted survival by 0.63 QALYs at a lifetime cost of $42 800 for $68 300 per QALY gained compared with patients on guideline‐directed therapy alone. ⁵³ These findings highlight the complex interplay between clinical efficacy and cost‐effectiveness in healthcare decision‐making, underscoring the challenges faced in balancing clinical benefits with affordability. This study encourages ongoing research to identify interventions that achieve optimal patient outcomes while addressing economic realities.

Moreover, treatment recommendations according to individual patient cohort characteristics should be encouraged. Notably, SGLT2 inhibitors have been reported to be more efficacious in Black participants. This may be due to the predisposition of Black patients to volume retention, which may result from altered renal sodium handling. A higher tendency for increased sodium retention has been associated with adverse HF outcomes. ⁵⁴ As such, incorporating SGLT1 inhibition may enhance the positive outcomes associated with the natriuretic effect of SGLT2 inhibitors further by reducing intestinal sodium absorption. It is crucial to recognize that the representation of Black participants in the included studies was limited, accounting for 4.7% (n = 658) of the overall sample. This proportion significantly underrepresents the Black cohort, highlighting the need for improved diversity and inclusion in research studies. Further research is warranted to explore the effect of sotagliflozin in this patient group, considering the prevalence, ⁵⁵ clinical outcomes ⁵⁶ and existing disparities ⁵⁷ , ⁵⁸ in the management of HF in Black patients.

Females are another cohort of patients for which disparities in HF management have been identified. ⁵⁹ In our study, 44% of the participants were female. Differences in sex hormones ⁶⁰ and genes related to hypertension development between men and women ⁵⁹ have resulted in the recommendation that cardiovascular outcomes ought to be examined by sex. ⁵⁹ Despite the cardiovascular benefits of SGLT2 inhibitors identified to be more pronounced in males in a recent review, ⁶¹ none of the studies included in this review conducted a sex‐based analysis. This underscores that further work is needed to encourage the research community to acknowledge potential disparities in treatment responses based on sex.

The safety profile of sotagliflozin also needs to be considered. Meta‐analyses demonstrated that sotagliflozin increased the risk of genital mycotic infections [RR = 2.83 (95% Cl: 2.04, 3.93)] ⁶² and genital infections [OR = 3.01 (95% CI: 2.18, 4.16)] ³¹ in T2DM participants. This is consistent with the mechanism of action of renal SGLT inhibition, which leads to a hyperglycaemic environment in the genitourinary tract that is conducive to microorganism growth. Additionally, it is hypothesized that glucosuria may impact local immune defences in the genitourinary system, increasing susceptibility to infections. ⁶³ Other significant adverse reactions identified in meta‐analyses were diarrhoea (44% ⁶² to 47% ³¹ higher risk compared with placebo) and volume depletion (25% ⁶² to 26% ³¹ higher risk compared with placebo). These gastrointestinal side effects may be associated with the inhibition of intestinal SGLT1, resulting in higher concentrations of osmotically active glucose and galactose in the gastrointestinal tract. ⁶² , ⁶⁴

Limitations were identified for this review. This study included only English‐language papers, potentially leading to the oversight of relevant records written in other languages. Additionally, the terms comprising the composite HF outcome varied across studies. The RCTs also lacked adequate information regarding the evaluations undertaken to diagnose and define an HF event. Moreover, the RCTs neglected to report crucial details, such as the change in ejection fraction. Furthermore, the two trials that compared sotagliflozin with active comparators were excluded from the meta‐analysis. ²² , ²⁵ The lack of comparison with an active comparator further restricts the generalizability of the findings, also indicting that more head‐to‐head trials are needed to gain a comprehensive understanding of the clinical application of dual compared with selective SGLT2 inhibitors. Two RCTs ²³ , ²⁴ administered antidiabetic drugs to both the intervention and control cohorts. Consequently, outcomes derived from these RCTs may be due to the concurrent use of medication, which could enhance or obscure the effects of the intervention, rather than the intervention itself. Furthermore, the eligibility criteria employed in this systematic review did not impose restrictions according to follow‐up duration. This could introduce heterogeneity into the systematic review, with different follow‐up durations potentially leading to diverse outcomes. However, by excluding the trial ²² with a follow‐up period of <52 weeks, we aimed to enhance the internal validity and overall robustness of the systematic review. Another concern involves the small sample sizes and limited events in seven ²² , ²³ , ²⁴ , ²⁵ , ²⁶ , ²⁷ , ²⁸ of the included RCTs. Nonetheless, their inclusion serves to mitigate publication bias and facilitates the incorporation of a more diverse array of study designs, populations, interventions and the identification of less common outcomes and rare adverse events. Lastly, there is a possibility of outcome bias as one of the studies included participants with HF. ¹²

Conclusions

Sotagliflozin demonstrated its efficacy by significantly reducing the risk of HF events and MACE in patients with T2DM. Accompanying these cardiovascular advantages, there has been a consistent decline in weight and SBP, reinforcing its metabolic efficacy. While these results underscore the potential of sotagliflozin as a pivotal therapeutic option for HF management in patients with T2DM, it is crucial to pursue further studies focusing on long‐term follow‐ups. These would not only establish its optimal use and long‐term safety profile but also determine if the risk reduction achieved with dual SGLT inhibition surpasses that of selective SGLT2 inhibition. Based on the outcomes of this study, we have confidence that sotagliflozin is as effective, if not more effective, than the SGLT2 inhibitors currently in practice.

Conflict of interest statement

Authors MAB, JP, PS, RT, DBB, JK and RM have no relevant financial or non‐financial interests to disclose. Author SP declares the following activities/interests, which may be considered potential competing interests: AstraZeneca lecture fees and Napp Pharmaceuticals lecture fees.

Supporting information

Appendix S1. Search Strategy.

Appendix S2. Grade quality assessment rubric.

Appendix S3. Composite heart failure breakdown.

Appendix S4. Analysis for change in Ejection Fraction.

Appendix S5. Location for RCT sites.

Appendix S6. Population characteristics and publication bias.

Appendix S7. Meta‐analysis outcomes.

Bantounou, M. A. , Sardellis, P. , Plascevic, J. , Awaes‐Mahmood, R. , Kaczmarek, J. , Black Boada, D. , Thuemmler, R. , and Philip, S. (2025) Meta‐analysis of sotagliflozin, a dual sodium‐glucose‐cotransporter 1/2 inhibitor, for heart failure in type 2 diabetes. ESC Heart Failure, 12: 968–979. 10.1002/ehf2.15036.

Data availability statement

The data are available upon reasonable request via contact with the corresponding author.