“Is sotagliflozin a ‘wonder drug’? A review of its impact on cardiovascular, diabetic, renal, neuroprotective, and hepatic outcomes”

Abstract

Heart failure (HF) and diabetes mellitus frequently co-occur, with an incidence of HF among diabetics ranging from 9% to 22%. Clinical research underscores that shared pathophysiological pathways link these conditions, driving advancements in therapeutic strategies that target neuro-hormonal modulation and sodium-glucose co-transporter 2 (SGLT2) inhibition. The SOLOIST-WHF and SCORED trials highlighted the efficacy of sotagliflozin, a dual sodium-glucose co-transporters 1/2 (SGLT1/2) inhibitor, in patients with HF and chronic kidney disease (CKD), demonstrating reductions in cardiovascular mortality and HF-related hospitalizations. Trials with other SGLT2 inhibitors, like dapagliflozin and empagliflozin, in HF, diabetes, and renal disease also showed significant reductions in major adverse cardiovascular events, hospitalizations, and improved kidney function. Furthermore, SGLT2 inhibitors have shown neuroprotective effects, potentially benefiting patients with Alzheimer’s and Parkinson’s diseases. Dual SGLT1/2 inhibitors, by targeting glucose transport in the renal and intestinal systems, not only reduce blood glucose but also improve insulin sensitivity, weight loss, and cardiovascular health. Sotagliflozin specifically impacts postprandial glucose absorption, mitigating the risks of hypoglycemia and hyperglycemia-related complications. In diabetic CKD, SGLT inhibitors promote renal protection by reducing glucose reabsorption, diuresis, and systemic inflammation. Neuroprotective effects of these agents, including reduced oxidative stress and inflammatory markers, show promise in treating neurodegenerative diseases. While adverse effects like hypoglycemia and ketoacidosis remain concerns, tailored dosing, and monitoring strategies may mitigate these risks. Thus, SGLT inhibitors, especially dual inhibitors like sotagliflozin, offer broad therapeutic benefits in diabetes, HF, CKD, and potentially neurological conditions.

Introduction

The incidence of heart failure in patients with diabetes is between 9% and 22% with the incidence even higher in patients above the age of 60, and the recent clinical trials have attributed this striking coincidence with the shared pathophysiology of heart failure and diabetes[1]. The prevalence of type 2 diabetes mellitus (T2DM) increased significantly by 147% from 1990 to 2019 across 38 Organization for Economic Co-operation and Development countries, with Luxembourg (439%) and Ireland (411%) showing the highest incidence rates. In 2019, T2DM accounted for 2.67% of all-cause deaths, highlighting its growing public health burden[2]. There are numerous different types of antidiabetic drugs including metformin, sulfonylureas such as glipizide and glyburide, meglitinides such as nateglinide and repaglinide, alpha-glucosidase inhibitors such as acarbose, miglitol, amylin analogs such as pramlintide, dipeptidyl dipeptidase inhibitors such as sitagliptin and saxagliptin, insulin, SGLT-2 inhibitors such as dapagliflozin, empagliflozin and sotagliflozin, thiazolidinediones such as pioglitazone, and incretin mimetics such as exenatide and liraglutide[3]. With the advancement of neurohormonal modulation techniques, there has been a tremendous increase in the favorable outcomes in various cardiovascular abnormalities, including heart failure, diabetes, and renal insufficiency with the results of large randomized-controlled trials adding to the practice of evidence-based medicine[4]. The SOLOIST-WHF and SCORED trials established positive results for sotagliflozin in patients with heart failure and chronic kidney disease with T2DM[5]. Sotagliflozin, a dual inhibitor of sodium-glucose co-transporters 1 and 2 (SGLT1 and SGLT2) is effective in managing blood glucose levels in diabetic individuals by reducing glucose absorption in the intestines and enhancing glucose excretion through the kidneys. In terms of efficacy, sotagliflozin has demonstrated non-inferiority to other SGLT2 inhibitors such as empagliflozin in reducing HbA1c levels and has also been proven to be superior to placebo in glycemic control[6]. The SCORED trial found that sotagliflozin reduced the risk of cardiovascular death and hospitalization due to heart failure, demonstrating benefits beyond glycemic control[7]. With regard to safety, it has been shown that sotagliflozin has a lower risk of hypoglycemia as compared to empagliflozin and placebo[6]. Moreover, a meta-analysis has shown that sotagliflozin was associated with marked reduction in albuminuria and slower decline in estimated glomerular filtration rate (eGFR), showcasing its potential renal protective effects[8]. With the emerging evidence on the efficacy of dual SGLT1/2 inhibitors and the selective SGLT2 inhibitors, we formulated a research narrative to explore the superior efficacy of sotagliflozin in light of published literature in terms of cardiovascular, diabetic, renal, and neuroprotective outcomes.

Highlights.

• Sodium-glucose co-transporter 2 (SGLT2) inhibitors reduce cardiovascular mortality and hospitalizations.

• SGLT2 inhibitors reduce major adverse cardiovascular events.

• Sotagliflozin improves glycemic control, reduces HbA1c, and offers weight reduction.

• SGLT2 and dual sodium-glucose co-transporters 1/2 inhibitors show nephroprotective and neuroprotective effects.

Cardiovascular outcomes

Heart failure stands as a prominent global health concern, impacting over 50 million individuals worldwide. Despite considerable advancements in its treatment, patients diagnosed with heart failure confront a notably poor prognosis and experience a diminished quality of life. Additionally, it remains the predominant cause of hospitalization among the elderly demographic[9]. Diabetes significantly increases the risk of cardiovascular diseases due to chronic hyperglycemia and insulin resistance, leading to several complications such as atherosclerosis, hypertension, diabetic cardiomyopathy, endothelial dysfunction, and autonomic neuropathy[10]. SGLT2 dual SGLT 1/2 inhibitors represent a pharmacotherapeutic class characterized by their dual capacity to regulate glucose levels and regulate cardioprotective effects.

SGLT2 inhibitors function by blocking the SGLT2 protein, responsible for glucose reabsorption in the renal tubules, thereby augmenting urinary glucose excretion and subsequently reducing blood glucose concentrations. Beyond glycemic modulation, SGLT2 inhibitors manifest additional cardioprotective attributes through diverse mechanisms[11]. A pivotal mechanism involves the attenuation of sodium-hydrogen exchange (NHE) activity in cardiomyocytes. SGLT2 inhibitors downregulate NHE activity, a process integral to sodium homeostasis with potential implications for blood pressure reduction[12]. Furthermore, these inhibitors enhance cardiac energetics by promoting the myocardium’s utilization of ketones as a substrate, thereby enhancing efficiency and diminishing workload[13]. Additionally, SGLT2 inhibitors exert anti-inflammatory effects systemically, including within cardiac tissues, thereby conferring protection against putative damage[14]. Renal hyperfiltration, implicated in renal impairment, may also be mitigated by SGLT2 inhibitors, contributing to overall cardiovascular health^[15,16^].

Crucially, clinical trials substantiate the cardioprotective efficacy of SGLT2 inhibitors. The EMPA-REG OUTCOME trial demonstrated a reduction in major adverse cardiovascular events (MACE) with empagliflozin. The trial also reported a lower incidence of death from any cause or hospitalization due to heart failure^[17,18^]. Similarly, the CANVAS trial exhibited that patients treated with canagliflozin showed a lower risk of MACE and hospitalization due to heart failure[18]. The DECLARE-TIMI 58 trial showed that dapagliflozin was non-inferior to placebo in terms of MACE as compared to placebo. It did, however, result in a lower rate of hospitalization for heart failure[19]. The CREDENCE trial for canagliflozin demonstrated decreased risks of end-stage kidney disease, hospitalization due to heart failure, and MACE in patients with T2D and chronic kidney disease[20].

Furthermore, dedicated trials such as DAPA-HF and EMPEROR-Reduced underscore the efficacy of dapagliflozin and empagliflozin in reducing heart failure hospitalization and cardiovascular mortality in patients with reduced ejection fraction^[21,22^]. SGLT1/2 dual inhibitors, concurrently inhibiting both SGLT1 and SGLT2 proteins, confer additional advantages. Apart from glycemic control and shared mechanisms with SGLT2 inhibitors, they enhance insulin sensitivity and induce weight loss, thereby reducing cardiovascular risk. Dual SGLT1/2 inhibitors have demonstrated efficacy in reducing oxidative stress, a process implicated in cellular damage and cardiovascular pathogenesis. Additionally, these inhibitors reduce inflammation and fibrosis through SGLT1 inhibition, thereby mitigating the scarring of cardiac tissue associated with heart failure[23].

Sotagliflozin, a dual inhibitor of SGLT1/2, demonstrated promising efficacy in the SOLOIST-WHF trial. It exhibited a substantial reduction in the incidence of cardiovascular events and improvements in heart failure outcomes among individuals diagnosed with T2D and experiencing recent exacerbation of heart failure. In T2D patients recently hospitalized for worsening heart failure, a noteworthy decrease in the frequency of cardiovascular fatalities, hospitalization, and urgent visits related to heart failure was observed compared to a control cohort over a median follow-up period of 9 months[24]. In the SCORED trial, the SGLT1/2 inhibitor sotagliflozin exhibited a reduced likelihood of cardiovascular deaths, and heart failure hospitalizations when compared to the placebo[25]. Table 1 provides a detailed overview of the key clinical trials investigating the cardiovascular effects of SGLT2 inhibitors and dual SGLT1/2 inhibitors, elucidating their impact on outcomes such as cardiovascular mortality, MACE, heart failure hospitalization, and other pertinent endpoints.

Table 1.

Overview of the key clinical trials investigating the cardiovascular effects of SGLT2 inhibitors and dual SGLT1/2 inhibitors, and their impact on outcomes such as cardiovascular mortality, major adverse cardiovascular events (MACE), and heart failure hospitalization

Title	Year	Trial	Drug	Results of cardiovascular outcomes
Canagliflozin and renal outcomes in type 2 diabetes and nephropathy	2019	CREDENCE[20]	Canagliflozin	Dapagliflozin demonstrated a reduced risk of MACE and hospitalization due to heart failure as compared to placebo
Canagliflozin and cardiovascular and renal events in type 2 diabetes	2017	CANVAS[18]	Canagliflozin	Dapagliflozin demonstrated a reduced risk of MACE and hospitalization due to heart failure as compared to placebo
Dapagliflozin in patients with heart failure and reduced ejection	2019	DAPA-HF[21]	Dapagliflozin	Dapagliflozin demonstrated a reduced risk of combined outcome of worsening heart failure or death from cardiovascular causes as compared to placebo
Dapagliflozin in patients with chronic kidney disease	2020	DAPA-CKD[26]	Dapagliflozin	Dapagliflozin demonstrated a reduced risk of combined outcome of death from cardiovascular causes or hospitalization due to heart failure as compared to placebo
Dapagliflozin and endurance cardiovascular outcomes in type 2 diabetes	2019	DECLARE-TIMI 58[19]	Dapagliflozin	Dapagliflozin demonstrated a reduced risk of combined outcome of cardiovascular death or hospitalization due to heart failure but was non-inferior to Placebo in terms of MACE
Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction	2022	DELIVER[27]	Dapagliflozin	Dapagliflozin demonstrated a reduced risk of worsening heart failure events and cardiovascular deaths as compared to placebo
Cardiovascular and renal outcomes with empagliflozin in heart failure	2020	EMPEROR-Reduced[22]	Empagliflozin	Empagliflozin demonstrated a reduced risk of combined outcome of cardiovascular death or hospitalization due to heart failure as compared to placebo
Empagliflozin in patients with chronic kidney disease	2023	EMPA-KIDNEY[28]	Empagliflozin	Empagliflozin demonstrated a reduced risk of combined outcome of cardiovascular death or hospitalization due to heart failure compared to placebo
Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes	2020	EMPA-REG OUTCOME[17]	Empagliflozin	Empagliflozin demonstrated reduced risk of MACE and combined outcome of death from any cause or hospitalization due to heart failure
Empagliflozin in heart failure with a preserved ejection fraction	2021	EMPEROR-Preserved[29]	Empagliflozin	Empagliflozin demonstrated a reduced risk of combined outcome of cardiovascular death or hospitalization due to heart failure as compared to placebo
Cardiovascular outcomes with ertugliflozin in type 2 diabetes	2020	VERTIS-CV[30]	Ertugliflozin	Ertugliflozin demonstrated non-inferiority to placebo in terms of major adverse cardiovascular events (MACE)
Sotagliflozin in patients with diabetes and recent worsening heart failure	2021	SOLOIST-WHF[24]	Sotagliflozin	Sotagliflozin demonstrated a reduced risk of cardiovascular deaths, hospitalizations and urgent visits for heart failure as compared to placebo
Sotagliflozin in patients with diabetes and chronic in disease	2021	SCORED[25]	Sotagliflozin	Sotagliflozin demonstrated reduced risk of the combined outcome of cardiovascular deaths, hospitalizations due to heart failure, and urgent visits for heart failure as compared to placebo

In addition to Randomized Controlled Trials, a network meta-analysis conducted by Teo et al[31], comparing SGLT2 inhibitors to dual SGLT1/2 inhibitors unveiled a lower risk for stroke and myocardial infarction by the use of SGLT1/2 inhibitors as compared to SGLT2 inhibitors. But SGLT1/2 inhibitors showed an increased risk of diarrhea and hypoglycemia[31]. These findings collectively underscore the promising therapeutic example presented by both dual SGLT1/2i and SGLT2i for managing cardiac risks in individuals with T2D. Their cardioprotective effects arise from a confluence of mechanisms, including diminished NHE, enhanced cardiac energetics, reduced inflammation, heightened insulin sensitivity, and weight loss. Consistent findings from clinical trials affirm the efficacy of these agents, reinforcing their role in cardiovascular risk reduction.

Diabetic outcome

Diabetes presents a formidable challenge to global healthcare services, as highlighted in the International Diabetes Federation Diabetes Atlas (2021). The prevalence of diabetes is substantial, affecting 10.5% of the adult population (20–79 years), with a rising trend. Among the 537 million individuals diagnosed with diabetes, 90% are classified as having T2DM. Projections indicate that by 2045, approximately one in eight adults worldwide will be living with diabetes[32]. Given the escalating prevalence and associated morbidity and mortality, the imperative to choose effective, low-side-effect treatments is evident.

Numerous U.S. Food and Drug Administration-approved medications exist for diabetes management[33]. Adverse events of antidiabetic medication may range from hypoglycemia, gastrointestinal (GI) upset, angio-edema, genitourinary infections, dehydration, to severe events like hypoglycemic coma, heart failure, lactic acidosis, pancreatitis, and diabetic ketoacidosis^[34–36^]. Though the side effects of anti-diabetic medications are to some extent specific to drug class, but hypoglycemia and weight gain are common side effects, particularly with insulin therapy which is the main treatment for type 1 diabetes mellitus (T1DM)[35]. An increasing concern revolves around the notion that weight gain induced by the majority of diabetic medications could attenuate their clinical benefits. Therefore, opting for a medication with weight-reducing or weight-neutral properties is deemed more advantageous for patients[37].

Sotagliflozin stands out as a novel and insulin-independent diabetic medication, exerting its effects through the dual inhibition of SGLT-1 and SGLT-2 receptors. The SGLT-2 receptor primarily resides in the primary convoluted tubule segments 1 and 2 (S1–S2) of the nephron, responsible for absorbing 90% of the filtered glucose load[38]. In diabetic patients, there is an overproduction of SGLT-2 receptors, and inhibiting these receptors facilitates urinary glucose excretion, contributing to the maintenance of balanced blood glucose levels[39]. Conversely, SGLT-1 serves as the primary transporter for glucose absorption in the GI tract and is also involved in reabsorbing 10% of the filtered glucose load in the renal proximal tubule segment 3[38]. Complete inhibition of SGLT-1 has been reported to induce glucose-galactose malabsorption, leading to profound diarrhea[38]. This leads to development of an agent with potent SGLT-2 inhibition and partial SGLT-1 inhibitor.

Sotagliflozin has demonstrated efficacy in both type 1 and type 2 diabetes patients by reducing HbA1c levels, fasting, and postprandial glucose, and improving daily total, basal, and bolus insulin doses[40]. It exhibits the ability to delay postprandial intestinal glucose absorption while enhancing glucagon-like peptide-1 (GLP-1) levels and reducing gastric inhibitory peptide[40]. Due to its selective impact on the SGLT1 receptor, it is linked to reduced overall glucose absorption, resulting in decreased insulin and c-peptide secretion in the bloodstream.

In comparison to the SGLT2 inhibitor empagliflozin, the SGLT1/2 inhibitor sotagliflozin is associated with significantly increased incremental aGLP-1 and tGLP-1 during the 0–5 h breakfast interval, as well as a notable increase in incremental aGLP-1 during the entire 0–14-h interval[41]. Musso et al[42], in their analysis of 3238 patients with T1DM, found that sotagliflozin is linked to significantly lower rates of hypoglycemia. Another analysis of 16 411 patients with T2DM revealed that sotagliflozin led to reductions in body weight, blood glucose, and systolic blood pressure[43]. Though both SGLT2 and SGLT1/2 dual inhibitors are associated with weight reduction, dual inhibitors are more effective and potent^[44,45^]. Consequently, sotagliflozin presents a promising prospect as a diabetic drug, preserving the benefits of SGLT2 inhibitors and offering additional advantages through SGLT1 inhibition.

While sotagliflozin shows promise in diabetes management, vigilance in monitoring and mitigating potential side effects remains a concern. The safety profile of both sotagliflozin and SGLT2 inhibitors is comparable. Sotagliflozin is linked to dose-dependent GI side effects, such as nausea and diarrhea[46]. Notably, the diarrhea is generally mild and manageable[47]. Similar to other SGLT-2 inhibitors, the use of sotagliflozin is associated with an increased incidence of side effects triggered by glycosuria, including genital mycotic infections^[43,48^]. The most concerning side effects of sotagliflozin are hypoglycemia and diabetic ketoacidosis. Notably, trials involving insulin-naive individuals with type 2 diabetes reported no incidence of hypoglycemia[46]. For type 1 diabetes, phase III trials indicated a similar rate of severe hypoglycemia in the sotagliflozin and placebo groups using subcutaneous insulin. However, in the subgroup of participants in the inTandem3 study with an insulin pump, severe hypoglycemia appeared to be twice as common in sotagliflozin users[47], This underscores the need for further investigation into the effectiveness and dose calculation of sotagliflozin in combination with insulin pumps. At week 52, hypoglycemia events were significantly less frequent with sotagliflozin added to optimized insulin therapy versus placebo in adults with T1D at any HbA1c level. Hypoglycemia increased as HbA1c decreased in all groups, but the sotagliflozin groups experienced a reduced rate of hypoglycemia relative to placebo at lower HbA1c levels[49]. The data underscores that while hypoglycemia poses a risk with the use of sotagliflozin, the incidence is considerably lower. The incorporation of glucose monitoring, coupled with optimized insulin therapy, appears to be a crucial strategy in further reducing the chances of hypoglycemia.

Ketoacidosis is a serious adverse event and could be life-threatening. Though the risk is more than placebo-treated individuals but less than values reported for canagliflozin[47]. The elevated frequency of ketoacidosis in sotagliflozin users employing insulin pumps, as opposed to those without pumps (4.4% vs. 2.1%), provides an opportunity to mitigate the risk. This could be achieved by either avoiding the use of sotagliflozin in this specific population or through vigilant monitoring and early recognition of pump failure[47]. Clinical trials with all approved SGLT2 inhibitors, including dapagliflozin, empagliflozin, and canagliflozin, have indicated an increased risk of diabetic ketoacidosis[50]. Comparative data on the incidence of diabetic ketoacidosis in patients treated with either SGLT-2 inhibitors or sotagliflozin would provide valuable insights. Implementing an enhanced risk mitigation plan resulted in a lower incidence of diabetic ketoacidosis, suggesting that this risk can be effectively managed through patient education[51]. Minimizing the risk of diabetic ketoacidosis necessitates careful patient selection and the judicious down-titration of basal insulin doses[42].

Renal outcomes

The pathophysiology of kidney disease involves insidious structural and functional damage, resulting in albuminuria, decreased glomerular filtration rate, and complications with the passage of time. CKD is often a complication of diabetes and hypertension, which increase intraglomerular pressure and activate pathways causing glomerulosclerosis and fibrosis. Diabetic kidney disease affects 20%–40% of diabetic patients, exacerbating CKD through chronic hyperglycemia, inflammation, and oxidative stress. Hypertension further strains the kidneys, accelerating CKD progression. Effective management of blood glucose and blood pressure can slow CKD progression, but advanced stages may require renal replacement therapies like dialysis or transplantation. The interplay between diabetes, hypertension, and obesity creates a synergistic effect, worsening kidney health and increasing cardiovascular risks[52]. Sotagliflozin, a dual SGLT1/2 inhibitor, and SGLT2 inhibitors have been proven to be useful for CKD through their nephroprotective effects[53]. They improve albuminuria and exert their nephroprotective effect independent of glucose-lowering effect[54].

SGLT2 inhibitors exert renoprotective effects through diverse mechanisms. (a) They eliminate excess glucose through a glucosuric effect by reducing renal glucose reabsorption. SGLT2 receptors are found on the luminal membranes of epithelial cells that line the first and second segments of the PCT. About 90% of glucose reabsorption occurs in this segment. SGLT2 inhibitors bind to these receptors with greater affinity than glucose and can prevent the reabsorption of a large amount of filtered glucose (up to 100 mg/dl) even at low concentrations[55]. This glucose effect is also associated with osmotic diuresis and natriuresis. The osmotic diuresis may be up to 400 ml/day and hypovolemia. All these effects lead to a decrease in blood pressure without increasing heart rate, which undoubtedly contributes to renal protection^[56,57^]. SGLT2 inhibitors cause a change in tubular metabolism and energy substrate utilization by decreasing reliance on glucose for energy production, increasing fatty acid utilization, and suppressing lipotoxic cell damage. They also suppress NHE-3, but renoprotection via this mechanism is still unclear[58]. SGLT2 inhibitors also reduce inflammation and fibrosis by decreasing circulating levels of pro-inflammatory and profibrogenic mediators. Metabolic effects include increased glycosuria, increased urinary energy loss, increased gluconeogenesis, decreased TCA, increased ketone body utilization, decreased mTORC1 hyperactivation, decrease tubular damage, and decreased podocyte damage[59].

Several meta-analyses of RCTs and real-world observational studies have indicated reductions in the risk of AKI by the usage of SGLT2 inhibitors up to 30%–40%. However, the initial dip in eGFR by SGLT2 inhibitors can accentuate an acute adverse event so, they should be used cautiously if eGFR <45 ml/min/1.73 m². Caution associated with the use of SGLT2 inhibitors includes genitourinary mycotic infections, renal neoplasms, previously AKI, Fournier’s gangrene, and interaction with antihypertensive drugs like RAAS blockers, loop diuretics/thiazide diuretics.

Sotagliflozin is a dual SGLT1 and SGLT2 inhibitor. SGLT1 receptors are found on the luminal membranes of the cells lining the third segment of the PCT. These receptors are also found on the apical membranes of enterocytes. Nephroprotective effects of sotagliflozin are similar to SGLT2 inhibitors but there are some differences.

Sotagliflozin inhibits SGLT1 receptors in enterocytes, delaying GI glucose uptake, resulting in reduced post-prandial hyperglycemia. SOTA also increases the secretion of intestinal hormones which tend to enhance insulin sensitivity and mitochondrial bioenergetics, leading to additional nephroprotective effects. By reducing blunted glucose uptake and improving insulin sensitivity, it lowers the tubular glucose load and UGE, which explains the difference between the SOTA and SGLT2 inhibitors. After cessation of therapy, SOTA exerts Greater preventive effects on kidney function loss than SGLT2 inhibitors. Other effects like reduction in eGFR, Urine Albumin-to-Creatinine Ratio (UACR), uric acid, blood pressure (BP), and albumin are similar to SGLT2 inhibitors^[60,61^].

Neuroprotective outcomes

In addition to diabetic and cardiovascular effects, recent literature has shown that SGLT2 inhibitors and sotagliflozin also have neuroprotective effects[62]. SGLT2 inhibitors are not completely specific for SGLT2 co-receptors and also impact SGLT1 to different degrees. Sotagliflozin exhibits the highest affinity for SGLT1 receptors and hence, is a “dual SGLT1/SGLT2 inhibitor”[63]. Research in animals and humans has confirmed a connection between T2DM and neurological conditions. T2DM is a significant risk factor for stroke and Alzheimer’s disease (AD). Since they are abundant in the central nervous system and modulate neuron membrane potential through sodium transport, SGLT2 receptors can be used to treat neurological illnesses. These receptors are selectively expressed in the blood-brain barrier (BBB) and triggered by post-ischemic cerebral hyperglycemia, worsening neuronal injury[64]. SGLT2 inhibitors have been studied for their anti-inflammatory effects in neurodevelopmental diseases, including downregulating the expression of proteins like TGF-β, IL-6, CRP, NF-κB, TNF-α, and MCP-1. Numerous studies showed that SGLT2 inhibitors can reduce free radicals and upregulate antioxidant systems like glutathione (GSH) and superoxide dismutase across the BBB[65]. They have proved beneficial in AD, Parkinson’s disease, epilepsy, and autism spectrum disorder[66]. But the data on neurological effects of sotagliflozin is very limited. This warrants future research on this topic to explore the potential of this drug in the field of neurology.

Hepatic outcomes^[67,68^]

Liver disease is the third leading cause of mortality in cystic fibrosis patients and at present ursodeoxycholic acid is the mainstay of treatment with limited efficacy leading to high number of patients requiring liver transplantation. Sotagliflozin has shown significant benefits in the treatment of liver disease in cystic fibrosis in an experiment on rabbits[67]. SGLT1 is upregulated in multiple CF-affected organs including liver. Sotagliflozin, an SGLT1 inhibitor, acts by improving liver disease and thus reducing mortality besides other systematic benefits in CFLD. It suppressed endoplasmic reticulum stress markers, in IRE1A/XBP1-mediated UPR pathway in liver and decreased ER stress markers in lung, pancreas, and kidney. Sotagliflozin treatment resulted in decreased inflammation mediated by NF-kB pathway, and by cytokines, TNF, and IL-6 in CFLD rabbits. The drug enhanced hepatic gene expression including PCK1 gene involved in gluconeogenesis, GYS2 gene expression involved in glycogen synthesis and CYP7A1, FGF21, and PPARA genes involved in bile acid synthesis. Non-alcoholic steatohepatitis (NASH) characterized by hepatic inflammation, steatosis, and fibrosis is found in CFLD. Sotagliflozin treatment, by decreasing SGLT1 protein and SLC5A1 transcription, led to improved NASH characteristics. It also improved the elevated bile acids and alleviated hepatic biliary cirrhosis in CF rabbits. There were no side effects observed with the use of treatment as there was weight gain and improved appetite in experimental rabbits and no sign of secondary bacterial lung infection. There is a potential of using sotagliflozin for the treatment of liver disease in cystic fibrosis patients after testing efficacy of drug at cellular level in CF patients and by observing long-term effects in other animals.

The previously approved SGLT2 inhibitors, canagliflozin, dapagliflozin and empagliflozin, have beneficial role in alleviating NAFLD/NASH. SGLT2i act by decreasing hyperglycemia, visceral adiposity, serum uric acid level, oxidative stress, and inflammation and by increasing adiponectin[68]. However, there is no data on the efficacy of sotagliflozin, a dual SGLT2/SGLT1, for NAFLD treatment.

Innovations in diabetes management

Sotagliflozin’s dual SGLT1/2 inhibition forecasts a paradigm shift in diabetes care, tackling systemic complications beyond glycemic control. By uniquely addressing cardiovascular risks (reducing heart failure events), renal decline, and metabolic dysregulation, it transcends traditional glucose-centric therapies. Early evidence of neuroprotective and hepatic benefits further stations it as a multisystem modulator, offering a holistic approach to diabetes-related comorbidities. While risks like GI effects require optimization, its ability to concurrently mitigate diverse complications redefines therapeutic strategies. This dual-target mechanism paves the way for integrated, preventive care models, emphasizing sotagliflozin’s potential to advance individualized treatment frameworks and inspire future multifactorial therapies in chronic disease management.

Limitations

This narrative review, although comprehensive, has some limitations. First, its non-systematic methodology results in a potential selection bias, as the inclusion of studies appears subjective rather than according to predefined criteria, risking an incomplete synthesis of evidence. The review highlights positive outcomes from trials like SOLOIST-WHF and SCORED but incompletely addresses conflicting data, such as sotagliflozin’s dose-dependent GI side effects and variable hypoglycemia risk in insulin pump users. While neuroprotective and hepatic benefits are postulated, the extrapolation from SGLT2 inhibitors to sotagliflozin lacks robust evidence, keeping in mind the limited direct data on its neurological effects. The review also relies on preclinical findings (e.g. hepatic outcomes in rabbits) without clinical validation, overstating translational relevance. Comparative conclusions about sotagliflozin’s superiority to SGLT2 inhibitors are weakened by the lack of head-to-head trials and heterogeneity in trial designs, populations, and endpoints. Furthermore, the discussion understates trade-offs highlighted in meta-analyses, such as dual inhibitors’ higher hypoglycemia and diarrhea risks versus marginal cardiovascular advantages. Finally, long-term safety and real-world efficacy remain under-explored, undermining the generalizability of the findings. These limitations underscore the need for systematic reviews, direct comparative trials, and more rigorous evidence to validate the proposed benefits of dual SGLT1/2 inhibitors.

Conclusion

In conclusion, both sotagliflozin and SGLT2 inhibitors demonstrate efficacy in managing various aspects of T2DM. The comparative analysis presented in this manuscript highlights the significant therapeutic potential of sotagliflozin in managing a spectrum of diabetic, cardiovascular, renal, and neuroprotection outcomes compared to other SGLT2 inhibitors. Sotagliflozin’s multifaceted mechanism of action, targeting both SGLT1 and SGLT2 transporters, may confer added benefits, particularly in reducing renal complications and modulating neurovascular function. Both classes of drugs improve glycemic control and may have indirect neuroprotective effects, although direct evidence in this regard is limited. Integrating these drugs into clinical practice offers a comprehensive approach to diabetes management, but further research is needed to fully understand their comparative efficacy and long-term effects, especially in the area of neuroprotection.

Ethical approval

Ethics approval was not required for this review.

Consent

Informed consent was not required for this review.

Sources of funding

The authors did not receive any financial support for this work. No funding has been received for the conduct of this study.

Author contributions

Writing – original draft, conceptualization, methodology: E.F.; writing – original draft, methodology; data analysis: H.I.; writing – original draft, data analysis: F.F.; writing – original draft: J.J.; writing – original draft: O.U.R.; writing – review and editing: A.S.; writing – review and editing: B.A.; writing – review and editing: S.K.; writing – review and editing: A.A.

Conflicts of interest disclosure

The authors declare that there is no conflict of interest.

Research registration unique identifying number (UIN)

Not applicable.

Guarantor

Aymar Akilimali.

Provenance and peer review

Not invited.

Data availability statement

Not applicable.