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Sotagliflozin, the first dual SGLT inhibitor: current outlook and perspectives
Cardiovascular Diabetology volume 18, Article number: 20 (2019)
Sotagliflozin is a dual sodium–glucose co-transporter-2 and 1 (SGLT2/1) inhibitor for the treatment of both type 1 (T1D) and type 2 diabetes (T2D). Sotagliflozin inhibits renal sodium–glucose co-transporter 2 (determining significant excretion of glucose in the urine, in the same way as other, already available SGLT-2 selective inhibitors) and intestinal SGLT-1, delaying glucose absorption and therefore reducing post prandial glucose. Well-designed clinical trials, have shown that sotagliflozin (as monotherapy or add-on therapy to other anti-hyperglycemic agents) improves glycated hemoglobin in adults with T2D, with beneficial effects on bodyweight and blood pressure. Similar results have been obtained in adults with T1D treated with either continuous subcutaneous insulin infusion or multiple daily insulin injections, even after insulin optimization. A still ongoing phase 3 study is currently evaluating the effect of sotagliflozin on cardiovascular outcomes (ClinicalTrials.gov NCT03315143). In this review we illustrate the advantages and disadvantages of dual SGLT 2/1 inhibition, in order to better characterize and investigate its mechanisms of action and potentialities.
Diabetes, especially type 2 diabetes, is a chronic and complex disease, which requires a multi-targeted approach tailored to the single patient. Despite the large therapeutic armamentarium available, however, this goal remains difficult to achieve.
SGLT inhibitors, a new class of oral hypoglycemic agents, have proved to be extremely effective and reliable in reducing hyperglycemia. Their insulin-independent mechanism of action inhibits sodium–glucose co-transporters, thus decreasing the renal glucose threshold (to ~ 100 mg/dL) and promoting urinary glucose excretion, without increasing the risk of hypoglycemia. Moreover, they modify several aspects of human metabolism, and some have, unexpectedly, shown great efficacy in reducing important cardiovascular events [1, 2].
The development of inhibitors targeting SGLT began with experiments with the compound phloridzin, first isolated in 1835 by French chemists from the root bark of the apple tree, and subsequently found to improve blood glucose levels in animals . In 1975, DeFronzo et al. . showed that phloridzin infusion in dogs increased fractional excretion of glucose by 60%, whereas glomerular filtration rate and renal plasma flow remained unchanged. Despite these results, phloridzin was abandoned as a potential treatment of type 2 diabetes due to its rapid degradation and poor absorption in the gastrointestinal tract, where it is hydrolysed into glucose and phloretin, which in turn inhibit facilitative glucose transporters, such as GLUT-1 , the main glucose transporter in non-insulin-dependent tissues.
SGLT is the acronym of the original name (sodium–glucose linked transporter; then modified to sodium-dependent glucose co-transporter) of a family counting at least six different isoforms in humans . Of these, SGLT-1 and SGLT-2 have been widely studied because of their fundamental role in glucose and sodium transport across the brush border of gut and kidney cells, through an active mechanism exploiting the Na + electrochemical gradient generated by active sodium extrusion by the basolateral sodium/potassium-ATPase .
In physiologic conditions, SGLT-1 is responsible for glucose absorption in the small intestine, and for the reabsorption of nearly 10% of the filtered glucose load in the renal proximal tubule segment 3 (S3), while SGLT-2 is primarily expressed in the renal proximal tubule segment 1 and 2 (S1–S2) and is responsible for the reabsorption of ≈ 90% of the filtered glucose load . Given its biological characteristics we would expect the inhibition of SGLT-2 to prevent the reabsorption of at least 80% of the glucose load. However, when SGLT2s are completely inhibited, or absent, as in knockout mice, ≈ 30–40% of glucose is still reabsorbed from urine . Powell et al., observed that the absence of SGLT2s leads to a urinary glucose excretion of 30% of filtered glucose, while in SGLT2/SGLT1 double knockout mice the glycosuric effect was threefold greater , suggesting that when SGLT2 is inhibited, SGLT1 is forced to work at maximal transport capacity. Subsequently, Vallon’s group showed the same compensatory action of SGLT1 on renal glucose reabsorption in both acute and chronic use of SGLT2 inhibitors , however, robust evidence to confirm this hypothesis is still unavailable.
Several SGLT inhibitors (SGLTis) are already available in many countries (dapagliflozin, canagliflozin, empagliflozin, ipragliflozin)  while others are in the final phases of development (ertugliflozin, sotagliflozin). The currently available SGLT-2 inhibitors share similar pharmacokinetic characteristics and have similar effects on glycemic control; sotagliflozin, however, acts on both sodium–glucose co-transporters 1 and 2 . In this review, we explore the potential advantages of sotagliflozin, compared to other selective SGLT-2is, given its unique characteristics of strong affinity for SGLT-2 and mild selectivity for SGLT-1.
Distribution and role of SGLT-1
In a 2015 study, Vrhovac et al. . used novel affinity-purified antibodies for human SGLT-1 (hSGLT-1) and SGLT-2 (hSGLT-2) to identify locations of SGLT-2 in the human kidney and SGLT-1 in the human kidney, small intestine, liver, heart and lung . In the kidneys, hSGLT-2 and hSGLT-1 were found on the brush border membrane (BBM) of proximal tubule S1/S2 and S3 segments, respectively, (namely in the same location as in mice and rats). However, in contrast to rodents, hSGLT-1 was not expressed in the ascending limb of Henle and in the macula densa. Moreover, the expression of both hSGLTs was identical for both sexes. In the small intestine, hSGLT-1 was expressed on the BBM of enterocytes and subapical vesicles. Using double labeling with glucagon-like peptide 1 (GLP-1) or glucose-dependent insulinotropic peptide (GIP), SGLT-1 was also found in GLP-1-secreting L cells and GIP secreting K cells in mice. hSGLT-1 was expressed in the biliary duct cells of the liver, (as in rats). In the lungs, hSGLT-1 was found in alveolar epithelial type 2 cells and in bronchiolar Clara cells. Double labeling with aquaporin 1 immuno-localized hSGLT-1 in the human heart capillaries, instead of in the myocyte sarcolemma, as previously supposed.
These findings indicate that hSGLT-1 has several extra-renal functions, i.e. the regulation of the secretion of entero-endocrine cells, and the release of glucose from heart capillaries, which could provide cardiovascular benefits. However, the actual role played by SGLT-1 in these tissues has still not been established. Consequently, the potentially positive and negative effects of its inhibition are yet to be determined.
Structure of sotagliflozin
Sotagliflozin, also known as LX4211, is a small, orally available molecule, which inhibits both SGLT-1 and SGLT-2. In humans the selectivity for SGLT-2, however, is 20-fold greater compared to SGLT-1, with an IC50 (concentration causing half of maximal inhibition) of 0.0018 µΜ and of 0.036 µM for SGLT-2 and SGLT-1, respectively . Its chemical structure, (2S,3R,4R,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-methylsulfanyloxane-3,4,5-triol, is shown in Fig. 1.
Sotagliflozin’s effectiveness in inhibiting SGLT-2 is similar to that of the selective SGLT-2 inhibitors dapagliflozin and canagliflozin, but it is > 10-fold more potent than the latter molecules in inhibiting SGLT-1 . Its effects on SGLT-1 in other tissues are, however, less known. As reported below, sotagliflozin does not seem to affect renal SGLT-1, suggesting that its low affinity has clinical effects only in tissues where SGLT-1 is highly expressed (i.e. the gut). Another possibility is that sotagliflozin acts as a potent intestinal SGLT1 inhibitor because there are higher levels of sotagliflozin in the intestinal lumen than in the general circulation.
Evidence for the benefit of this class of drugs comes from a large real-world evidence study evaluating the risk of hospitalization for heart failure and death from any cause in patients with type 2 diabetes treated with SGLT-2 inhibitors, mainly dapagliflozin and canagliflozin . Two recent clinical trials with empagliflozin and canagliflozin (EMPAREG and CANVAS, respectively), involving subjects with type 2 diabetes and high cardiovascular (CV) risk, have shown a significant reduction in the primary endpoint of Major Adverse Cardiovascular Events (MACE) and heart failure [2, 16,17,18]. Another clinical trial, the DECLARE-TIMI58, whose results have been recently published, showed that dapagliflozin treatment in patients with type 2 diabetes who had, or were at risk of, atherosclerotic cardiovascular disease (i.e. more than 60% of patients in primary prevention), did not show better results in preventing MACE than placebo, but did result in lower rates of cardiovascular death or hospitalization for heart failure . Even though several studies are currently exploring the reasons for these interesting results [20,21,22,23]; the profound changes induced by glycosuria on substrate availability and localization in the myocardium remain unexplored .
Moreover, dedicated CVOTs with canagliflozin or dapagliflozin have not shown a significant reduction in all-cause mortality after treatment with these drugs . Ongoing Phase III studies are exploring the cardiovascular benefits of ertugliflozin (ClinicalTrials.gov: NCT01986881) and sotagliflozin (ClinicalTrials.gov NCT03315143). In contrast to SGLT-2, SGLT-1 is reported to be highly expressed in both human autopsied hearts and murine perfused hearts (as assessed by immunostaining and immunoblotting with membrane fractionation) in the sarcolemma of cardiomyocytes  or more probably in the capillaries . Moreover, Von Lewinski et al. demonstrated that both GLUT-4 and SGLT-1 have an insulin-dependent inotropic effects on the heart, indeed the inhibition of PI3-kinase and either SGLT1 or GLUT4 results in a loss of these functions, probably due to the reduction of glucose substrates in the cardiomyocytes.
Further, SGLT-1 and GLUT1 seem to be closely linked to each other. In protein fractions, in fact, SGLT-1 co-localizes with GLUT1, which is normally localized to the sarcolemma, and to a lesser extent with GLUT4, which can be translocated from intracellular stores to the sarcolemma when required. Despite these findings, no inhibitor effects on cardiac SGLT1, have been demonstrated, at least at therapeutic doses tested .
Further insight into SGLT-1’s function in the heart could derive from investigating the effects of phloridzin, a powerful dual SGLT inhibitor, unfortunately exploitable only in animal models. In recent experiments, phloridzin perfusion did not affect baseline cardiac function; however, results from its administration during ischemia–reperfusion injury suggest a possible negative effect of SGLT-1 inhibition. Indeed, the cardio-protective effect due to ischemic preconditioning was nullified when rat hearts were pre-treated with phloridzin; showing slower recovery of left ventricular contractions and a significant decrease in tissue ATP content associated with reductions in glucose uptake, as well as lactate output (indicating glycolytic flux), during ischemia–reperfusion . These findings, however, were in ex vivo experiments conducted in artificial conditions, on excised murine Langendorff hearts in which the changes in overall substrate fluxes in chronic whole body SGLT-i treatments (i.e., with removal of gluco- and lipo-toxicity, increased ketones) are overwhelmed by an acute and uncompensated reduction in intracellular glucose. Nevertheless, SGLT-1 expression in the heart seems to be regulated by the overall myocardial glucose metabolism. In fact, myocardial SGLT-1 expression increases in both human subjects with end-stage cardiomyopathy secondary to type 2 diabetes and in ob/ob obese mice (a model of type 2 diabetes with altered myocardial glucose metabolism). Conversely, decreased cardiac expression of SGLT-1 was observed in STZ-treated mice, a model of type 1 diabetes (T1D). Although the reason for the divergent SGLT-1 expression in type 1 and type 2 diabetes is uncertain, it seems conceivable that increased SGLT-1 may be related to Free Fatty Acid-induced insulin-resistance, with increased SGLT-1 as an adaptation to the known reduction in cardiac GLUT1 and GLUT4 expression, resulting in hyperinsulinemia . Therefore, even if sotagliflozin is able to inhibit myocardial SGLT-1, its role in restoring intracellular substrate utilization (including restored GLUT-4-mediated glucose uptake) is expected to prevail over the possible negative effect of SGLT-1 inhibition due to the reduction of glucose myocardial substrate with a consequent less viability in response to ischemia. Clearly, experiments that directly measure myocardial glucose uptake during sotagliflozin administration, and any findings on its inhibition of cardiac SGLT1 (e.g., the planned study with dapagliflozin, see Clinicaltrials.gov NCT03313752) could resolve this controversy.
A recent study to explore sotagliflozin’s effects on cardiovascular outcomes was conducted in subjects carrying a haplotype of 3 SGLT-1 loss-of-function mutations (Asn51Ser, Ala411Thr, His615Gln). The authors used a Mendelian randomization approach to estimate the 25-year effect of a reduction of 20 mg/dL in 2-h glucose through SGLT1 inhibition showing a reduction in the prevalence of obesity, and incidence of diabetes, heart failure and death .
Moreover, considering that recent studies have suggested that controlling postprandial glucose (PPG) could reduce the incidence of cardiovascular complications [31, 32], the improvement in PPG and glucose profile obtained with sotagliflozin may improve cardiovascular outcomes.
As explained above, SGLT-2 is primarily responsible for renal glucose reabsorption (≈ 90%), while SGLT-1 accounts for the remaining 10% under physiological conditions. Given this role in renal glucose reabsorption, the expectation that SGLT-2 inhibitors would reduce renal glucose reabsorption by over 80% has been widely contradicted by clinical trials with other SGLT-2 inhibitors. Some authors have proposed SGLT-1 compensation in renal glucose reabsorption as a possible explanation [33, 34]. In fact, a double SGLT-2/SGLT-1 inhibitor like sotagliflozin would be able to overcome this problem by inhibiting glucose reabsorption more efficiently. Indeed, a study conducted by Powell’s group showed that the use of an oral SGLT-2/SGLT-1 inhibitor, known as LP-925219, was able to maximally reduce glucose renal reabsorption in SGLT-2/SGLT-1 DKO mice compared to WT, SGLT-2 KO or SGLT-1 KO mice .
Table 1 shows the percentage inhibition of renal glucose reabsorption at different dosages of sotagliflozin, empagliflozin and dapagliflozin, calculated from dose ranging studies in type 2 diabetic patients. Sotagliflozin seems to have a similar glycosuric effect to other selective SGLT-2 inhibitors, even if the percentage inhibition of glucose reabsorption appears numerically lower. Indeed, sotagliflozin induced UGE reaches a plateau of ~ 60 g/24 h at 200 mg daily dose, with no further increments for escalating doses (Table 1); it seems therefore conceivable that either the efficacy of sotagliflozin for renal SGLT-1 or its selectivity is too low to exert a measurable (and clinically valuable) effect.
Interestingly, clinical studies have shown progressive improvements in glycemic control, in terms of HbA1c, FPG and PPG, with incremental doses of sotagliflozin, in the absence of corresponding increases in UGE , confirming the limited action of sotagliflozin on renal SGLT-1, but also strongly suggesting that the partial intestinal SGLT-1 inhibition is clinically relevant.
A confirmation that the inhibition of intestinal (rather than renal) SGLT-1 is clinically relevant could come from testing sotagliflozin in patients with low eGFR, and therefore low filtered glucose in the kidneys. Zambrowicz et al. conducted a double-blind, placebo controlled study, to determine whether the efficacy of sotagliflozin is preserved in patients with type 2 diabetes and moderate to severe renal impairment. This study showed a significant reduction of PPG after 7 days of sotagliflozin 400 mg daily treatment, which was maintained in patients with an eGFR < 45 mL/min/1.73 m2 .
On the other hand, there was no significant improvement in HbA1c in patients with moderate renal impairment (eGFR 30–59 mL/min/1.73 m2) treated with dapagliflozin and canagliflozin compared to placebo [42, 43]. Similarly, empagliflozin was tested in patients with mild renal impairment (eGFR 30–60 mL/min/1.73 m2) with only minor results . It is thus clear that the dependence of selective SGLT-2 inhibitors on renal function represents a limitation in the efficacy of these drugs in patients with renal impairment. Considering that type 2 diabetes is a major risk factor for chronic kidney disease and that glycemic control can reduce the risk of microvascular complications and the progression of chronic kidney disease (CKD) , the use of sotagliflozin in patients with CKD represents an important new therapeutic opportunity.
By inhibiting SGLT-1, sotagliflozin delays glucose absorption in the distal small intestine and colon, consequently reducing Post Prandial Glucose (PPG) and improving glycemic control in type 2 diabetes subjects [15, 41].
Treatment with increasing doses of canagliflozin (an SGLT-2 inhibitor with low potency SGLT-1 inhibition) given 10 min before a mixed meal, produced a significant reduction in PPG only with doses higher than 200 mg; this effect, however, was observed only for the first meal after dosing . Therefore, a subsequent study, conducted to investigate the effect of a single 300 mg dose of canagliflozin on intestinal glucose absorption, demonstrated that this dosage reduces PPG and insulin concentration in healthy subjects, delaying the rate of appearance of oral glucose, likely through the transient inhibition of intestinal SGLT-1 .
None of the studies published so far has identified the real mechanism by which sotagliflozin inhibits SGLT-1. Importantly, it is unclear whether sotagliflozin interacts with SGLT-1 only locally (interacting with the co-transporters on the extracellular intestinal luminal side), as reported by Wright et al.  or also systemically, after intestinal absorption of the drug. In the first case, the effects of sotagliflozin on PPG should be evident a few hours after drug ingestion, independently of its plasma half-life. Daily drug administration, however, has shown positive effects on both fasting plasma glucose (FPG) and PPG.
In a dose-ranging study, the efficacy, safety and tolerability of four oral doses of sotagliflozin (75 mg once daily, 200 mg once daily, and 200 mg twice daily and 400 mg once daily) were tested in patients with type 2 diabetes inadequately controlled on metformin. Sotagliflozin improved glycemic control by reducing HbA1c and FPG in a dose dependent manner throughout the 12-week observation period (maximum efficacy was achieved with 400 mg once daily), with no corresponding increase in urinary glucose excretion (UGE) suggesting that the greater efficacy observed with 400 mg once daily dose compared to 200 mg daily dose, is achieved through clinically meaningful SGLT1 inhibition in the GI tract .
In a previous study  the authors showed that treatment with LX4211 (150 mg or 300 mg daily) also significantly lowered 2-h postprandial glucose (PPG) levels in each treatment group as compared with placebo with no difference between the used doses; moreover an increase in GLP-1 and PYY has been observed from 0 to 13 h after meal in subjects treated with 300 mg single dose LX4211 suggesting (but not demonstrating) that the post-prandial effect might also be obtained with q.d. dosing.
In an explorative study, Brian Zambrowicz et al.  examined the efficacy of sotagliflozin (alone or in combination with sitagliptin) in both mice and humans. Results from the study seem to suggest that the inhibition of SGLT-1 by sotagliflozin lasts longer than the first meal.
The effect of sotagliflozin on main outcomes in type 2 diabetes subjects, as reported in the main clinical trials available, is shown in Fig. 2.
The hypothesized mechanism is that sotagliflozin’s partial inhibition of intestinal SGLT1 results in delayed glucose uptake, which induces the release of GLP-1 and PYY by L cells, and that the increased levels of active GLP-1 may contribute to improved glycemic control in treated patients . However, a double tracer study to measure glucose transit and absorption throughout the day, with (various) sotagliflozin dosages, is probably needed, at least to demonstrate its important intestinal effects.
Initial studies in mice treated with LX 2761, a non-absorbable SGLT-1 inhibitor, showed reductions in fasting plasma glucose (FPG) and PPG, improvement in glycemic control, without increased glucosuria, and an increase in circulating levels of GLP-1 and peptide YY (PYY), hormones that suppress the appetite .
In a rodent model, Hara et al. demonstrated that oral administration of canagliflozin suppresses GIP secretion, by inhibiting SGLT-1 in the upper part of the intestine, and reduces the excursion of blood glucose under hyperglycemic conditions (OGTT), by increasing total GLP-1 levels. Interestingly, the action of canagliflozin on GLP-1-producing cells may be determined by increased glucose delivery to the lower part of the small intestine . Since this increase in GLP-1 is not observed with more SGLT-2 selective inhibitors, such as empagliflozin , it is safe to assume that the increase in GLP-1 is a consequence of intestinal SGLT-1 and subsequent delayed glucose absorption.
Additionally, it is well established that delaying glucose absorption in more distal parts of the gut increases GLP-1 secretion . In a single-dose study with sotagliflozin at 300 mg in 12 patients with type 2 diabetes, there was a significant increase in GLP-1 and PYY, accompanied by a significant decrease in plasma glucose and insulin doses . Nevertheless, the sotagliflozin-induced increase in GLP-1 levels following a glucose load in mice treated with this compound and in SGLT-1 knockout (−/−) but not in SGLT-2 knockout (−/−) mice strongly suggests, at least in a murine model, that SGLT-1 inhibition elicits GLP-1 secretion from intestinal L cells  leading to increased glucose and decreased pH in cecal (large colon) contents. Further, delayed glucose absorption in the gut might make more glucose available to intestinal microbiota. Glucose fermentation in the colon produces short-chain fatty acids (SCFAs), a potential trigger for GLP-1 secretion [55, 56]. Previous studies have shown that ingestion of dietary-resistant starch, which delays glucose absorption, leads to an increased production of SCFAs, through glucose fermentation, and enhances circulating levels of GLP-1 and PYY in rodents . Interestingly, sotagliflozin-treated mice (and SGLT-1 ko mice) have a lower pH of cecal contents after glucose challenge, suggesting that sotagliflozin reduces plasma glucose by triggering GLP-1 secretion through intestinal SCFA production .
GLP-1 secretion from L cells, however, is not solely due to the presence of glucose in the intestinal lumen and direct contact between the substrate and secreting cells. As an example, GLP-1 is secreted in a biphasic pattern: the first peak appears 15–30 min after the meal (earlier than the appearance of glucose in the lower gut), and is followed by second peak at 90–120 min . Moreover, murine data show an involvement of cholinergic neurons in the upper intestine, which may stimulate GLP-1 secretion in L cells in the lower intestine . Other studies have suggested that SGLT3, a glucose sensor that does not transport glucose, expressed in the upper small intestine may modulate the afferent vagal nerve to finally stimulate GLP-1 release . Whatever the mechanism(s), it appears evident that at least part of sotagliflozin’s effect on glucose metabolism could be mediated by an increase in GLP-1 secretion, although the actual contribution needs to be experimentally measured.
Finally, a blood intestine recirculation through bile (prolonging intestinal interaction between sotagliflozin and SGLT-1) might be hypothesized.
This scenario is, however, challenged by a recent study by Solini et al. . In their in vitro model, the authors showed that dapagliflozin (a highly selective SGLT-2 inhibitor) increases glucagon by acutely upregulating SGLT-1 expression in islet alpha cells independently of SGLT-2 inhibition.
Acarbose stimulates GLP-1 secretion in both healthy and diabetic subjects . Therefore, sotagliflozin seems, at least in part, to share the effects of acarbose.
Metformin could represent another possible factor interfering with glucose handling in the gut . Recent human data have shown that metformin modifies bile acid recirculation and gut microbiota resulting in enhanced entero-endocrine hormone secretion . Moreover, the higher potency of Delayed-Release (DR) metformin formulations (characterized by higher metformin availability in the distal gut, with less systemic absorption ) clearly indicate the predominant lower bowel-mediated mechanism of action of this widely-used drug, eventually stimulating GLP-1 secretion . Further, metformin seems to have a direct action on microbiota, determining a significant increase of protective bacterial genera such as Akkermansia muciniphila and Clostridium cocleatum in mice. In humans with type 2 diabetes, metformin treatment promotes the restoration of relative abundance of specific genera, such as Akkermansia and Lactobacillus [67, 68]. It appears obvious that delayed glucose absorption in the lower gut (sotagliflozin) with a concomitant change in lower gut microbiota (metformin) could reciprocally interact. Whether this interaction really modulates glucose metabolism is still unknown. A schematic overview of intestinal sotagliflozin effects is shown below (Fig. 3).
Dual SGLT-1 and DPP-4 inhibition
Given that SGLT-1 inhibition enhances GLP-1 secretion and DPP-4 inhibition prolongs endogenous GLP-1 half-life, a synergic effect on glucose control in type 2 diabetes is to be expected. In patients with type 2 diabetes, administration of canagliflozin (100 mg daily for 3 days) led to a twofold increase in GLP1 levels from baseline, and concomitant treatment with tenelegliptin led to a fourfold increase in GLP-1 levels of from baseline [69, 70]. Intriguingly, an improvement in beta cell incretin sensitivity has been described in Type 2 diabetes patients treated with dapagliflozin , and a mild increase in GLP-1 levels has also been observed with empagliflozin. These gliflozins, however, have no inhibitory action on SGLT-1 [72, 73] and should not therefore be able to directly increase GLP-1 secretion. Recent data from Bonner et al. demonstrated that SGLT-1 and SGLT-2 are specifically expressed in pancreatic alpha cells , where SGLT-2 inhibition determines increased glucagon secretion. The recent discovery that pancreatic alpha cells secrete GLP-1 , with possible prevailing paracrine effects, makes this mechanism particularly interesting.
The utility of co-administering DPP-4 inhibitors and SGLT-2 inhibitors is now well established [76,77,78], although with apparently less than additive efficacy. As mentioned above, sotagliflozin enhances GLP-1 secretion, and a higher efficacy is therefore expected when combined with a DPP-4 inhibitor. In a first, explorative study, Zambrowicz et al.  confirmed these expectations both in mice and in humans. Obese C57BL6J mice were treated with sotagliflozin 60 mg/kg, sitagliptin 30 mg/Kg, a combination of both or inactive vehicle, and an open-label, 3 treatment, 3 crossover study was conducted at a single center, where patients with type 2 diabetes randomly received sotagliflozin, sitagliptin or a combination of both (ClinicalTrials.gov identifier: NCT01441232). A significant increase in active GLP-1, after a meal challenge containing glucose, was observed in the combination therapy groups compared to the others, suggesting a synergic effect of the two drugs. Unfortunately, the study was too short (2 weeks) to demonstrate the synergic effect of the two inhibitions on HbA1c levels. To date, another clinical trial, exploring the addition of sotagliflozin (as compared with empagliflozin) in patients taking a DPP-4 inhibitor alone or with metformin (SOTA-EMPA) is currently recruiting (ClinicalTrials.gov identifier: NCT03351478.
Moreover, an adjuvant and additional effect on the glycaemic control and body weight of a combination therapy with SGLT-2 and GLP1-RA is also desirable as reported in recent clinical trial [79, 80]. Future studies investigating the effects of combination therapy with GLP-1 and sotagliflozin might give positive and stronger results.
The use of sotagliflozin in type 1 diabetes
Despite recent advances in the treatment of type 1 diabetes due to the introduction of new fast-acting and basal insulin analogs, insulin pumps and the possibility of continuous glucose monitoring (CGM) the majority of type 1 diabetic patients do not achieve and maintain adequate glycosylated hemoglobin levels . While almost all new drugs for type 2 diabetes lose their efficacy in presence of euglycemia, thus reducing the risk of hypoglycemia, the latter still represents one of the major barriers to achieving euglycemia in type 1 diabetes. Randomized controlled trials assessing the adjunctive use of liraglutide, sitagliptin and metformin in type 1 diabetes patients have not shown consistent or sustained reductions in glycated hemoglobin levels or increases in episodes of severe hypoglycemia or diabetic ketoacidosis [82,83,84]. Since the blood glucose lowering effect of SGLT inhibition is minimal in the presence of euglycemia, and since the euglycemic action of these drugs is completely insulin independent, SGLT inhibitors might theoretically represent a valid adjunctive therapy in patients with type 1 diabetes.
In a type 1 diabetes rat model , SGLT-2 inhibitors were reported to improve blood glucose levels, increase UGE and protect remaining islet β-cell function by reducing the oxidative stress induced by glucose toxicity. Several studies with selective SGLT-2 inhibitors have been conducted in patients with Type 1 diabetes, confirming the efficacy of this new approach [86,87,88].
The effect of sotagliflozin on glycemic control was first evaluated in a type 1 diabetes mouse model . In this study, sotagliflozin notably improved glycemic control in diabetic mice, maintained on a low insulin dose, without increasing hypoglycemic events. Subsequently, several studies were conducted to assess the effects of sotagliflozin added to insulin therapy in subjects with type 1 diabetes.
In the main trial, inTandem 3  the primary end point was a glycated hemoglobin level lower than 7.0% at week 24, without episodes of severe hypoglycemia or diabetic ketoacidosis, while secondary end points were the change from baseline to week 24 in glycated hemoglobin level and the possible reduction in daily bolus insulin dose, body weight and systolic blood pressure. Up to 28.6% of the sotagliflozin group achieved the challenging primary end point (HbA1c < 7% at week 24, with no episodes of severe hypoglycemia or diabetic ketoacidosis), with a greater reduction in the glycated hemoglobin level from baseline in the sotagliflozin group than in the placebo group (difference, − 0.46 percentage points; P < 0.001) (Fig. 4). In the sotagliflozin group, the placebo-corrected reductions from baseline in the mean daily total, bolus, and basal doses of insulin were − 5.3 units per day (− 9.7%), − 2.8 units per day (− 12.3%), and − 2.6 units per day (− 9.9%), respectively (P < 0.001 for all comparisons). The decrease in body weight and in systolic blood pressure from baseline to week 24 was significantly higher in the sotagliflozin group than in the placebo group (difference, − 2.98 kg; P < 0.001; difference, − 3.5 mmHg; P = 0.002 respectively).
Sands et al. conducted another randomized, multicenter, placebo-controlled, double-blind study to evaluate sotagliflozin, as adjunct therapy in adult subjects with type 1 diabetes . The primary outcome of the study was the effect of sotagliflozin therapy on change from baseline of total daily bolus insulin dose during the treatment period. The results demonstrated a percent variation from baseline in total daily bolus insulin administration that was − 32.0% in the sotagliflozin group and − 6.4% in the placebo group (P = 0.007) respectively. HbA1c decreased by 0.55% from baseline after treatment with sotagliflozin, compared with 0.06% in the placebo group (P = 0.002). Moreover, sotagliflozin treatment also reduced mean body weight compared with an increase in the placebo group (− 1.7 kg vs 0.5 kg) (P = 0.005). The results of other two Phase 3 clinical trials in the sotagliflozin T1D program, inTandem1 (ClinicalTrials.gov: NCT02384941) and inTandem2 (ClinicalTrials.gov: NCT02421510), have been recently published. Both trials aim to evaluate efficacy (change from baseline to week 24 in glycated hemoglobin level, daily bolus insulin, fasting plasma glucose, body weight) and safety (number of severe hypoglycemia  and diabetic ketoacidosis [DKA] episodes) of the use of sotagliflozin, 200 mg or 400 mg, in adult patients with type 1 diabetes. The novelty of these studies, compared to inTandem3, is to provide, as shown in the study design in Fig. 5, a preliminary 6-week phase for the optimization of insulin therapy.
In summary, treatment with sotagliflozin in combination with insulin in subjects with type 1 diabetes, significantly decreased glycated hemoglobin level, insulin dosage, body weight and systolic blood pressure, and, more importantly, without increasing the occurrence of hypoglycemia. Its key effect could be related to the reduction in postprandial glucose, which consequently leads patients on sotagliflozin to decrease insulin bolus.
Diabetic ketoacidosis and other side effects
As with other SGLT-2 inhibitors , the use of sotagliflozin leads to an increase in side effects triggered by glycosuria, e.g. genital mycotic infections, (the most common issue). Moreover, consistent with its inhibitory effect on SGLT-1 receptors, sotagliflozin is also accompanied by gastrointestinal side effects as reported in the inTandem 3 trial  (diarrhea occurred in 4.1% of the sotagliflozin group vs 2.3% in the placebo group). Besides these two rare and well tolerated side effects, various clinical trials have raised another important concern: the risk of hypoglycemia and ketoacidosis (DKA). In the cited phase 3, double-blind trial, whose results were published by Garg et al. , 1402 type 1 diabetes patients were randomly assigned to received insulin therapy or sotagliflozin (400 mg daily) or placebo for 24 weeks, reporting a lower event rate of documented hypoglycemia with a blood glucose level of less than 55 mg per deciliter or lower in sotagliflozin group compared to placebo, while the percentage of patients who had an episode of documented hypoglycemia with a blood glucose level of 70 mg per deciliter or lower was similar in the sotagliflozin group and the placebo group (96.3% [673 of 699 patients] and 95.3% [670 of 703], respectively). Similar results were obtained in a study conducted by Pier et al., in which the efficacy and safety of empagliflozin therapy (2.5 mg; 10 mg and 25 mg) compared to placebo was evaluated in type 1 diabetes patients. The rate of symptomatic hypoglycaemic episodes with glucose ≤ 3.0 mmol/L, not requiring assis-tance, was similar between groups over 30 days . Similarly, treatment with dapagliflozin determined a comparable incidence of hypoglycaemia events in patients treated with different doses of SGLT2-inhibitor compared to placebo (0.1% in each of the dapagliflozin groups vs 0.1%). Moreover, most hypoglycemic events were from add-on to insulin and add-on to sulfonylureas therapies .
Moreover in the inTandem 3 study, the sotagliflozin group had a higher incidence of ketoacidosis episodes compared to the placebo group (3.0% vs 0.6%). In fact, 1.6% of subjects in the sotagliflozin group discontinued the trial due to DKA vs 0.1% of the placebo group. Although the definition of DKA differed between trials, similar occurrence of DKA episodes have been described with the use of dapagliflozin .
A formal warning for the increased risk of DKA with SGLTs has been issued by the FDA . Different mechanisms have been proposed to explain this important side effect. First, the reduced glucose concentration partially switches ATP generation from glucose to FFA (Free fatty acids); while this mechanism is responsible for loss of fat mass, it might also determine a mild increase in the genesis of ketones (similar to that usually reached during fasting). Further, the reduced insulin dose, when SGLT-2 inhibitors are associated with insulin therapy, may not be sufficient to block gluconeogenesis in the liver, with a net consumption of oxaloacetate (for gluconeogenesis) impeding the entrance of FFA-derived AcCoA, which in turn are converted to ketones. A vicious circle may also be induced by the inhibition of SGLT-2 in alpha cells which leads to an increase in glucagon with consequent stimulation of ketogenesis in the liver . Moreover, a reduction in renal clearance of ketones with SGLT-2 inhibition has been described in animal models  and may represent another mechanism responsible for DKA with SGLT-2 inhibitor drugs.
A recently published meta-analysis of the three hallmark CV outcome trials (EMPA-REG OUTCOME, CANVAS, DECLARE TIMI-58) has documented, despite the unquestionable benefits on reducing hospitalisation for heart failure and progression of renal disease, a two-fold increase in the risk of DKA with the use of this drug class . However, expecially in type 1 diabetes, instead of considering SGLT inhibitors as responsible for the increase in DKA episodes, patients treated with SGLTis should be considered as more vulnerable to DKA episodes. Indeed, ketoacidosis per se represents a known risk in type 1 diabetes. A recent systematic review of the literature, found a 5 to 10% overall prevalence of ketoacidosis in type 1 diabetic adult patients , comparable to the incidence of DKA observed in the SGLT inhibitor trials [100,101,102]. Monitoring for ketosis, discontinuation of SGLTis before surgical procedures, and caution during stressful situations could be sufficient to mitigate the risk of DKA during SGLTi treatment, especially for patients on insulin pump therapy, in which a malfunction of the infusion set may increase the risk of DKA. With proper education, these episodes are probably entirely avoidable. And the benefits obtained with SGLTi treatment certainly outweigh the risks, especially if the latter are well understood and managed by both physicians and patients. Further, by delaying glucose absorption, sotagliflozin may reduce the need for ultra-fast insulin  in type 1 diabetes.
Although the specific CardioVascular Outcome Trial is still under way, it can be affirmed that sotagliflozin seems to share all the advantages of the other, already available, SGLT-2 selective inhibitors. In contrast with other SGLT-2is, however, sotagliflozin has the added advantage of delaying glucose absorption in the intestine. Although it is evident that this inhibition may be important in reducing post-prandial glucose (or at least in delaying and lowering the glucose peak), too many pathophysiologic mechanisms are still poorly studied. More importantly, the possible interactions of sotagliflozin with other common drugs (metformin, interacting through microbiota changes in the lower gut; DPP-4 inhibitors, prolonging sotagliflozin-induced GLP-1 secretion) give hope for significant positive interactions. But again, specific studies are needed.
In conclusion, sotagliflozin seems to represent a promising treatment for both type 1 and type 2 diabetes, either alone or in combination with metformin or DPP-4 inhibitors in type 2 diabetes or, with an adequate insulin protocol, in type 1 diabetes. The dual inhibition of both SGLT-1 and SGLT-2 improves the efficacy of this SGLT inhibitor also in mild and severe CKD, suggesting an extended use also in frail patients where therapeutic options are currently limited.
type 2 diabetes
type 1 diabetes
sodium–glucose co-transporter inhibitors
Major Adverse Cardiovascular Events
post prandial glucose
fasting plasma glucose
urinary glucose excretion
glucagon like peptide-1
gastro inhibitor peptide
intestinal peptide YY
short chain fatty acids
free fatty acids
Mahaffey KW, Neal B, Perkovic V, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Fabbrini E, Sun T, Li Q, et al. Canagliflozin for primary and secondary prevention of cardiovascular events: results from the CANVAS program (canagliflozin cardiovascular assessment study). Circulation. 2018;137(4):323–34.
Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117–28.
Petersen C. Analyse des phloridzins. Ann Acad Sci Fr 1835;15:178.
DeFronzo RA, Goldberg M, Agus ZS. The effects of glucose and insulin on renal electrolyte transport. J Clin Investig. 1976;58(1):83–90.
Ehrenkranz JR, Lewis NG, Kahn CR, Roth J. Phlorizin: a review. Diabetes Metab Res Rev. 2005;21(1):31–8.
Scheepers A, Joost HG, Schurmann A. The glucose transporter families SGLT and GLUT: molecular basis of normal and aberrant function. JPEN J Parenter Enteral Nutr. 2004;28(5):364–71.
Wright EM, Loo DD, Panayotova-Heiermann M, Lostao MP, Hirayama BH, Mackenzie B, Boorer K, Zampighi G. ‘Active’ sugar transport in eukaryotes. J Exp Biol. 1994;196:197–212.
Wright EM, Loo DD, Hirayama BA. Biology of human sodium glucose transporters. Physiol Rev. 2011;91(2):733–94.
Sha S, Devineni D, Ghosh A, Polidori D, Chien S, Wexler D, Shalayda K, Demarest K, Rothenberg P. Canagliflozin, a novel inhibitor of sodium glucose co-transporter 2, dose dependently reduces calculated renal threshold for glucose excretion and increases urinary glucose excretion in healthy subjects. Diabetes Obes Metab. 2011;13(7):669–72.
Powell DR, DaCosta CM, Gay J, Ding ZM, Smith M, Greer J, Doree D, Jeter-Jones S, Mseeh F, Rodriguez LA, et al. Improved glycemic control in mice lacking Sglt1 and Sglt2. Am J Physiol Endocrinol Metab. 2013;304(2):E117–30.
Rieg T, Masuda T, Gerasimova M, Mayoux E, Platt K, Powell DR, Thomson SC, Koepsell H, Vallon V. Increase in SGLT1-mediated transport explains renal glucose reabsorption during genetic and pharmacological SGLT2 inhibition in euglycemia. Am J Physiol Renal Physiol. 2014;306(2):F188–93.
Scheen AJ. Pharmacodynamics, efficacy and safety of sodium-glucose co-transporter type 2 (SGLT2) inhibitors for the treatment of type 2 diabetes mellitus. Drugs. 2015;75(1):33–59.
Lapuerta P, Zambrowicz B, Strumph P, Sands A. Development of sotagliflozin, a dual sodium-dependent glucose transporter 1/2 inhibitor. Diabetes Vasc Dis Res. 2015;12(2):101–10.
Vrhovac I, Balen Eror D, Klessen D, Burger C, Breljak D, Kraus O, Radovic N, Jadrijevic S, Aleksic I, Walles T, et al. Localizations of Na(+)-d-glucose cotransporters SGLT1 and SGLT2 in human kidney and of SGLT1 in human small intestine, liver, lung, and heart. Pflugers Arch. 2015;467(9):1881–98.
Zambrowicz B, Freiman J, Brown PM, Frazier KS, Turnage A, Bronner J, Ruff D, Shadoan M, Banks P, Mseeh F, et al. LX4211, a dual SGLT1/SGLT2 inhibitor, improved glycemic control in patients with type 2 diabetes in a randomized, placebo-controlled trial. Clin Pharmacol Ther. 2012;92(2):158–69.
Washburn WN, Poucher SM. Differentiating sodium-glucose co-transporter-2 inhibitors in development for the treatment of type 2 diabetes mellitus. Expert Opin Investig Drugs. 2013;22(4):463–86.
Kosiborod M, Cavender MA, Fu AZ, Wilding JP, Khunti K, Holl RW, Norhammar A, Birkeland KI, Jorgensen ME, Thuresson M, et al. Lower risk of heart failure and death in patients initiated on sodium-glucose cotransporter-2 inhibitors versus other glucose-lowering drugs: the cvd-real study (comparative effectiveness of cardiovascular outcomes in new users of sodium-glucose cotransporter-2 inhibitors). Circulation. 2017;136(3):249–59.
Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Law G, Desai M, Matthews DR, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644–57.
Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Silverman MG, Bansilal S, Bhatt DL, Leiter LA, et al. The design and rationale for the dapagliflozin effect on cardiovascular events (DECLARE)-TIMI 58 trial. Am Heart J. 2018;200:83–9.
Singh JS, Fathi A, Vickneson K, Mordi I, Mohan M, Houston JG, Pearson ER, Struthers AD, Lang CC. Research into the effect Of SGLT2 inhibition on left ventricular remodelling in patients with heart failure and diabetes mellitus (REFORM) trial rationale and design. Cardiovasc Diabetol. 2016;15:97.
Tanaka A, Shimabukuro M, Okada Y, Taguchi I, Yamaoka-Tojo M, Tomiyama H, Teragawa H, Sugiyama S, Yoshida H, Sato Y, et al. Rationale and design of a multicenter placebo-controlled double-blind randomized trial to evaluate the effect of empagliflozin on endothelial function: the EMBLEM trial. Cardiovasc Diabetol. 2017;16(1):48.
Mordi NA, Mordi IR, Singh JS, Baig F, Choy AM, McCrimmon RJ, Struthers AD, Lang CC. Renal and cardiovascular effects of sodium-glucose cotransporter 2 (SGLT2) inhibition in combination with loop Diuretics in diabetic patients with Chronic Heart Failure (RECEDE-CHF): protocol for a randomised controlled double-blind cross-over trial. BMJ Open. 2017;7(10):e018097.
Natali A, Nesti L, Fabiani I, Calogero E, Di Bello V. Impact of empagliflozin on subclinical left ventricular dysfunctions and on the mechanisms involved in myocardial disease progression in type 2 diabetes: rationale and design of the EMPA-HEART trial. Cardiovasc Diabetol. 2017;16(1):130.
Inzucchi SE, Zinman B, Wanner C, Ferrari R, Fitchett D, Hantel S, Espadero RM, Woerle HJ, Broedl UC, Johansen OE. SGLT-2 inhibitors and cardiovascular risk: proposed pathways and review of ongoing outcome trials. Diabetes Vasc Dis Res. 2015;12(2):90–100.
Schnell O, Standl E, Catrinoiu D, Genovese S, Lalic N, Lalic K, Skrha J, Valensi P, Ceriello A. Report from the 3rd cardiovascular outcome trial (CVOT) summit of the diabetes & cardiovascular disease (D&CVD) EASD study group. Cardiovasc Diabetol. 2018;17(1):30.
von Lewinski D, Gasser R, Rainer PP, Huber MS, Wilhelm B, Roessl U, Haas T, Wasler A, Grimm M, Bisping E, et al. Functional effects of glucose transporters in human ventricular myocardium. Eur J Heart Fail. 2010;12(2):106–13.
Elfeber K, Stumpel F, Gorboulev V, Mattig S, Deussen A, Kaissling B, Koepsell H. Na(+)-d-glucose cotransporter in muscle capillaries increases glucose permeability. Biochem Biophys Res Commun. 2004;314(2):301–5.
Kashiwagi Y, Nagoshi T, Yoshino T, Tanaka TD, Ito K, Harada T, Takahashi H, Ikegami M, Anzawa R, Yoshimura M. Expression of SGLT1 in human hearts and impairment of cardiac glucose uptake by phlorizin during ischemia-reperfusion injury in mice. PLoS ONE. 2015;10(6):e0130605.
Dominguez Rieg JA, Chirasani VR, Koepsell H, Senapati S, Mahata SK, Rieg T. Regulation of intestinal SGLT1 by catestatin in hyperleptinemic type 2 diabetic mice. Lab Investig J Tech Methods Pathol. 2016;96(1):98–111.
Seidelmann SB, Feofanova E, Yu B, Franceschini N, Claggett B, Kuokkanen M, Puolijoki H, Ebeling T, Perola M, Salomaa V, et al. Genetic variants in SGLT1, glucose tolerance, and cardiometabolic risk. J Am Coll Cardiol. 2018;72(15):1763–73.
Cavalot F, Petrelli A, Traversa M, Bonomo K, Fiora E, Conti M, Anfossi G, Costa G, Trovati M. Postprandial blood glucose is a stronger predictor of cardiovascular events than fasting blood glucose in type 2 diabetes mellitus, particularly in women: lessons from the San Luigi Gonzaga Diabetes Study. J Clin Endocrinol Metab. 2006;91(3):813–9.
Ceriello A. The post-prandial state and cardiovascular disease: relevance to diabetes mellitus. Diabetes Metab Res Rev. 2000;16(2):125–32.
Maurer TS, Ghosh A, Haddish-Berhane N, Sawant-Basak A, Boustany-Kari CM, She L, Leininger MT, Zhu T, Tugnait M, Yang X, et al. Pharmacodynamic model of sodium-glucose transporter 2 (SGLT2) inhibition: implications for quantitative translational pharmacology. AAPS J. 2011;13(4):576–84.
Abdul-Ghani MA, DeFronzo RA, Norton L. Novel hypothesis to explain why SGLT2 inhibitors inhibit only 30–50% of filtered glucose load in humans. Diabetes. 2013;62(10):3324–8.
Powell DR, Smith MG, Doree DD, Harris AL, Xiong WW, Mseeh F, Wilson A, Gopinathan S, Diaz D, Goodwin NC, et al. LP-925219 maximizes urinary glucose excretion in mice by inhibiting both renal SGLT1 and SGLT2. Pharmacol Res Perspect. 2015;3(2):e00129.
Rosenstock J, Cefalu WT, Lapuerta P, Zambrowicz B, Ogbaa I, Banks P, Sands A. Greater dose-ranging effects on A1C levels than on glucosuria with LX4211, a dual inhibitor of SGLT1 and SGLT2, in patients with type 2 diabetes on metformin monotherapy. Diabetes Care. 2015;38(3):431–8.
Heise T, Jordan J, Wanner C, Heer M, Macha S, Mattheus M, Lund SS, Woerle HJ, Broedl UC. Pharmacodynamic effects of single and multiple doses of empagliflozin in patients with type 2 diabetes. Clin Ther. 2016;38(10):2265–76.
List JF, Woo V, Morales E, Tang W, Fiedorek FT. Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes. Diabetes Care. 2009;32(4):650–7.
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, Kusek JW, Eggers P, Van Lente F, Greene T, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604–12.
Nathan DM, Kuenen J, Borg R, Zheng H, Schoenfeld D, Heine RJ. Group Ac-DAGS: translating the A1C assay into estimated average glucose values. Diabetes Care. 2008;31(8):1473–8.
Zambrowicz B, Lapuerta P, Strumph P, Banks P, Wilson A, Ogbaa I, Sands A, Powell D. LX4211 therapy reduces postprandial glucose levels in patients with type 2 diabetes mellitus and renal impairment despite low urinary glucose excretion. Clin Ther. 2015;37(1):71 e12–82 e12.
Kohan DE, Fioretto P, Tang W, List JF. Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control. Kidney Int. 2014;85(4):962–71.
Inagaki N, Kondo K, Yoshinari T, Ishii M, Sakai M, Kuki H, Furihata K. Pharmacokinetic and pharmacodynamic profiles of canagliflozin in Japanese patients with type 2 diabetes mellitus and moderate renal impairment. Clin Drug Investig. 2014;34(10):731–42.
Barnett AH, Mithal A, Manassie J, Jones R, Rattunde H, Woerle HJ, Broedl UC. investigators E-RRt: efficacy and safety of empagliflozin added to existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney disease: a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2014;2(5):369–84.
Group TDCaCTR. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;13:977–86.
Polidori D, Sha S, Mudaliar S, Ciaraldi TP, Ghosh A, Vaccaro N, Farrell K, Rothenberg P, Henry RR. Canagliflozin lowers postprandial glucose and insulin by delaying intestinal glucose absorption in addition to increasing urinary glucose excretion: results of a randomized, placebo-controlled study. Diabetes Care. 2013;36(8):2154–61.
Ghezzi C, Hirayama BA, Gorraitz E, Loo DD, Liang Y, Wright EM. SGLT2 inhibitors act from the extracellular surface of the cell membrane. Physiol Rep. 2014. https://doi.org/10.14814/phy2.12058.
Zambrowicz B, Ding ZM, Ogbaa I, Frazier K, Banks P, Turnage A, Freiman J, Smith M, Ruff D, Sands A, et al. Effects of LX4211, a dual SGLT1/SGLT2 inhibitor, plus sitagliptin on postprandial active GLP-1 and glycemic control in type 2 diabetes. Clin Ther. 2013;35(3):273 e277–285 e277.
Trico D, Baldi S, Tulipani A, Frascerra S, Macedo MP, Mari A, Ferrannini E, Natali A. Mechanisms through which a small protein and lipid preload improves glucose tolerance. Diabetologia. 2015;58(11):2503–12.
Powell DR, Smith MG, Doree DD, Harris AL, Greer J, DaCosta CM, Thompson A, Jeter-Jones S, Xiong W, Carson KG, et al. LX2761, a sodium/glucose cotransporter 1 inhibitor restricted to the intestine, improves glycemic control in mice. J Pharmacol Exp Ther. 2017;362(1):85–97.
Hira T, Koga T, Sasaki K, Hara H. Canagliflozin potentiates GLP-1 secretion and lowers the peak of GIP secretion in rats fed a high-fat high-sucrose diet. Biochem Biophys Res Commun. 2017;492(2):161–5.
Ferrannini E, Muscelli E, Frascerra S, Baldi S, Mari A, Heise T, Broedl UC, Woerle HJ. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Investig. 2014;124(2):499–508.
Zheng MY, Yang JH, Shan CY, Zhou HT, Xu YG, Wang Y, Ren HZ, Chang BC, Chen LM. Effects of 24-week treatment with acarbose on glucagon-like peptide 1 in newly diagnosed type 2 diabetic patients: a preliminary report. Cardiovasc Diabetol. 2013;12:73.
Powell DR, Smith M, Greer J, Harris A, Zhao S, DaCosta C, Mseeh F, Shadoan MK, Sands A, Zambrowicz B, et al. LX4211 increases serum glucagon-like peptide 1 and peptide YY levels by reducing sodium/glucose cotransporter 1 (SGLT1)-mediated absorption of intestinal glucose. J Pharmacol Exp Ther. 2013;345(2):250–9.
Edfalk S, Steneberg P, Edlund H. Gpr40 is expressed in enteroendocrine cells and mediates free fatty acid stimulation of incretin secretion. Diabetes. 2008;57(9):2280–7.
Hirasawa A, Tsumaya K, Awaji T, Katsuma S, Adachi T, Yamada M, Sugimoto Y, Miyazaki S, Tsujimoto G. Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120. Nat Med. 2005;11(1):90–4.
Zhou J, Martin RJ, Tulley RT, Raggio AM, McCutcheon KL, Shen L, Danna SC, Tripathy S, Hegsted M, Keenan MJ. Dietary resistant starch upregulates total GLP-1 and PYY in a sustained day-long manner through fermentation in rodents. Am J Physiol Endocrinol Metab. 2008;295(5):E1160–6.
Herrmann C, Goke R, Richter G, Fehmann HC, Arnold R, Goke B. Glucagon-like peptide-1 and glucose-dependent insulin-releasing polypeptide plasma levels in response to nutrients. Digestion. 1995;56(2):117–26.
Anini Y, Brubaker PL. Muscarinic receptors control glucagon-like peptide 1 secretion by human endocrine L cells. Endocrinology. 2003;144(7):3244–50.
Lee EY, Kaneko S, Jutabha P, Zhang X, Seino S, Jomori T, Anzai N, Miki T. Distinct action of the alpha-glucosidase inhibitor miglitol on SGLT3, enteroendocrine cells, and GLP1 secretion. J Endocrinol. 2015;224(3):205–14.
Solini A, Sebastiani G, Nigi L, Santini E, Rossi C, Dotta F. Dapagliflozin modulates glucagon secretion in an SGLT2-independent manner in murine alpha cells. Diabetes Metab. 2017;43(6):512–20.
Wachters-Hagedoorn RE, Priebe MG, Heimweg JA, Heiner AM, Elzinga H, Stellaard F, Vonk RJ. Low-dose acarbose does not delay digestion of starch but reduces its bioavailability. Diabet Med. 2007;24(6):600–6.
Bailey CJ, Wilcock C, Scarpello JH. Metformin and the intestine. Diabetologia. 2008;51(8):1552–3.
Napolitano A, Miller S, Nicholls AW, Baker D, Van Horn S, Thomas E, Rajpal D, Spivak A, Brown JR, Nunez DJ. Novel gut-based pharmacology of metformin in patients with type 2 diabetes mellitus. PLoS ONE. 2014;9(7):e100778.
DeFronzo RA, Buse JB, Kim T, Burns C, Skare S, Baron A, Fineman M. Once-daily delayed-release metformin lowers plasma glucose and enhances fasting and postprandial GLP-1 and PYY: results from two randomised trials. Diabetologia. 2016;59(8):1645–54.
Buse JB, DeFronzo RA, Rosenstock J, Kim T, Burns C, Skare S, Baron A, Fineman M. The primary glucose-lowering effect of metformin resides in the gut, not the circulation: results from short-term pharmacokinetic and 12-week dose-ranging studies. Diabetes Care. 2016;39(2):198–205.
Wu H, Esteve E, Tremaroli V, Khan MT, Caesar R, Manneras-Holm L, Stahlman M, Olsson LM, Serino M, Planas-Felix M, et al. Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Nat Med. 2017;23(7):850–8.
de la Cuesta-Zuluaga J, Mueller NT, Corrales-Agudelo V, Velasquez-Mejia EP, Carmona JA, Abad JM, Escobar JS. Metformin is associated with higher relative abundance of mucin-degrading Akkermansia muciniphila and several short-chain fatty acid-producing microbiota in the gut. Diabetes Care. 2017;40(1):54–62.
Takebayashi K, Hara K, Terasawa T, Naruse R, Suetsugu M, Tsuchiya T, Inukai T. Effect of canagliflozin on circulating active GLP-1 levels in patients with type 2 diabetes: a randomized trial. Endocr J. 2017;64(9):923–31.
Takebayashi K, Inukai T. Effect of sodium glucose cotransporter 2 inhibitors with low SGLT2/SGLT1 selectivity on circulating glucagon-like peptide 1 levels in type 2 diabetes mellitus. J Clin Med Res. 2017;9(9):745–53.
Ahn CH, Oh TJ, Kwak SH, Cho YM. Sodium-glucose cotransporter-2 inhibition improves incretin sensitivity of pancreatic beta-cells in people with type 2 diabetes. Diabetes Obes Metab. 2018;20(2):370–7.
Grempler R, Thomas L, Eckhardt M, Himmelsbach F, Sauer A, Sharp DE, Bakker RA, Mark M, Klein T, Eickelmann P. Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: characterisation and comparison with other SGLT-2 inhibitors. Diabetes Obes Metab. 2012;14(1):83–90.
Han S, Hagan DL, Taylor JR, Xin L, Meng W, Biller SA, Wetterau JR, Washburn WN, Whaley JM. Dapagliflozin, a selective SGLT2 inhibitor, improves glucose homeostasis in normal and diabetic rats. Diabetes. 2008;57(6):1723–9.
Bonner C, Kerr-Conte J, Gmyr V, Queniat G, Moerman E, Thevenet J, Beaucamps C, Delalleau N, Popescu I, Malaisse WJ, et al. Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion. Nat Med. 2015;21(5):512–7.
Mezza T, Muscogiuri G, Sorice GP, Clemente G, Hu J, Pontecorvi A, Holst JJ, Giaccari A, Kulkarni RN. Insulin resistance alters islet morphology in nondiabetic humans. Diabetes. 2014;63(3):994–1007.
Scheen AJ. DPP-4 inhibitor plus SGLT-2 inhibitor as combination therapy for type 2 diabetes: from rationale to clinical aspects. Expert Opin Drug Metab Toxicol. 2016;12(12):1407–17.
Cinti F, Moffa S, Impronta F, Cefalo CM, Sun VA, Sorice GP, Mezza T, Giaccari A. Spotlight on ertugliflozin and its potential in the treatment of type 2 diabetes: evidence to date. Drug Des Devel Ther. 2017;11:2905–19.
Dey J. SGLT2 inhibitor/DPP-4 inhibitor combination therapy-complementary mechanisms of action for management of type 2 diabetes mellitus. Postgrad Med. 2017;129(4):409–20.
Ludvik B, Frias JP, Tinahones FJ, Wainstein J, Jiang H, Robertson KE, Garcia-Perez LE, Woodward DB, Milicevic Z. Dulaglutide as add-on therapy to SGLT2 inhibitors in patients with inadequately controlled type 2 diabetes (AWARD-10): a 24-week, randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2018;6(5):370–81.
Frias JP, Guja C, Hardy E, Ahmed A, Dong F, Ohman P, Jabbour SA. Exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy (DURATION-8): a 28 week, multicentre, double-blind, phase 3, randomised controlled trial. Lancet Diabetes Endocrinol. 2016;4(12):1004–16.
Cryer PE. Mechanisms of hypoglycemia-associated autonomic failure in diabetes. N Engl J Med. 2013;369(4):362–72.
Mathieu C, Zinman B, Hemmingsson JU, Woo V, Colman P, Christiansen E, Linder M, Bode B, Investigators AO. Efficacy and safety of liraglutide added to insulin treatment in type 1 diabetes: the ADJUNCT ONE treat-to-target randomized trial. Diabetes Care. 2016;39(10):1702–10.
Petrie JR, Chaturvedi N, Ford I, Brouwers M, Greenlaw N, Tillin T, Hramiak I, Hughes AD, Jenkins AJ, Klein BEK, et al. Cardiovascular and metabolic effects of metformin in patients with type 1 diabetes (REMOVAL): a double-blind, randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. 2017;5(8):597–609.
Ellis SL, Moser EG, Snell-Bergeon JK, Rodionova AS, Hazenfield RM, Garg SK. Effect of sitagliptin on glucose control in adult patients with Type 1 diabetes: a pilot, double-blind, randomized, crossover trial. Diabet Med. 2011;28(10):1176–81.
Oelze M, Kroller-Schon S, Welschof P, Jansen T, Hausding M, Mikhed Y, Stamm P, Mader M, Zinssius E, Agdauletova S, et al. The sodium-glucose co-transporter 2 inhibitor empagliflozin improves diabetes-induced vascular dysfunction in the streptozotocin diabetes rat model by interfering with oxidative stress and glucotoxicity. PLoS ONE. 2014;9(11):e112394.
Henry RR, Rosenstock J, Edelman S, Mudaliar S, Chalamandaris AG, Kasichayanula S, Bogle A, Iqbal N, List J, Griffen SC. Exploring the potential of the SGLT2 inhibitor dapagliflozin in type 1 diabetes: a randomized, double-blind, placebo-controlled pilot study. Diabetes Care. 2015;38(3):412–9.
Perkins BA, Cherney DZ, Partridge H, Soleymanlou N, Tschirhart H, Zinman B, Fagan NM, Kaspers S, Woerle HJ, Broedl UC, et al. Sodium-glucose cotransporter 2 inhibition and glycemic control in type 1 diabetes: results of an 8-week open-label proof-of-concept trial. Diabetes Care. 2014;37(5):1480–3.
Henry RR, Thakkar P, Tong C, Polidori D, Alba M. Efficacy and safety of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, as add-on to insulin in patients with type 1 diabetes. Diabetes Care. 2015;38(12):2258–65.
Powell DR, Doree D, Jeter-Jones S, Ding ZM, Zambrowicz B, Sands A. Sotagliflozin improves glycemic control in nonobese diabetes-prone mice with type 1 diabetes. Diabetes Metab Syndr Obes. 2015;8:121–7.
Garg SK, Henry RR, Banks P, Buse JB, Davies MJ, Fulcher GR, Pozzilli P, Gesty-Palmer D, Lapuerta P, Simo R, et al. Effects of sotagliflozin added to insulin in patients with type 1 diabetes. N Engl J Med. 2017;377(24):2337–48.
Sands AT, Zambrowicz BP, Rosenstock J, Lapuerta P, Bode BW, Garg SK, Buse JB, Banks P, Heptulla R, Rendell M, et al. Sotagliflozin, a dual SGLT1 and SGLT2 inhibitor, as adjunct therapy to insulin in type 1 diabetes. Diabetes Care. 2015;38(7):1181–8.
Chao EC, Henry RR. SGLT2 inhibition–a novel strategy for diabetes treatment. Nat Rev Drug Discov. 2010;9(7):551–9.
Pieber TR, Famulla S, Eilbracht J, Cescutti J, Soleymanlou N, Johansen OE, Woerle HJ, Broedl UC, Kaspers S. Empagliflozin as adjunct to insulin in patients with type 1 diabetes: a 4-week, randomized, placebo-controlled trial (EASE-1). Diabetes Obes Metab. 2015;17(10):928–35.
Fioretto P, Giaccari A, Sesti G. Efficacy and safety of dapagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in diabetes mellitus. Cardiovasc Diabetol. 2015;14:142.
Dandona P, Mathieu C, Phillip M, Hansen L, Griffen SC, Tschope D, Thoren F, Xu J, Langkilde AM. Investigators D-: efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (DEPICT-1): 24 week results from a multicentre, double-blind, phase 3, randomised controlled trial. Lancet Diabetes Endocrinol. 2017;5(11):864–76.
Fda.gov. FDA Drug Safety Communication: FDA Warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood. 2015.
Cohen JJ, Berglund F, Lotspeich WD. Renal tubular reabsorption of acetoacetate, inorganic sulfate and inorganic phosphate in the dog as affected by glucose and phlorizin. Am J Physiol. 1956;184(1):91–6.
Zelniker TA, Wiviott SD, Raz I, Im K, Goodrich EL, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Furtado RHM, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet. 2019;393(10166):31–9.
Fazeli Farsani S, Brodovicz K, Soleymanlou N, Marquard J, Wissinger E, Maiese BA. Incidence and prevalence of diabetic ketoacidosis (DKA) among adults with type 1 diabetes mellitus (T1D): a systematic literature review. BMJ Open. 2017;7(7):e016587.
Taylor SI, Blau JE, Rother KI. SGLT2 Inhibitors May Predispose to Ketoacidosis. J Clin Endocrinol Metab. 2015;100(8):2849–52.
Peters AL, Buschur EO, Buse JB, Cohan P, Diner JC, Hirsch IB. Euglycemic diabetic ketoacidosis: a potential complication of treatment with sodium-glucose cotransporter 2 inhibition. Diabetes Care. 2015;38(9):1687–93.
Handelsman Y, Henry RR, Bloomgarden ZT, Dagogo-Jack S, DeFronzo RA, Einhorn D, Ferrannini E, Fonseca VA, Garber AJ, Grunberger G, et al. American association of clinical endocrinologists and american college of endocrinology position statement on the association of Sglt-2 inhibitors and diabetic ketoacidosis. Endocr Pract. 2016;22(6):753–62.
Muchmore DB. The need for faster insulin. J Diabetes Sci Technol. 2017;11(1):157–9.
CMAC wrote/edited the review and provided the final version of the manuscript, FC, SM, FI, GS and TM contributed to writing the manuscript, AG designed the work and reviewed/edited the article, AP contributed to the discussion providing interesting suggestions. All the authors read and approved the final manuscript.
We thank David Powell for constructive criticism and insights, and Serena Rotunno who provided editorial assistance in the preparation of this manuscript.
The authors declare that they have no competing interests.
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Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.
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This study was supported by grants to AG from the Università Cattolica del Sacro Cuore (Fondi Ateneo Linea D.3.2 Sindrome Metabolica), from the Italian Ministry of Education, University and Research (PRIN 2010JS3PMZ_011) and to TM from EFSD/Novonordisk and EFSD/Lilly, and to C.M.A.C from Fondazione AMD (BORSE DI STUDIO IN MEMORIA DI ADOLFO ARCANGELI).
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Cefalo, C.M.A., Cinti, F., Moffa, S. et al. Sotagliflozin, the first dual SGLT inhibitor: current outlook and perspectives. Cardiovasc Diabetol 18, 20 (2019). https://doi.org/10.1186/s12933-019-0828-y
- SGLT2 inhibitors
- Hypoglycemic therapy