SGLT2 Inhibitors: Physiology and Pharmacology : Kidney360

Journal Logo

Basic Science for Clinicians

SGLT2 Inhibitors: Physiology and Pharmacology

Wright, Ernest M.

Author Information
Kidney360 2(12):p 2027-2037, December 2021. | DOI: 10.34067/KID.0002772021
  • Free
  • SDC

Abstract

Introduction

Rather unexpectedly to endocrinologists, sodium glucose cotransporter-2 (SGLT2) in the kidney has become a major target for the treatment of type 2 diabetes mellitus (T2DM). As a background, the kidneys normally filter 120–180 g (0.67–1 mol) of glucose from plasma every 24 hours, and less than half a gram (3 mmol) is excreted in the urine. Smith et al. reported in 1933 that the reabsorption of the filtered load of glucose was completely inhibited by intravenous phlorizin (phloretin-2’-β-D-glucopyranoside), a naturally occurring plant glucoside (1). Fast forwarding half a century, DeFronzo and colleagues found that “phlorizinising” diabetic rats diminished their hyperglycemia and restored their insulin sensitivity, suggesting phlorizin could be used as a therapy for T2DM (2). Oral phlorizin was not considered to be a viable therapy owing to its hydrolysis by intestinal lactase, and the diarrhea caused by inhibition of intestinal SGLT1.

The pharmaceutical industry set its sights on developing an oral SGLT2 inhibitor to treat T2DM after the cloning and characterizing of the intestinal and renal SGLTs in 1987–1992 (3–10). This was encouraged by reports that familial renal glucosuria (FRG; OMIM 233100) is a benign disorder (11). The initial effort was pioneered by Tsujihara at Tanabe Seryaku in Japan (12), who tested oral phlorizin derivatives on renal glucose excretion in rodents that culminated in the prodrug T-1095 (13). Other drug houses in Japan, the United States, and Europe rapidly followed (for example, see 14–16), resulting in three high-affinity SGLT2 drugs, dapagliflozin, canagliflozin, and empagliflozin, approved in 2013–2014. This class of drugs are sometimes referred to as gliflozins.

Common features of these drugs are that they are aryl-C- glucosides (Figure 1) that have low nanomolar affinities for SGLT2, and a high selectivity over SGLT1 (Table 1). Another key to their success is SGLT2 is found on the luminal membrane of the early segments of the renal proximal tubule, and virtually nowhere else in the body. For these reasons, it was reasonable to expect these drugs would not encounter adverse side effects.

F1
Figure 1.:
The chemical structure of phlorizin, empagliflozin (Jardiance), dapagliflozin (Forxiga), and canagliflozin (Invokana). Note that phlorizin is an O-glucoside that can be hydrolyzed by the intestinal brush border lactase, whereas the aryl-glucosides are not. The selectivity of these sodium glucose cotransporter (SGLT) inhibitors is given in Table 1. Modified from Wright, 2013 (9).
Table 1. - Kinetics of human SGLT2 and SGLT1
COLUMN ONE SGLT2 SGLT1
Glucose Km (mM) 5 2
Galactose Km (mM) >>100 6
aMDG Km (mM) 6 4
Sodium Km (mM) 25 75
Na+/glucose coupling 1 2
Turnover 35 s−1(38) 30–60 s−1
Phlorizin Ki (nM) 12 140
Dapagliflozin Ki (nM) 6 400
Phlorizin IC50 (nM) 21 290
Dapagliflozin IC50 (nM) (15) 1 1400
Canaglifozin IC50 (nM) (15) 3 700
Empaglifozin IC50 (nM) (15) 3 8300
Sotagliflozin IC50 (nM) (62) 2 40
All data collected on human SGLT2 and SGLT1 clones expressed in cultured cells at -60 mV and 37°C (35,36), except for the turnover of SGLT2 that was in Xenopus leavis oocytes at 22°C (38). IC50 values are for inhibition of aMDG uptakes. aMDG, xx.

SGLT Biology

SGLT1 and SGLT2 are members of the SLC5 gene family, a subdivision of an ancient superfamily of sodium cotransporters (8–10,17). SGLT1 (SLC5A1) is predominantly expressed the small intestine, and to a lesser extent the kidney cortex, whereas SGLT2 (SLC5A2) is virtually restricted to the renal cortex. The genes code for near-identical proteins with approximately 670 amino acids organized in 14 transmembrane helices. A core of 10 TM helices coding for the glucose, and sodium binding sites are shared with other sodium transporters in bacteria and animals. SGLT2 is located solely in the luminal membrane of the S1 and S2 segments of the proximal tubule, and SGLT1 in the luminal membrane of the S3 segment (18). In the intestine, SGLT1 is restricted to the brush border membrane of mature enterocytes (8,18).

The functional properties of both transporters have been documented in studies of SGLT1 and SGLT2 expressed in heterologous expression systems. Table 1 summarizes the results obtained in cultured cells at 37°C. Both SGLTs show a similar affinity for glucose, Km 2, and 5 mM, and similar turnover numbers of 30–60 s−1 (the number of complete kinetic cycles per second). The major differences are in the number of sodium ion needed to drive glucose transport, the Na+/glucose coupling ratio is 2 for SGLT1 and 1 for SGLT2, and the sugar and inhibitor selectivity.

Figure 1 shows the chemical structure of phlorizin and three of the first inhibitors approved for the treatment of T2DM. All are glucosides, but empagliflozin ((Jardiance), dapagliflozin (Forxiga), and canagliflozin (Invokana) are aryl-C-glucosides that are not cleaved by lactase. These inhibitors are more potent against SGLT2 than SGLT1 with inhibitors constants in the range of 1–12 nanomoles, and are more selective for SGLT2, 2700-fold for Jardiance (Table 1). This difference in potency between SGLT2 and SGLT1 must be due to differences in structure of the aglycones, but this has not been rigorously addressed. However, subtle differences in the structure of aglycones determine whether they are SGLT1 substrates or inhibitors (19). Although the SGLT2 drug inhibitor constants are quite similar, the oral clinical dose is 100–300 mg for Invokana but only 10–25 mg for Jardiance and Forxiga.

The distribution of SGLTs in human subjects has been limited to gene expression and immunohistochemistry on postmortem and/or surgically resected tissues. However, these methods do not provide information about their functional activity in tissues. To remedy this we have turned to positron emission tomography (PET) with a specific, nonmetabolized SGLT tracer, Me4FDG (α-methy-4-[18F]-fluoro-4-deoxy-D-glucopyranoside), in both animal and human subjects (20–22). PET is a non-invasive imaging method with high spatial (2 mm) and temporal resolution (seconds) to follow 18F distribution in living subjects (23). Me4FDG is transported by SGLT1 and SGLT2, but not by facilitated glucose transporters, GLUTs (21). Figure 2 shows the steady-state distribution of Me4FDG injected intravenously into two subjects, a control (A) and (B), a patient with FRG (OMIM 2333100) (8,11). This male patient with FRG has a homozygous SGLT2 mutation, Ala305Val, associated with a defect in renal glucose reabsorption resulting in the urinary excretion of 66 g (370 mmol) per 1.73 m2 per 24 hours (24).

F2
Figure 2.:
Distribution of SGLT activity as visualized by Me4FDG positron emission tomography (PET) in a control subject (A) and a patient with familial renal glucosuria (FRG) (B). Me4FDG is a specific substrate for SGLTs (21) (Sala-Rabanal et al., 2016). Each subject was injected intravenously with 10 mCi of Me4FDG and whole-body PET scans were collected 60 minutes later. The scans were normalized to the highest region of Me4FDG uptake (red). In both, there was no uptake into brain (or lungs) owing to the absence of SGLTs in the blood-brain barrier, but there was modest activity in the kidney, skeletal muscle, and testis. In the control, there was no Me4FDG in the urinary bladder, whereas Me4FDG was excreted into the bladder in the patient with FRG. Adapted from Wright et al. 2011 (8); and Wright et al. (in preparation).

In the control subject, accumulation of Me4FDG is observed in the renal cortex and regions of the liver, with modest accumulations in skeletal muscle and testis. None is found in the brain or the urinary bladder, the former is due to the lack of SGLTs in the blood-brain barrier, and the latter is due to the reabsorption of Me4FDG from the glomerular filtrate by SGLTs in the proximal tubule. A similar distribution is seen in the patient with FRG, with the exception that in the kidney Me4FDG is shifted from the cortex toward the renal pelvis, and is excreted into the urinary bladder. The time course of Me4FDG excretion into the bladder of the patient with FRG is shown in Figure 3, relative to that for control subjects with or without treatment with Jardiance (empagliflozin). Me4FDG excretion for the patient with FRG reached 3.5% of the injected dose in 75 minutes, compared with none for the control, and 7% after treatment with Jardiance. The SGLT2 inhibitors also inhibited Me4FDG reabsorption in mouse microPET studies (25).

F3
Figure 3.:
The time course of Me4FDG excretion into the urinary bladder in control subject, a control treated with oral Jardiance (empagliflozin), and the patient with FRG shown in Figure 2 . In each, 10 mCi of Me4FDG (370 MBq) was injected intravenously and a dynamic scan over the abdomen was taken for up to 75 minutes. The total activity in the urinary bladder in MBq is plotted against time. The plot + Jardiance is for a control subject given a 25 mg oral dose of Jardiance 2 hours before the PET scan. Wright et al. unpublished.

To distinguish between SGLT1 and SGLT2 in PET studies, we developed a [18F]-labeled SGLT2 inhibitor, 4-[18F]fluoro-dapagloflozin, F-DAPA, where 18F replaces the −OH group on C#4 in the pyranose ring (25). In rodent, intravenous (i.v.) injection results in rapid F-DAPA binding to the kidney that is displaced after i.v. dapagliflozin or phlorizin. The specific binding of F-DAPA to the whole kidney was 6× higher than nonspecific binding, and no specific binding was observed for other parts of the body, brain, heart, skeletal muscle, liver, or salivary glands. In human subjects, Jardiance significantly reduced the modest Me4FDG uptake into liver and skeletal muscle, but not the heart (unpublished).

The time course of F-DAPA distribution in the rat is shown in Supplemental Movie 1 (25). After i.v. injection, there was a rapid accumulation of F-DAPA in the renal cortex that approached a steady state in 20 minutes. After i.v. injection of dapagliflozin (or phlorizin, not shown) there was a rapid displacement of F-DAPA from the kidney cortex, reabsorption of the tracer into blood and excretion into the intestine. Of particular note, there was no excretion of F-DAPA into the urinary bladder, before or after displacement with dapagliflozin or phlorizin. The mechanisms of F-DAPA reabsorption from the glomerular filtrate and secretion by the liver are unknown. Similar F-DAPA PET experiments were conducted on human subjects, but these were not successful owing to a very rapid metabolism of the tracer.

The location of specific F-DAPA binding in mouse kidney was refined by autoradiography (Figure 4). In this experiment, F-DAPA was injected intravenously, the kidney was harvested after 60 minutes, and the distribution of F-DAPA was examined in thin frozen sections (25). As shown for the whole kidney (Figure 4A), F-DAPA binding was restricted to the outer cortex, and at higher magnification to tubules close to the glomeruli (Figure 4, B and C). This distribution of F-DAPA binding mimics SGLT2 gene expression and SGLT2 immunocytochemistry in the mouse, rat, and human kidneys, that is, in S1 and S2 segments of the proximal tubule (6,18).

F4
Figure 4.:
The distribution of SGLT2 in the mouse kidney as determined by 4-[ 18 F]fluoro-dapaglifozin (F-DAPA) autoradiography. A mouse was injected intravenously with 4 mCi of F-DAPA and the kidney was harvested after 60 minutes and prepared for autoradiography. The figure shows the grain density and hematoxylin and eosin staining for a section of the whole kidney (A), a higher magnification view of the outer cortex (B), and a higher magnification view of tubules surrounding a single glomerulus. The scale bars are 1 mm in (A), and 100 µm in (B) and (C). These result shows that SGLT2 is confined to the outer cortex in the mouse kidney, specifically to some tubules surrounding the glomeruli. Reprinted from Ghezzi et al. 2017 (25).

The results shown in Supplemental Movie 1, Figures 2, 3, and 4, are explained by the activity of SGLTs in the reabsorption of glucose in the proximal tubule, specifically SGLT2. Me4FDG micro-PET experiments on wild-type, SGLT1-null, and SGLT2-null mice confirmed the importance of SGLT2 and SGLT1 in renal glucose reabsorption, and SGLT1 in intestinal absorption. The lack of SGLT activity in mouse heart, liver, and skeletal muscle may be due to a species difference from human (21,26).

Glucose Reabsorption

The understanding of glucose handling by the human kidney is that after glomerular filtration of glucose, virtually all of the filtered load is reabsorbed in healthy subjects (Figure 5A). Reabsorption occurs in the proximal tubule because no glucose is found at the end of the straight S3 segment (27). The SGLT2 inhibitors are believed to be freely filtered, as for phlorizin (28), where they then bind to SGLTs in the luminal membrane of the epithelial cells in the proximal tubule. In the dog kidney, the clearance of [3-H]-phlorizin was identical to that for creatinine, and none was excreted in the urine.

F5
Figure 5.:
A drawing showing the organization of a cortical nephron (A), and a model for glucose reabsorption from the glomerular filtrate by the epithelium lining the S1 and S2 segments of the proximal tubule (B). Glucose is freely filtered from plasma by the glomerulus, and then completely reabsorbed in the proximal tubule (highlighted in green). No glucose is detected in tubular fluid by the end of the proximal tubule. A major fraction of the filtered glucose is reabsorbed in S1 and S2 by SGLT2, then any remaining glucose in S3 is mopped up by SGLT1. (B) Glucose is absorbed from the tubules by SGLTs in the luminal membrane, driven by the sodium electrochemical potential gradient. Glucose accumulated in the epithelium then diffuses into blood through GLUT2 in the basolateral membrane. The sodium gradient across the luminal membrane is maintained by the Na+/K+ pump in the basolateral membrane. The net result is the reabsorption of glucose and salt from the glomerular filtrate. Major differences between SGLT2 in S1/S2 and SGLT1 in S3 is that SGLT2 drugs specifically block glucose transport in S1 and S2, whereas phlorizin blocks transport in S1, S2, and S3.

The SGLT2 drugs, even at saturating plasma concentrations only inhibit glucose reabsorption by 40–50% (29). The remaining amount in the glomerular filtrate is largely salvaged by SGLT1 activity in S3. This has been confirmed in mice with knockouts of the SGLT1 and SGLT2 genes (21,30), and it is also evident in patients with SGLT2 “knock-out” mutations, where glucose excretion is less than the filtered load (see 8).

SGLTs are expressed in the luminal membrane of the proximal tubule, SGLT2 in the S1/S2 segments (Figure 5B) and SGLT1 in the S3 segment. Glucose uptake into the epithelia across the luminal membrane is driven by the Na+ electrochemical potential gradient across the membrane, then glucose diffuses out into blood across the basolateral membrane through the facilitated glucose transporter GLUT2 (21). Na+ that enters the cells through SGLTs is transported out across the basolateral membrane by Na+/K+ pumps. In the S1 and S2, the net result is that one Na+ is absorbed for every glucose molecule (and one anion to maintain electroneutrality), whereas in S3 two Na+ ions are absorbed for every glucose molecule. Given a glucose reabsorption of 120–180 g (0.67–1 mol) of glucose per day, the stoichiometry of the SGLTs, glucose-coupled sodium absorption only accounts for <10% of the total sodium reabsorption in the proximal tubule. At clinical doses, the SGLT2 inhibitors only reduce total glucose absorption by some 50%, so there is only a modest effect on urinary sodium excretion, given the ability of the distal tubule to reabsorb the increased salt load.

Mechanism of Na+ Glucose Transport

Much more is known about the mechanism of glucose transport by SGLT1 than for SGLT2, simply due to the much higher activity of SGLT1 in heterologous expression systems such as Xenopus laevis oocytes (6,8,9). This has been partially rectified by the discovery that coexpression of MAP17 increased SGLT2 expression in oocytes (31). MAP17 (PDZK1IP1) is small protein expressed in the plasma membrane, endoplasmic reticulum, and Golgi apparatus of many cell types, and is involved in cargo transport between the Golgi and plasma membrane. In the mouse proximal tubule, MAP17 is expressed in the brush border membrane of the S1 and S2 segments, where it is involved in the endocytosis of the sodium phosphate cotransporter NaPi-IIa from the brush border into the trans-Golgi network (32). MAP17 interacts indirectly with the cytoplasmic C-terminal domain of NaPi-IIa through a PDZ protein. However, there is no comparable C-terminal domain of SGLT2, but there is evidence that MAP17 may be a β-subunit of SGLT2 in the plasma membrane of the S1 and S2 segments (31,33).

SGLT2 is robustly expressed in cultured mammalian cells at 37°C (34–37), and there is no MAP17 in these cells (32,33). The kinetic properties of SGLT2 in cultured cells and oocytes are similar (35,38), and those for HEK293T cells are summarized in Table 1.

The kinetics of SGLT2 and SGLT1 are very similar in that they are sodium cotransporters with an obligatory coupling of glucose and sodium transport that is specifically blocked by phlorizin. The glucose affinities are 5 and 2 mM for glucose, with maximum enzymatic turnover numbers of 30–60 s−1. Such data refute earlier claims that these are low-affinity, high-capacity, and high-affinity, low-capacity transporters. The major kinetic differences between SGLT2 and SGLT1 are: (1) stoichiometry of Na+ and glucose transport (1 for SGLT2, and 2 for SGLT1); (2) sugar specificity (galactose is transported by SGLT1 but rather poorly for SGLT2); (3) the requirement of SGLT2 for MAP17; (4) the high selectivity of SGLT2 for inhibitors; and (5) high SGLT1 capacitive currents are evident for SGLT1 but not SGLT2 (these have been instrumental in developing kinetic models, see Figure 6).

F6
Figure 6.:
A model for glucose transport by SGLT2. The transporter in the plasma membrane is shown as a double-gated protein where, in the absence of ligands, both gates are closed. The binding of external sodium (green circle) to the Na2 site opens the external gate to allow external glucose (yellow hexagon) to bind. After glucose is bound, the external gate closes after sugar binding to trap the sugar in the middle of the protein before the inner gate opens to permit Na+ and glucose to exit into the cytoplasm in one step. Finally, the transporter returns to the starting position. The net result is strict coupling of one sodium and one glucose transport across the membrane during one transport cycle.

A kinetic model for Na+ and glucose transport by SGLT2 is presented in Figure 6. This is largely on the basis of the wealth of experimental biochemical, molecular, and biophysical data collected for SGLT1 (see 8,17). The transporter is represented as a double-gated membrane protein that exists in a minimum of interconvertible five states (C1, C2, C3, C4, C6). The distribution of these depends on the Na+ and glucose concentrations on each side of the membrane, and the voltage across the membrane. Under physiologic conditions, with the extracellular Na+ and glucose concentrations of 145 m-equiv/l and 5 mM, and a membrane potential of -60 mV, and the direction of Na+/glucose is into the cell. In the kinetic scheme, extracellular Na+ binds first to open the extracellular gate (C1–C2) and, after extracellular glucose binding, the external gate closes (C2–C3). The intracellular gate then opens to permit Na+ and glucose to exit into the cytoplasm (C4–C6). The intracellular release of ligands is presumed to be stochastic, unlike our original symmetrical model with a C5 state (8,17,39). The final step is the transition of the inward to outward facing conformations (C6–C1). The apo-transporter is charged, valance -1, and the major effect of voltage in on the distribution between C6 and C1, and this is the origin of the fast, transient SGLT1 capacitive currents in the absence of ligands (8,40,41).

The model accounts for the strict coupling between Na+ and glucose transport that is completely reversible—the direction and rate of transporter simply depends on the ligand concentrations on each side of the membrane and the membrane potential. In the case of SGLT1, the capacitive currents provide an entree into estimating the rate constants for the each step in the kinetic cycle, and determining the total number of transporters in the plasma membrane. This topic is beyond the scope of this review, but interested readers are directed elsewhere (8,17). Suffice to say that a single set of rate constants account for SGLT1 kinetics.

SGLT Inhibitors

Phlorizin and other SGLT blockers are high-affinity, competitive inhibitors that are only active from the extracellular surface in the presence of Na+ (17,37,39,42,43). Inhibition is reversible, but the OFF-time constants are slower for the specific SGLT2 inhibitors than phlorizin (15,36). Phloretin, the phlorizin aglycone, is a low affinity nonspecific inhibitor of SGLTs (8). This, together with the high affinity of phlorizin relative to glucose, has led to the view that the glucose moiety of phlorizin binds to the glucose-binding site of SGLTs, and the phloretin binds at an adjacent site within 15 Å (44).

A molecular interpretation of inhibitor interactions with SGLTs is illustrated in Figure 7. Phlorizin and the SGLT2 drugs bind to the external surface of SGLTs in the outside open Na+ bound conformation. As shown in Figure 7A, phlorizin enters with the glucose moiety approaching the glucose binding site, and the aglycone approaching an external vestibule. Once bound, the inhibitors lock the transporter in an outward-facing conformation. Although binding is reversible, the OFF rate is slow due to the interactions the aglycone and the vestibule, and this accounts for the high affinity of phlorizin relative to glucose.

F7
Figure 7.:
Inhibitor binding to SGLT2. (A) External phlorizin approaching the glucose binding site binding in the sodium bound outward open conformation. The glucose moiety of phlorizin binds to the glucose binding pocket and the aglycone moiety is stuck in the outer vestibule. (B) A structural model of SGLT2 with glucose in the occluded binding site, and the location of the Na2 binding site. From Ghezzi et al. 2018 (27). The protein has a core structure of 10 transmembrane helices (TM 10 not shown for clarity) with glucose. We propose that the external gate formed by residues L84, F98, F453, and the extracellular helical loop EL8b. Glucose is bound through H-bonds to N75, H80, E99, K321, and W291, and hydrophobic binding to Y290. These residues are conserved in SGLT1. Y290, at least in part contributes to the internal gate. (C) The SGLT phlorizin binding site in the center of the membrane protein. The glucose moiety binds to the glucose binding site, and the aglycone occupies an outer vestibule bounded by the external ends of TM1, TM2, TM3, and TM10 (17). Y290, the internal gate is highlighted in yellow. (D) An atomic model of phorizin and dapagliflozin bound to SGLT2 (47). This shows the superimposition of the glucose moiety of dapagliflozin and phlorizin with glucose in the sugar site, and the superimposition of the aglycones in the external vestibule. H80, F98 and H268 form a cage above the inhibitor (H268 is replaced by D268 in SGLT1.

Structural models on the basis of the atomic structure of the bacterial isoform, vSGLT (45,46) provide additional insight into inhibitor binding (47). The transporters have a core structure composed of 10 transmembrane helices with a central sugar binding site (N75, H80, E99, K321, Y290, and W291), external (L84, F98, F453), and internal (Y290) gates, and a Na2 sodium-binding site centered around S393 (Figure 7B). All these residues are conserved between SGLT2, SGLT1, and vSGLT (see 8,17), and their functional importance in SGLT1 has been confirmed by studies of cysteine mutants (40,48,49,50). Similar studies with SGLT2 have not yet been carried out.

The precise location of the inhibitor-binding site shown in Figure 7, B–D. This has been determined by molecular-docking studies on SGLT1 and SGLT2 structural models, and verified for SGLT1 by mutations of coordinating residues (47). The glucose moiety of phlorizin binds in the glucose binding site, and the aglycone is found in an external vestibule bounded by the external ends of TM1, TM2, TM3, and TM10. Phloretin overlaps with the aglycones. Mutation of SGLT1 side-chains predicted to interact with inhibitors, for example, F101, reduces phlorizin binding by 200-fold without influencing glucose transport. In SGLT2, the bound inhibitors are capped by H80, F98, and H268 on the long extracellular loop connecting TM5 and TM6. This cap forms an aromatic cage around the central aromatic ring of the aglycone tail in SGLT2 but not SGLT1, and so may contribute to the differences in selectivity of SGLT inhibitors.

Dapagliflozin binding also involves the glucose moiety binding to the glucose site, and the aglycone tail overlaps with the phlorizin tail in the external facing vestibule, but with the minor difference that dapagliflozin lies deeper in the pocket. Simulations of inhibitor binding also indicate the external gate partially closes after binding, due to a rigid rotation of TM9, an inward bend of the outer half of TM10, and the inward movement of the extracellular loop between TM5 and TM6. These helical rearrangements have been observed in real time by fluorescence measurements on fluorophores covalently bound within the sugar-binding site (17,50).

Unfortunately, the structural models do not account for the selectivity of inhibitors for SGLT2 over SGLT1 (Table 1). Nevertheless, they do account for the sidedness of inhibitor binding as cytoplasmic phlorizin and SGLT2 drugs fail to gain access to the sugar binding site due to steric clashes (47).

To date, there are few reports of SGLT1 specific inhibitors, but there has been some interest in the pharmaceutical companies in dual SGLT1/SGLT2 inhibitors, such as sotaglifozin (Table 1). The objectives were to control blood glucose, especially in type 1 diabetes, by reducing intestinal absorption, and inhibiting renal SGLT2 and SGLT1 (see 51).

SGLT2 Inhibitors in Heart and Kidney Failure

An unanticipated outcome of the Jardiance cardiac safely trial was that patients who were diabetic and treated with Jardiance showed a remarkable reduction in hospitalization and mortality for heart failure (52). This cardio protection is a SGLT2 inhibitor class effect, and it persists in patients who are nondiabetic (53–55). SGLT2 inhibitors are now approved for the treatment of heart failure. Although there is no direct evidence for a relationship between the kidney and heart in the effects of SGLT2 inhibitors, there is rodent data suggesting an off-target effect on cardiac sodium proton exchangers (NHE1). The most compelling experiments come from Zuurbier’s group, who tested the effect of SGLT2 inhibitors on the intracellular Na+ and Ca++ concentrations in isolated cardiac myocytes, and the onset of contraction in an ischemic mouse heart model (56–58). At pharmacologically relevant doses, 0.25–1 µM, the inhibitors produce fast lowering of the intracellular Na and Ca concentrations that are consistent with inhibition of NHE1. Indirect support was achieved by molecular docking studies of the drugs with a homology model of NHE1. The glucose moiety of the drugs reportedly binds to the Na+ binding site and the aglycone to the adjacent extracellular vestibule (our preliminary studies also find vestibule leading canonical glucose binding site, Bisignano et al., unpublished). The effect of SGLT2 inhibitors on cardiac NHE1 are consistent with the current thinking that elevated myocyte Na and Ca intracellular concentrations are drivers of heart failure and cardiac death. Whether these rodents studies will translate into patients is unknown, but I do note that clinical trials on other potent NHE1 inhibitors have not been successful, such as the cariporide GUARDIAN and EXPEDITION trials (59).

After the cardiac safely trials, it emerged the SGLT2 inhibitors produced a comparable reduction in the progression of CKD in patients who were diabetic and nondiabetic (60,61). The underlying mechanisms are not understood, because it is unclear at what points the inhibitors act in the natural progression of kidney disease. In particular, the potential importance of renal sodium protein exchangers, principally NHE3 in the proximal tubule, has yet to be clarified.

Summary

Oral SGLT inhibitors are rapidly absorbed from the gastrointestinal tract into blood, where they bind to plasma proteins and circulate throughout the vascular tree with a half-life of 10–14 hours. The free drugs are filtered from plasma at the glomerulus where they then bind to the luminal membrane of the proximal tubule. The SGLT2 inhibitors bind to SGLT2 in the luminal membrane of the early (S1 and S2) segments of the nephron, where they may block up to 60% of glucose reabsorption. Glucose that escapes reabsorption in S1 and S2 segments is normally salvaged by SGLT1 in the late proximal tubule (S3). The nonspecific inhibitor phlorizin binds to SGLT2 in S1 and S2, and to SGLT1 in S3, causing complete inhibition of glucose reabsorption. In mice, this has been confirmed using SGLT2 and SGLT1 null-mice, and may be inferred in humans with “knock-out” mutations of SGLT2 (FRG). There have been efforts to develop dual SGLT2/SGLT1 inhibitors, such as sotagliflozin (Table 1), but these have not yet gained Food and Drug Administration approval for the treatment of diabetes. Considerable progress has been made in understanding the mechanism of action of SGLT inhibitors at a molecular level, but additional work remains to account for their selectivity for SGLT2 over SGLT1.

There is a remarkable ability of SGLT2 drugs to lower the progression of heart and kidney disease, and, at least for heart disease, this may be due to an off-target effect on the cardiac sodium proton exchanger NHE1.

Disclosures

E. Wright reports being a consultant on SGLTs for various pharmaceutical companies, including Boehringer Ingelheim, from 2006 to 2015.

Funding

This work was supported by National Institutes of Health grant DK19567 and the Mellinkoff endowed chair in Medicine.

Acknowledgments

I am indebted to my students, fellows, and collaborators for their contributions to SGLT biology over the past decades, who are recognized here in the cited papers and reviews.

Author Contributions

E. Wright conceptualized the study, was responsible for the investigation, and wrote the original draft.

Supplemental Material

This article contains supplemental material online at http://kidney360.asnjournals.org/lookup/suppl/doi:10.34067/KID.0002772021/-/DCSupplemental.

Supplemental Movie 1. The time course of the distribution of F-DAPA in abdomen of the rat. After i.v. delivery there was rapid distribution throughout the vascular tree, peaking at 2 minutes (3% I.D. per gram of plasma) before falling to a quasi-steady value of 0.35% I.D. per gram. In contrast, there was rapid binding to the kidney cortex, at 5.5% I.D. per gram, which is displaced by i.v dapagliflozin (and phlorizin, not shown). No F-DAPA appeared in the urine throughout the experiment, but it was transiently found in the renal vein, and then the liver and small intestine. Taken from Ghezzi et al. 2017 (25).

References

1. Chasis H, Jolliffe N, Smith HW: The action of phlorizin on the excretion of glucose, xylose, sucrose, creatinine and urea by man. J Clin Invest 12: 1083–1090, 1933 https://doi.org/10.1172/JCI100559
2. Rossetti L, Smith D, Shulman GI, Papachristou D, DeFronzo RA: Correction of hyperglycemia with phlorizin normalizes tissue sensitivity to insulin in diabetic rats. J Clin Invest 79: 1510–1515, 1987 https://doi.org/10.1172/JCI112981
3. Hediger MA, Turk E, Wright EM: Homology of the human intestinal Na+/glucose and Escherichia coli Na+/proline cotransporters. Proc Natl Acad Sci U S A 86: 5748–5752, 1989 https://doi.org/10.1073/pnas.86.15.5748
4. Hediger MA, Coady MJ, Ikeda TS, Wright EM: Expression cloning and cDNA sequencing of the Na+/glucose co-transporter. Nature 330: 379–381, 1987 https://doi.org/10.1038/330379a0
5. Wells RG, Pajor AM, Kanai Y, Turk E, Wright EM, Hediger MA: Cloning of a human kidney cDNA with similarity to the sodium-glucose cotransporter. Am J Physiol 263: F459–F465, 1992 https://doi.org/10.1152/ajprenal.1992.263.3.F459
6. Kanai Y, Lee WS, You G, Brown D, Hediger MA: The human kidney low affinity Na+/glucose cotransporter SGLT2. Delineation of the major renal reabsorptive mechanism for D-glucose. J Clin Invest 93: 397–404, 1994 https://doi.org/10.1172/JCI116972
7. You G, Lee WS, Barros EJ, Kanai Y, Huo TL, Khawaja S, Wells RG, Nigam SK, Hediger MA: Molecular characteristics of Na(+)-coupled glucose transporters in adult and embryonic rat kidney. J Biol Chem 270: 29365–29371, 1995 https://doi.org/10.1074/jbc.270.49.29365
8. Wright EM, Loo DD, Hirayama BA: Biology of human sodium glucose transporters. Physiol Rev 91: 733–794, 2011 https://doi.org/10.1152/physrev.00055.2009
9. Wright EM: Glucose transport families SLC5 and SLC50. Mol Aspects Med 34: 183–196, 2013 https://doi.org/10.1016/j.mam.2012.11.002
10. Gyimesi G, Pujol-Giménez J, Kanai Y, Hediger MA: Sodium-coupled glucose transport, the SLC5 family, and therapeutically relevant inhibitors: From molecular discovery to clinical application. Pflugers Arch 472: 1177–1206, 2020 https://doi.org/10.1007/s00424-020-02433-x
11. Santer R, Kinner M, Lassen CL, Schneppenheim R, Eggert P, Bald M, Brodehl J, Daschner M, Ehrich JH, Kemper M, Li Volti S, Neuhaus T, Skovby F, Swift PG, Schaub J, Klaerke D: Molecular analysis of the SGLT2 gene in patients with renal glucosuria. J Am Soc Nephrol 14: 2873–2882, 2003 https://doi.org/10.1097/01.ASN.0000092790.89332.D2
12. Tsujihara K, Hongu M, Saito K, Inamasu M, Arakawa K, Oku A, Matsumoto M: Na(+)-glucose cotransporter inhibitors as antidiabetics. I. Synthesis and pharmacological properties of 4′-dehydroxyphlorizin derivatives based on a new concept. Chem Pharm Bull (Tokyo) 44: 1174–1180, 1996 https://doi.org/10.1248/cpb.44.1174
13. Oku A, Ueta K, Arakawa K, Ishihara T, Nawano M, Kuronuma Y, Matsumoto M, Saito A, Tsujihara K, Anai M, Asano T, Kanai Y, Endou H: T-1095, an inhibitor of renal Na+-glucose cotransporters, may provide a novel approach to treating diabetes. Diabetes 48: 1794–1800, 1999 https://doi.org/10.2337/diabetes.48.9.1794
14. Washburn WN: Development of the renal glucose reabsorption inhibitors: A new mechanism for the pharmacotherapy of diabetes mellitus type 2. J Med Chem 52: 1785–1794, 2009 https://doi.org/10.1021/jm8013019
15. 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 14: 83–90, 2012 https://doi.org/10.1111/j.1463-1326.2011.01517.x
16. Isaji M: Sodium-glucose cotransporter inhibitors for diabetes. Curr Opin Investig Drugs 8: 285–292, 2007
17. Loo DDF, Wright EM: Sugar Transport Across Epithelia. In: Studies of Epithelial Transporters and Ion Channels: Ion Channels and Transporters of Epithelia in Health and Disease, edited by Hamilton KL, Devor DC, Vol. 3, Cham, Springer International Publishing, 2020, pp 211–254 https://doi.org/10.1007/978-3-030-55454-5_6
18. Vrhovac I, Balen Eror D, Klessen D, Burger C, Breljak D, Kraus O, Radović N, Jadrijević S, Aleksic I, Walles T, Sauvant C, Sabolić I, Koepsell H: 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 467: 1881–1898, 2015 https://doi.org/10.1007/s00424-014-1619-7
19. Hirayama BA, Díez-Sampedro A, Wright EM: Common mechanisms of inhibition for the Na+/glucose (hSGLT1) and Na+/Cl-/GABA (hGAT1) cotransporters. Br J Pharmacol 134: 484–495, 2001 https://doi.org/10.1038/sj.bjp.0704274
20. Yu AS, Hirayama BA, Timbol G, Liu J, Basarah E, Kepe V, Satyamurthy N, Huang SC, Wright EM, Barrio JR: Functional expression of SGLTs in rat brain. Am J Physiol Cell Physiol 299: C1277–C1284, 2010 https://doi.org/10.1152/ajpcell.00296.2010
21. Sala-Rabanal M, Hirayama BA, Ghezzi C, Liu J, Huang SC, Kepe V, Koepsell H, Yu A, Powell DR, Thorens B, Wright EM, Barrio JR: Revisiting the physiological roles of SGLTs and GLUTs using positron emission tomography in mice. J Physiol 594: 4425–4438, 2016 https://doi.org/10.1113/JP271904
22. Kepe V, Scafoglio C, Liu J, Yong WH, Bergsneider M, Huang SC, Barrio JR, Wright EM: Positron emission tomography of sodium glucose cotransport activity in high grade astrocytomas. J Neurooncol 138: 557–569, 2018 https://doi.org/10.1007/s11060-018-2823-7
23. Phelps ME: PET Molecular Imaging and Its Biological Applications, Springer, 2004, p 621
24. Calado J, Loeffler J, Sakallioglu O, Gok F, Lhotta K, Barata J, Rueff J: Familial renal glucosuria: SLC5A2 mutation analysis and evidence of salt-wasting. Kidney Int 69: 852–855, 2006 https://doi.org/10.1038/sj.ki.5000194
25. Ghezzi C, Yu AS, Hirayama BA, Kepe V, Liu J, Scafoglio C, Powell DR, Huang SC, Satyamurthy N, Barrio JR, Wright EM: Dapagliflozin binds specifically to sodium-glucose cotransporter 2 in the proximal renal tubule. J Am Soc Nephrol 28: 802–810, 2017 https://doi.org/10.1681/ASN.2016050510
26. Sala-Rabanal M, Ghezzi C, Hirayama BA, Kepe V, Liu J, Barrio JR, Wright EM: Intestinal absorption of glucose in mice as determined by positron emission tomography. J Physiol 596: 2473–2489, 2018 https://doi.org/10.1113/JP275934
27. Ghezzi C, Loo DDF, Wright EM: Physiology of renal glucose handling via SGLT1, SGLT2 and GLUT2. Diabetologia 61: 2087–2097, 2018 https://doi.org/10.1007/s00125-018-4656-5
28. Silverman M: The in vivo localization of high-affinity phlorizin receptors to the brush border surface of the proximal tubule in dog kidney. Biochim Biophys Acta 339: 92–102, 1974 https://doi.org/10.1016/0005-2736(74)90335-6
29. Seman L, Macha S, Nehmiz G, Simons G, Ren B, Pinnetti S, Woerle HJ, Dugi K: Empagliflozin (BI 10773), a potent and selective SGLT2 inhibitor, induces dose-dependent glucosuria in healthy subjects. Clin Pharmacol Drug Dev 2: 152–161, 2013 https://doi.org/10.1002/cpdd.16
30. Powell DR, DaCosta CM, Gay J, Ding ZM, Smith M, Greer J, Doree D, Jeter-Jones S, Mseeh F, Rodriguez LA, Harris A, Buhring L, Platt KA, Vogel P, Brommage R, Shadoan MK, Sands AT, Zambrowicz B: Improved glycemic control in mice lacking Sglt1 and Sglt2. Am J Physiol Endocrinol Metab 304: E117–E130, 2013 https://doi.org/10.1152/ajpendo.00439.2012
31. Coady MJ, El Tarazi A, Santer R, Bissonnette P, Sasseville LJ, Calado J, Lussier Y, Dumayne C, Bichet DG, Lapointe JY: MAP17 is a necessary activator of renal Na+/glucose cotransporter SGLT2. J Am Soc Nephrol 28: 85–93, 2017 https://doi.org/10.1681/ASN.2015111282
32. Hernando N: NaPi-IIa interacting partners and their (un)known functional roles. Pflugers Arch 471: 67–82, 2019 https://doi.org/10.1007/s00424-018-2176-2
33. Calado J, Santos AR, Aires I, Lebre F, Nolasco F, Rueff J, Ramalho J: The Na+-coupled glucose transporter SGLT2 interacts with its accessory unit MAP17 in vitro and their expressions overlap in the renal proximal tubule. FEBS Lett 592: 3317–3326, 2018 https://doi.org/10.1002/1873-3468.13233
34. Pajor AM, Randolph KM, Kerner SA, Smith CD: Inhibitor binding in the human renal low- and high-affinity Na+/glucose cotransporters. J Pharmacol Exp Ther 324: 985–991, 2008 https://doi.org/10.1124/jpet.107.129825
35. Hummel CS, Lu C, Loo DD, Hirayama BA, Voss AA, Wright EM: Glucose transport by human renal Na+/D-glucose cotransporters SGLT1 and SGLT2. Am J Physiol Cell Physiol 300: C14–C21, 2011 https://doi.org/10.1152/ajpcell.00388.2010
36. Hummel CS, Lu C, Liu J, Ghezzi C, Hirayama BA, Loo DD, Kepe V, Barrio JR, Wright EM: Structural selectivity of human SGLT inhibitors. Am J Physiol Cell Physiol 302: C373–C382, 2012 https://doi.org/10.1152/ajpcell.00328.2011
37. 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 2: e12058, 2014 https://doi.org/10.14814/phy2.12058
38. Coady MJ, Wallendorff B, Lapointe JY: Characterization of the transport activity of SGLT2/MAP17, the renal low-affinity Na+/glucose cotransporter. Am J Physiol Renal Physiol 313: F467–F474, 2016
39. Adelman JL, Ghezzi C, Bisignano P, Loo DD, Choe S, Abramson J, Rosenberg JM, Wright EM, Grabe M: Stochastic steps in secondary active sugar transport. Proc Natl Acad Sci U S A 113: E3960–E3966, 2016 https://doi.org/10.1073/pnas.1525378113
40. Loo DD, Jiang X, Gorraitz E, Hirayama BA, Wright EM: Functional identification and characterization of sodium binding sites in Na symporters. Proc Natl Acad Sci U S A 110: E4557–E4566, 2013 https://doi.org/10.1073/pnas.1319218110
41. Loo DFW: Sugar transport across epithelia. In: Studies of Epithelial Transporters and Ion Channels, 2nd Ed., edited by Hamilton KL, Devor DC, Springer, 2020
42. Quick M, Tomasevic J, Wright EM: Functional asymmetry of the human Na+/glucose transporter (hSGLT1) in bacterial membrane vesicles. Biochemistry 42: 9147–9152, 2003 https://doi.org/10.1021/bi034842x
43. Eskandari S, Wright EM, Loo DD: Kinetics of the reverse mode of the Na+/glucose cotransporter. J Membr Biol 204: 23–32, 2005 https://doi.org/10.1007/s00232-005-0743-x
44. Diedrich DF: The comparative effects of some phlorizin analogs on the renal reabsorption of glucose. Biochim Biophys Acta 71: 688–700, 1963 https://doi.org/10.1016/0006-3002(63)91142-9
45. Faham S, Watanabe A, Besserer GM, Cascio D, Specht A, Hirayama BA, Wright EM, Abramson J: The crystal structure of a sodium galactose transporter reveals mechanistic insights into Na+/sugar symport. Science 321: 810–814, 2008 https://doi.org/10.1126/science.1160406
46. Watanabe A, Choe S, Chaptal V, Rosenberg JM, Wright EM, Grabe M, Abramson J: The mechanism of sodium and substrate release from the binding pocket of vSGLT. Nature 468: 988–991, 2010 https://doi.org/10.1038/nature09580
47. Bisignano P, Ghezzi C, Jo H, Polizzi NF, Althoff T, Kalyanaraman C, Friemann R, Jacobson MP, Wright EM, Grabe M: Inhibitor binding mode and allosteric regulation of Na+-glucose symporters. Nat Commun 9: 5245, 2018 https://doi.org/10.1038/s41467-018-07700-1
48. Sala-Rabanal M, Hirayama BA, Loo DD, Chaptal V, Abramson J, Wright EM: Bridging the gap between structure and kinetics of human SGLT1. Am J Physiol Cell Physiol 302: C1293–C1305, 2012 https://doi.org/10.1152/ajpcell.00397.2011
49. Jiang X, Loo DD, Hirayama BA, Wright EM: The importance of being aromatic: π interactions in sodium symporters. Biochemistry 51: 9480–9487, 2012 https://doi.org/10.1021/bi301329w
50. Gorraitz E, Hirayama BA, Paz A, Wright EM, Loo DDF: Active site voltage clamp fluorometry of the sodium glucose cotransporter hSGLT1. Proc Natl Acad Sci U S A 114: E9980–E9988, 2017 https://doi.org/10.1073/pnas.1713899114
51. Zambrowicz B, Ding ZM, Ogbaa I, Frazier K, Banks P, Turnage A, Freiman J, Smith M, Ruff D, Sands A, Powell D: Effects of LX4211, a dual SGLT1/SGLT2 inhibitor, plus sitagliptin on postprandial active GLP-1 and glycemic control in type 2 diabetes. Clin Ther 35: 273–285.e7, 2013 https://doi.org/10.1016/j.clinthera.2013.01.010
52. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; EMPA-REG OUTCOME Investigators: Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 373: 2117–2128, 2015 https://doi.org/10.1056/NEJMoa1504720
53. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Law G, Desai M, Matthews DR; CANVAS Program Collaborative Group: Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 377: 644–657, 2017 https://doi.org/10.1056/NEJMoa1611925
54. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Silverman MG, Zelniker TA, Kuder JF, Murphy SA, Bhatt DL, Leiter LA, McGuire DK, Wilding JPH, Ruff CT, Gause-Nilsson IAM, Fredriksson M, Johansson PA, Langkilde AM, Sabatine MS; DECLARE–TIMI 58 Investigators: Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 380: 347–357, 2019 https://doi.org/10.1056/NEJMoa1812389
55. McMurray JJV, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, Ponikowski P, Sabatine MS, Anand IS, Bělohlávek J, Böhm M, Chiang CE, Chopra VK, de Boer RA, Desai AS, Diez M, Drozdz J, Dukát A, Ge J, Howlett JG, Katova T, Kitakaze M, Ljungman CEA, Merkely B, Nicolau JC, O’Meara E, Petrie MC, Vinh PN, Schou M, Tereshchenko S, Verma S, Held C, DeMets DL, Docherty KF, Jhund PS, Bengtsson O, Sjöstrand M, Langkilde AM; DAPA-HF Trial Committees and Investigators: Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 381: 1995–2008, 2019 https://doi.org/10.1056/NEJMoa1911303
56. Baartscheer A, Schumacher CA, Wüst RC, Fiolet JW, Stienen GJ, Coronel R, Zuurbier CJ: Empagliflozin decreases myocardial cytoplasmic Na+ through inhibition of the cardiac Na+/H+ exchanger in rats and rabbits. Diabetologia 60: 568–573, 2017 https://doi.org/10.1007/s00125-016-4134-x
57. Uthman L, Baartscheer A, Bleijlevens B, Schumacher CA, Fiolet JWT, Koeman A, Jancev M, Hollmann MW, Weber NC, Coronel R, Zuurbier CJ: Class effects of SGLT2 inhibitors in mouse cardiomyocytes and hearts: inhibition of Na+/H+ exchanger, lowering of cytosolic Na+ and vasodilation. Diabetologia 61: 722–726, 2018 https://doi.org/10.1007/s00125-017-4509-7
58. Uthman L, Nederlof R, Eerbeek O, Baartscheer A, Schumacher C, Buchholtz N, Hollmann MW, Coronel R, Weber NC, Zuurbier CJ: Delayed ischaemic contracture onset by empagliflozin associates with NHE1 inhibition and is dependent on insulin in isolated mouse hearts. Cardiovasc Res 115: 1533–1545, 2019 https://doi.org/10.1093/cvr/cvz004
59. Pedersen SF, Counillon L: The SLC9A-C mammalian Na+/H+ exchanger family: Molecules, mechanisms, and physiology. Physiol Rev 99: 2015–2113, 2019 https://doi.org/10.1152/physrev.00028.2018
60. Heerspink HJL, Stefánsson BV, Correa-Rotter R, Chertow GM, Greene T, Hou FF, Mann JFE, McMurray JJV, Lindberg M, Rossing P, Sjöström CD, Toto RD, Langkilde AM, Wheeler DC; DAPA-CKD Trial Committees and Investigators: Dapagliflozin in patients with chronic kidney disease. N Engl J Med 383: 1436–1446, 2020 https://doi.org/10.1056/NEJMoa2024816
61. Heerspink HJL, Karasik A, Thuresson M, Melzer-Cohen C, Chodick G, Khunti K, Wilding JPH, Garcia Rodriguez LA, Cea-Soriano L, Kohsaka S, Nicolucci A, Lucisano G, Lin FJ, Wang CY, Wittbrodt E, Fenici P, Kosiborod M: Kidney outcomes associated with use of SGLT2 inhibitors in real-world clinical practice (CVD-REAL 3): A multinational observational cohort study. Lancet Diabetes Endocrinol 8: 27–35, 2020 https://doi.org/10.1016/S2213-8587(19)30384-5
62. Zambrowicz B, Ogbaa I, Frazier K, Banks P, Turnage A, Freiman J, Boehm KA, Ruff D, Powell D, Sands A: Effects of LX4211, a dual sodium-dependent glucose cotransporters 1 and 2 inhibitor, on postprandial glucose, insulin, glucagon-like peptide 1, and peptide tyrosine tyrosine in a dose-timing study in healthy subjects. Clin Ther 35: 1162–1173.e8, 2013 https://doi.org/10.1016/j.clinthera.2013.06.011
Keywords:

renal physiology; basic science; diabetes; glucose; heart failure; inhibitors; SGLT; SGLT2; sodium glucose transporters

Copyright © 2021 by the American Society of Nephrology