Review. SGLT inhibitors in management of diabetes

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1 SGLT inhibitors in management of diabetes Abd A Tahrani, Anthony H Barnett, Clifford J Bailey Summary The two main sodium glucose cotransporters (SGLTs), SGLT1 and SGLT2, provide new therapeutic targets to reduce hyperglycaemia in patients with diabetes. SGLT1 enables the small intestine to absorb glucose and contributes to the reabsorption of glucose filtered by the kidney. SGLT2 is responsible for reabsorption of most of the glucose filtered by the kidney. Inhibitors with varying specificities for these transporters (eg, dapagliflozin, canagliflozin, and empagliflozin) can slow the rate of intestinal glucose absorption and increase the renal elimination of glucose into the urine. Results of randomised clinical trials have shown the blood glucose-lowering efficacy of SGLT inhibitors in type 2 diabetes when administered as monotherapy or in addition to other glucose-lowering therapies including insulin. Increased renal glucose elimination also assists weight loss and could help to reduce blood pressure. Effective SGLT2 inhibition needs adequate glomerular filtration and might increase risk of urinary tract and genital infection, and excessive inhibition of SGLT1 can cause gastro-intestinal symptoms. However, the insulin-independent mechanism of action of SGLT inhibitors seems to offer durable glucose-lowering efficacy with low risk of clinically significant hypoglycaemia at any stage in the natural history of type 2 diabetes. SGLT inhibition might also be considered in conjunction with insulin therapy in type 1 diabetes. Introduction Chronic hyperglycaemia is a defining feature of diabetes mellitus, and consequent glucotoxicity most likely accounts for the associated microvascular disease, and contributes to premature macrovascular disease. Hence early and effective glycaemic control is fundamental to therapeutic intervention. In type 1 diabetes, hyperglycaemia is due to complete or almost complete loss of insulin-secreting β cells from the pancreatic islets of Langerhans. In type 2 diabetes, however, hyperglycaemia indicates insulin resistance coupled with abnormalities of insulin production and secretion and other endocrinopathies that collectively cause a highly heterogeneous and progressive disorder. 1 Treatment of type 2 diabetes is often complicated by coexistent obesity, which further impairs insulin action and aggravates hypertension, dyslipidaemia, inflammation, and other pathogenic factors that promote cardiovascular risk. 2 Although existing glucose-lowering therapies address many of the endocrine and metabolic derangements of diabetes, they often cannot reinstate or maintain longterm glycaemic control in many patients. 3 New types of glucose-lowering drugs are needed, preferably offering complementary and additional effectiveness to existing drugs, along with benefits against any of the common accompanying disorders such as obesity and cardiovascular disease. In this Review we consider the opportunity for a new therapeutic approach to improve the control of hyperglycaemia by alteration of the activity of sodium glucose cotransporters (SGLTs) in the intestine and the kidneys. Glucose in the gut and kidney Sodium glucose cotransporters SGLTs are secondary-active cell-membrane symporters that transfer sodium down its concentration gradient, usually into the cell, in conjunction with the inward transfer of specific hexose sugars or some other molecules against their concentration gradient. 4,5 An electrochemical gradient that allows sodium to enter the cell is generated by the active transport of sodium out of the cell at another location within the cell membrane hence the term secondary active. SGLTs should not be confused with facilitated glucose transporters (GLUTs) that mediate passive transfer of glucose across cell membranes down a concentration gradient. 6 However, as in both the intestine and kidney, the two different types of transporters can operate in tandem: SGLTs transfer glucose into the cell across the luminal membrane whereas GLUTs transfer glucose out of the cell across the basolateral membrane (figure 1). SGLTs are encoded by a subfamily of solute carrier genes that are members of the sodium substrate symporter family (table 1). The main SGLTs are SGLT1, which is responsible for glucose absorption from the small intestine, and SGLT2, which accounts for reabsorption of most of the glucose filtered by the kidney. SGLT1 is a high-affinity (K 0.5 of about 0 4 mm for glucose and about 3 0 mm for sodium), low-capacity glucose transporter with a 2:1 stoichiometry for sodium and glucose. Conversely, SGLT2 is a low-affinity (K 0.5 of about 2 0 mm for glucose and about 0 1 mm for sodium), high-capacity glucose transporter with a 1:1 stoichiometry for sodium and glucose. 4,5 Wright and colleagues 5,7 expanded knowledge of the mechanism by which SGLT1 and SGLT2 transfer glucose. SGLTs are large (about 75 kd) proteins with 14 transmembrane helices and an extracellular binding domain with varying specificity for different hexoses. Thus, although SGLT1 transports glucose, it also transports galactose with similar kinetics, whereas SGLT2 transports essentially only glucose. When sodium binds at an extracellular site, the molecular conformation is altered to expose the hexose binding domain. A hexose sugar occupying this domain causes further spatial rearrangement that enables inward translocation of the Published nline August 13, S (13) Centre of Endocrinology, Diabetes and Metabolism, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK, and Department of Diabetes and Endocrinology, Heart of England NHS Foundation Trust, Birmingham, UK (A A Tahrani MD, Prof A H Barnett MD); and School of Life and Health Sciences, Aston University, Birmingham, UK (Prof C J Bailey PhD) Correspondence to: Prof Clifford J Bailey, School of Life and Health Sciences, Aston University, Birmingham B4 7ET, UK [email protected] Published online August 13,

2 Enterocytes lining small intestine 2Na + K + Na + K + Na + SGLT1 Glucose GLUT2 Glucose Blood glucose Glucose GLUT1 K + Na + Glucose Figure 1: Sodium glucose cotransporters (SGLT1 and SGLT2) and facilitative glucose transporters (GLUT1 and GLUT2) in the intestine and renal proximal tubules SGLT1 is a high-affinity low-capacity transporter and SGLT2 is a low-affinity high-capacity cotransporter. SGLT1 and SGLT2 are secondary active cotransporters, driven by the Na + /K + -ATPase pump, which actively extrudes sodium across the basolateral membrane. 4,13,31 Substrate Epithelium lining proximal convoluted tubules Na + K + Na + K + Na + Apparent affinity for glucose (K 0 5 mm) SGLT2 Glucose GLUT2 Glucose Distribution 2Na + K + Na + SGLT1 SGLT1 (SLC5A1) Glucose, galactose 0 4 Intestine, trachea, kidney, heart, brain, testes, prostate SGLT2 (SLC5A2) Glucose 2 Kidney, brain, liver, thyroid, muscle, heart SGLT4 (SLC5A9) Glucose, mannose 2 Intestine, kidney, liver, brain, lung, trachea, uterus, pancreas SGLT5 (SLC5A10) Glucose ND Kidney cortex SGLT6 (SLC5A11) Myo-inositol, glucose 35 Brain, kidney, intestine SMIT1 (SLC5A3) Myo-inositol, glucose >30 Brain, heart, kidney, lung Apparent affinity values (K 0 5 ) are approximate as determined by inhibition of the transport of α-methyl-d-glucoside in various cell types, and tissue distribution of transporters is mostly based on mrna expression. Human SGLT3 (SLC5A4) is a glucosensor expressed in the enteric nervous system and muscle where it has a high affinity for myo-inositol (SGLT6 and SMIT1 also have a high affinity for myo-inositol). Based on data reviewed by Wright and colleagues. 5 ND=not determined. Table 1: Genes, substrates, and main sites for expression of sodium glucose cotransporters sodium and hexose to the cytosolic surface where dissociation occurs into the cytosol. 7 Inhibition of extracellular hexose binding by phlorizin and related glucosides competitively precludes the binding and transfer of the hexose substrates. Glucose handling in the gut Enterocytes lining intestinal villi express very large numbers of SGLT1 transporters in the apical (brush border) membrane. 8 Transfer of glucose (or galactose), along with sodium from the lumen, into the enterocyte is driven by active extrusion of sodium at the basolateral membrane via the Na + /K + -ATPase pump. 4,5 The increasing concentration of glucose within the cytosol of the enterocyte enables the passive transfer of glucose out of the cell across the basolateral membrane via the sodium-independent facilitative transporter GLUT2. 9 Fructose, which is at a very low concentration in interstitial fluid, is transported across the apical membrane by the sodium-independent glucose transporter-5 (GLUT5) down its concentration gradient. 4,5 In addition to its presence in the small intestine, SGLT1 is expressed in the kidney, heart, brain, prostate, and testes. 5 Glucose uptake via SGLT1 by intestinal K cells and L cells contributes to the secretion of gastric inhibitory polypeptide (GIP) and glucagonlike peptide 1 (GLP1) respectively, and upregulates GLUT2 production. 10 SGLT1 expression in the small intestine is responsive to the presence of sugars in the gut lumen. These sugars activate taste receptors, notably TAS1 subunit R3 and the G-protein gustducin, on a subpopulation of enteral endocrine cells that increase expression of SGLT1 in enterocytes, probably via secretion of hormones such as GLP1, GLP2, and GIP. 11 In patients with type 2 diabetes, expression of SGLT1 and other monosaccharide transporters in the duodenum could be three to four times higher than in individuals without diabetes, suggesting patients with type 2 diabetes have an increased capacity for glucose absorption. 12 Conversely, mutations in the SGLT1 gene result in glucose-galactose malabsorption with severe diarrhoea. 13 Glucose handling in the kidney The kidneys contribute significantly to glucose homoeostasis mainly by reabsorbing filtered glucose from the renal tubule and by gluconeogenesis. 14 The kidneys are estimated to produce up to approximately 2 (about μmol/kg per min) of glucose in the fasting state. This glucose production is derived through gluconeogenesis by the renal cortex, and most is used by the renal medulla. 14,15 In diabetic states, the kidneys (like the liver) have increased gluconeogenesis. 15 In healthy individuals with a glomerular filtration rate of 125 ml/min, about 180 L of plasma are filtered through the kidneys every day. If the average plasma glucose concentration is 5 5 mmol/l (100 mg/dl), this translates to approximately 180 g of glucose filtered daily into the proximal tubules, all of which is normally reabsorbed. As the plasma glucose concentration increases, the amount of filtered glucose increases, and this is all reabsorbed until the reabsorptive capacity of the tubules cannot keep pace with filtration the renal threshold when the plasma glucose concentration reaches about mmol/l), at which point excess glucose is eliminated in the urine (glucosuria). 2 Published online August 13,

3 CI Et Phlorizin Me S F CI Dapagliflozin Canagliflozin Empagliflozin Ipragliflozin F S Tofogliflozin Et Ertugliflozin CI Et Me CI S Luseogliflozin Et Me S CI LX-4211 Et H N N KGA-2727 H N NH 2 Figure 2: Inhibitors of the sodium glucose cotransporters SGLT2 and SGLT1 The inhibitors are variants of the natural product phlorizin. Dapagliflozin, canagliflozin, empagliflozin, ipragliflozin, tofogliflozin, ertugliflozin, and luseogliflozin are highly specific inhibitors of SGLT2. LX-4211 is a mixed inhibitor of SGLT1 and SGLT2, and KGA-2727 is a specific inhibitor of SGLT1. Normally about 9 of filtered glucose is reabsorbed by the high-capacity, low-affinity transporter SGLT2, located in the first (S1) segment of the proximal tubule. 4,5 The remainder of the glucose is reabsorbed by the highaffinity, low-capacity transporter, SGLT1, in the distal (S3) segment of the proximal tubule (figure 1). Similarly to glucose absorption by SGLT1 in the gut, the renal tubule operates an electrochemical gradient generated by the Na + /K + -ATPase located in the basolateral membrane. 4,5 Cells in the S1 segment that take up glucose at the luminal surface via SGLT2 transfer that glucose across the basolateral membrane via GLUT2, while cells in the S3 segment that take up glucose from the lumen via SGLT1 pass glucose across the basolateral membrane via GLUT1 (figure 1). The improved capacity for renal glucose reabsorption in diabetic states seems to indicate increased expression and activity of SGLT2 and GLUT2 in the proximal tubules, which will further contribute to hyperglycaemia. 16,17 This increased expression and activity might be an adaptation of persistent exposure to high glucose concentrations, possibly regulated in part by hepatic nuclear factor 1α. However, upregulation of tubular SGLT1 and GLUT2 expression has not been confirmed in some studies. 18 Familial renal glucosuria is an uncommon (<0 3% of the population) autosomal recessive condition caused by various (>40 known) mutations of the SGLT2 gene. These mutations result in renal glucosuria of up to 100 g per day, yet plasma glucose concentrations are normal, with otherwise apparently normal renal function and general health. 19 Development of SGLT inhibitors In the 1980s, Rossetti and colleagues 20 introduced the concept of normalisation of glucose concentrations by an increase in urinary glucose excretion. The researchers showed that phlorizin, a naturally occurring phenolic glycoside first isolated from apple tree bark in 1835, increased urinary glucose and lowered blood glucose in Published online August 13,

4 Dose (mg) IC 50 SGLT1 vs 2 Selective SGLT2 inhibitors Dapagliflozin vs 11 nmol/l Ratio ~1200:1 Canagliflozin vs 2 2 nmol/l Ratio 160: vs 2 2 nmol/l Ratio 160:1 T max (h) C max t 1/2 (h) Population and administration regimen ~160 ng/ml ~13 Healthy individuals steady state ~1 5 ~1 0 ug/ml 10 6 Type 2 diabetes single dose ~ ug/ml 13 1 Type 2 diabetes single dose Empagliflozin vs 3 1 nmol/l nmol/l 13 2 Type 2 diabetes steady state vs 3 1 nmol/l nmol/l 13 3 Type 2 diabetes steady state Ipragliflozin fold selectivity ~ ng/ml 17 8 Healthy individuals for SGLT2 vs SGLT1 Combined SGLT1 and SGLT2 inhibitor LX vs 1 8 nmol/l ng/ml 20 7 Type 2 diabetes steady state vs 1 8 nmol/l ng/ml 13 5 Type 2 diabetes steady state IC 50 =half maximum inhibitory concentration. T max =time to maximum circulating concentration. C max =maximum circulating concentration. t 1/2 =terminal half-life. Table 2: Summary of the pharmacokinetics of SGLT inhibitors published in clinical trials partly pancreatectomised rats. 20,21 Ironically, a century earlier, the glucosuric effect of phlorizin had been interpreted as indicative of causing diabetes. 21 In the 1990s, after the genes for SGLT1 and SGLT2 had been discovered, phlorizin was identified as an inhibitor of both of these transporters. However, phlorizin offered little oral bioavailability because of degradation at an -glucoside linkage by intestinal glucosidases. 21,22 Also, the poor selectivity for blockade of SGLT2 compared with SGLT1 in the intestine caused sufficient gastrointestinal side-effects to exclude this drug as a treatment for patients with type 2 diabetes. Although several potent selective SGLT2 inhibitors such as T1095, sergliflozin, and remogliflozin were developed, they were vulnerable to degradation by intestinal glucosidases at their -glucoside linkage and have not progressed in clinical development. 22,23 ral SGLT inhibitors that are either approved or in advanced clinical development have circumvented glucosidase degradation by replacement of the -glucoside linkage with a C-aryl linkage (figure 2) Another approach under consideration to inhibit SGLT2, ISIS (ISIS) is a short antisense oligonucleotide delivered by subcutaneous injection that targets SGLT2 mrna. 30 Inhibitors of SGLT2 eliminate g of glucose per day and sustain this for 2 years in clinical trials. 31 This elimination represents inhibition of reabsorption of about a third of the filtered glucose load. The extent to which SGLT2 can be inhibited varies with the dose, binding affinity, and retention time of the inhibitor at the transporter. Exposure of the inhibitor to the transporter also shows the rate at which the inhibitor is filtered and its secretion, active reabsorption, or both, by the proximal tubule. 32 Inhibition of glucose reabsorption by SGLT2 will be partly offset by the uptake of glucose by SGLT1. Thus, concomitant suppression of SGLT1 might enhance the glucosuria, but retained patency of glucose reabsorption by SGLT1 could prevent overt hypo glycaemia. Because inhibition of SGLT2 and SGLT1 is not insulin-dependent, and is not altered by deteriorating β-cell function or insulin resistance, these inhibitors should in principle be operative at any stage in the natural history of diabetic states, provided that glomerular filtration is adequate. However, although these inhibitors can reduce hyperglycaemia, they do not directly address the fundamental underlying endocrinopathies. Thus, although a sustained reduction in glucotoxicity improves the metabolic environment and reduces hyperglycaemia-related complications, presence of some insulin is always necessary to meet other physiological requirements. 23,31 Whereas most clinical studies have focused on drugs that predominantly inhibit SGLT2, preclinical studies with a selective SGLT1 inhibitor have been reported (KGA-2727, Kissei), 33 and a combined SGLT1 and SGLT2 inhibitor LX-4211 (Lexicon) has entered clinical development. 34 The theory behind a combined SGLT1 and SGLT2 inhibitor is that the SGLT1 inhibition defers and delays glucose absorption more distally along the intestine. This effect in itself should help to reduce the prandial glucose excursion, and might increase GLP1 and peptide YY secretion from intestinal L cells, which are more abundant in distal regions of the small intestine. These hormones in turn could slow later stages of gastric emptying and increase satiety; however, inhibitors of intestinal SGLT1 must be rapidly absorbed or degraded in the intestine to preclude unabsorbed glucose entering and fermenting in the large intestine. A bioavailable SGLT1 inhibitor that also acts on SGLT2 to reduce renal glucose reabsorption and enhance the glucosuria would further increase its blood glucosereducing effect. However, the inhibitory effect on renal SGLT1 should not be sufficiently potent or longacting to prolong glucose loss during hypoglycaemia. Pharmacokinetics Table 2 summarises available pharmacokinetics data for oral SGLT inhibitors. Dapagliflozin is the most studied SGLT2 inhibitor, and measurement of the urinary glucose creatinine ratio suggests that a 10 mg daily dose maintains an estimated glucosuric effect of g per day, if renal function is adequate. Bioavailability in patients without diabetes after a single 10 mg dose was about 78%. 35 Food consumption, sex, ethnicity, age, and weight had little effect on dapagliflozin pharmacokinetics, although few patients older than 75 years were tested. In patients with mild, moderate, and severe renal impairment, exposure to dapagliflozin was increased by 3, 5, and 8, respectively. However, glucose-lowering efficacy decreased 4 Published online August 13,

5 because the glucosuric efficacy of SGLT2 inhibitors depends on sufficient glomerular filtration; hence the use of dapagliflozin is not recommended in patients with estimated glomerular filtrations rate (egfr) less than 60 ml/min per 1 73 m². 35,36 In patients with mild or moderate hepatic impairment, dapagliflozin s pharmacokinetics were similar to those without hepatic impairment, but in patients with severe hepatic impairment in whom drug exposure is increased, an initially reduced dose of 5 mg is recommended. 37 Dapagliflozin is metabolised mainly by the uridine diphosphate glucuronosyl transferase UGT1A9 to an inactive 3--glucuronide metabolite, which is excreted via the urine (about 75%) and liver. 35 P450 CYP pathways are not much involved in the metabolism of dapagliflozin and its metabolites, and no clinically relevant drug interactions exist between dapagliflozin and metformin, pioglitazone, sitagliptin, glimepiride, voglibose, hydrochlorothiazide, bumetanide, valsartan, simvastatin, digoxin, warfarin, and rifampicin. Dapagliflozin area under the curve decreased by 22% in combination with rifampicin and increased by 19% in combination with simvastatin. 35,38 40 Canagliflozin ( mg/day) generates a glucosuria of g per day. Bioavailability is about 65% and metabolism is mostly by UGT1A9 and UGT2B4 to inactive metabolites. 41 About a third of a dose of canagliflozin is eliminated in the urine, mostly as the unchanged drug, and two-thirds appear in the faeces. Accordingly, systemic exposure to canagliflozin increases with renal impairment as glucosuric efficacy decreases. However, efficacy is sufficient, possibly indicating some suppression of SGLT1 as well as SGLT2, to enable use of canagliflozin in patients with an egfr of 45 ml/min per 1 73 m² with appropriately frequent monitoring. No clinically significant interactions through the P450 CYP pathways have been identified, and no evidence of glucose malabsorption exists. 41 Empagliflozin (10 and 25 mg/day) and ipragliflozin (150 mg/day) are also rapidly absorbed and produce substantial glucosuria. The drugs also undergo inactivation via uridine diphosphate glucuronosyl transferases, thus avoiding interactions with drug metabolism through the P450 CYP pathways Preliminary pharmacokinetic data for ertugliflozin (25 mg single dose) and tofogliflozin (20 mg single dose) in healthy volunteers has been described. 29,50 At tablet doses of 150 and 300 mg per day, LX4221, a dual SGLT1 and SGLT2 inhibitor with a propensity for blockage of the SGLT1 transporter, was absorbed with a Tmax (time to reach maximum circulating concentration) at about 3 h, producing glucosuria in patients with type 2 diabetes. 51 Circulating GLP-1 and peptide YY concentrations were increased, consistent with an anticipated deferral of glucose absorption to more distal regions of the small intestinal tract, but with no evidence of malabsorption. 51 Preliminary pharmacokinetic data for KGA-2727 (selective SGLT-1 inhibitor) indicate a high affinity to SGLT1 compared with SGLT2 (K i 435 [260] vs [9900] nm for SGLT1 vs SGLT2 respectively). 33 Pharmacodynamics and clinical studies Each of the SGLT2 inhibitors that has progressed into a phase 3 clinical trial has caused significant glucosuria in patients with type 2 diabetes, typically shown or estimated to be in excess of 50 g per day Moreover, each inhibitor improves glycaemic control and reduces bodyweight to a similar extent. Dapagliflozin, which is now approved in several regions including Europe and Australia, has consistently reduced glycated HbA 1c, fasting plasma glucose (FPG), and postprandial glucose (PPG) in patients with type 2 diabetes when used as monotherapy or as an add-on to other oral blood glucose-lowering drugs or insulin in randomised controlled trials (table 3). 52,56 68 The glucoselowering effect of dapagliflozin was similar in patients with short ( 10 years) or long (>10 years) duration of diabetes, and was somewhat greater in individuals with high baseline HbA 1c (>8%) compared with a low ( 8%) baseline HbA 1c. 65 In a meta-analysis of dapagliflozin (10 mg/day) treatment in studies mostly lasting for 6 months, a placebo-subtracted HbA 1c reduction from a baseline at or below 8% of 0 54% (95% CI 0 67% to 0 4) was reported. 69 The glucose-lowering effect of dapagliflozin is immediate, and HbA 1c values level out after weeks. In phase 3 trials almost every patient responded, and the effect was well maintained in studies lasting from 6 months to 2 years. 57,58,68 In combination with insulin plus one or two other oral drugs in patients with type 2 diabetes, dapagliflozin (10 mg/day) reduced the escalation of insulin dose (by 10 U/day from a baseline average of 77 U/day) occurring in the placebo group over 1 year; this was achieved with a reduction in HbA 1c of 0 61%. 64 In another study in patients with insulin-treated type 2 diabetes, addition of dapagliflozin enabled glycaemic control to be maintained when the insulin dose was roughly halved. 59 Blood glucose-lowering therapy with dapagliflozin was accompanied by weight loss compared with placebo or prevention of weight gain compared with active comparators such as metformin and glipizide, when used as monotherapy or add-on therapy in patients with type 2 diabetes. 58,63 This effect was consistent, typically about 2 3 kg below baseline or comparator, and sustained through 6 months to 2 years (table 3). In their metaanalysis, Clar and colleagues 69 calculated a weight reduction at 6 months from a baseline of about 90 kg by 1 81 kg (95% CI 2 04 to 1 57). 65,68 Slightly greater reductions were noted for studies of longer duration. 58,65,68 The reductions in bodyweight were typically associated with reductions in waist circum ference, and in studies in which body composition was measured, researchers noted that weight loss was mainly attributable to a decrease in fat mass, particularly visceral adipose tissue Published online August 13,

6 List et al 56 Duration: 12 weeks (n=389) Wilding et al 59 Baseline treatment: ADs+insulin (but no sulfonylurea) Duration: 12 weeks (n=71) Ferrannini et al 60 (n=485) Bailey et al 57 Baseline treatment: metformin (n=546) Strojek et al 61 Baseline treatment: glimepiride (n=597) Nauck et al 58 Baseline treatment: metformin Duration: 52 weeks (n=814) Henry et al 63 (n=641) Wilding et al 64 Baseline treatment: insulin±ad Duration: 48 weeks (n=808) Rosenstock et al 62 Baseline treatment: pioglitazone±ad Duration: 48 weeks (n=420) Groups Dapagliflozin 50 mg Metformin to 5 insulin dose Dapagliflozin 20 mg Dapagliflozin 10 mg Dapagliflozin (max 10 mg) Glipizide (max 20 mg) Dapagliflozin 10 mg + metformin XR Dapagliflozin 10 mg Metformin XR Dapagliflozin 5 mg Dapagliflozin 10 mg Baseline HbA 1c (%) 7 8 (1 0) 7 6 (0 8) 7 9 (0 9) 8 5 (0 9) 8 4 (0 7) 8 4 (0 9) 7 92 (0 90) 7 86 (0 94) 8 01 (0 96) 7 84 (0 87) 7 99 (0 90) 8 17 (0 96) 7 92 (0 82) 8 11 (0 96) 8 11 (0 75) 8 12 (0 78) 8 07 (0 79) 8 15 (0 74) 7 7 (0 9) 7 7 (0 9) 9 1 (1 3) 9 1 (1 3) 9 1 (1 3) 8 46 (0 78) 8 62 (0 89) 8 57 (0 82) 8 47 (0 77) 8 40 (1 03) 8 37 (0 96) 8 34 (1 00) HbA 1c change (%) 0 9 (0 1) 0 73 (0 1) 0 18 (0 1) p<0 001 for dapagliflozin vs placebo 0 69 ( 0 9 to 0 4) 0 61 ( 0 9 to 0 4) 0 09 ( 0 2 to 0 4) (p<0 05 dapagliflozin vs placebo) 0 58 (0 11) 0 77 (0 11) 0 89 (0 11) 0 23 (0 10) (p<0 001 for trend) 0 67 ( 0 81 to 0 53) 0 70 ( 0 85 to 0 56) 0 84 ( 0 98 to 0 70) 0 30 ( 0 44 to 0 16) (p<0 05 dapagliflozin vs placebo) 0 58 ( 0 61 to 0 27) 0 63 ( 0 67 to 0 32) 0 82 ( 0 83 to 0 51) 0 13 (p<0 0001) 0 52 ( 0 60 to 0 44) 0 52 ( 0 60 to 0 44) Between groups: 0 ( 0 11 to 0 11) 1 98 ( 2 13 to 1 83) 1 45 ( 1 59 to 1 31) 1 44 ( 1 59 to 1 29) p<0 001 for either mono vs combined therapy 0 32 ( 0 48 to 0 16) 0 49 ( 0 65 to 0 33) 0.54 ( 0 70 to 0 38) 0 47 p<0 001 vs placebo 0 95 ( 1 10 to 0 80) 1 21 ( 1 36 to 1 06) 0 54 ( 0 70 to 0 38) Data are mean (95% CI) or mean (SD). HbA 1c =glycated haemoglobin A 1c. ADs=oral antidiabetic drugs. XR=extended release. Table 3: Summar y of phase 3 randomised controlled trials with dapagliflozin of >12 weeks duration Baseline weight (kg) 92 (19) 88 (20) 89 (18) 1012 (153) 1034 (102) 1018 (165) 90 8 (22 8) 87 6 (17 1) 94 2 (187) 88 8 (19 0) 84 9 (17 8) 84 7 (16 3) 86 3 (17 5) 87 7 (19 2) (19 7) 88 5 (19 3) 87 2 (19 4) 93 0 (16 7) 93 3 (17 4) 94 5 (16 8) 94 5 (19 8) 87 8 (20 7) 84 8 (22 2) 86 4 (21 3) Weight change 3 4% ( 4 1 to 2 6) 1 7% ( 2 4 to 0 9) 1 2% ( 2 0 to 0 4) 43 ( 53 to 33) 45 ( 55 to 35) 19 ( 29 to 09) (p<0 05 dapagliflozin vs placebo) 3 3 (0 5) 2 8 (0 5) 3 2 (0 5) 2 2 (0 4) (p>0 05) 2 2 ( 2 7 to 1 8) 3 0 ( 3 5 to 2 6) 2 9 ( 3 3 to 2 4 ) 0 9 ( 1 4 to 0 4) (p< vs placebo) ( 1 08 to 0 15) 2 26 ( 1 47 to 0 21) 0 72 ( 2 17 to 0 92) (p<0 001 for dapagliflozin 10 0 mg vs placebo) 3 60 ( 4 12 to 3 09) 1 55 (1 03 to 2 07) Between groups: 4 7 ( 5 1 to 4 2) 3 33 ( 3 80 to 2 86) 2 73 ( 3 19 to 2 27) 1 36 ( 1 83 to 0 89) p<0 001 for dapagliflozin mono or combined vs metformin 1 78 ( 2 53 to 1 03) 1 82 ( 2 56 to 1 07) 2 43 ( 3 18 to 1 68) 0 82 p<0 001 vs placebo 1 35 (0 61 to 2 09) 0 69 ( 0 03 to 1 41) 2 99 (2 19 to 3 79) Canagliflozin ( mg/day for periods of 1 12 months in randomised controlled trials) has also been shown to lower FPG and PPG and reduce HbA 1c and bodyweight in patients with type 2 diabetes with similar efficacy when used as monotherapy or in combination with metformin, metformin plus pioglitazone or a sulfonylurea as triple therapy, and with insulin (table 4). 41,53,70 74 Because canagliflozin exerts low potency inhibition of SGLT1 as well as potent SGLT2 inhibition, a dual-isotope study of its intestinal effects was undertaken. This study showed a 2 reduction in PPG over 0 2 h with apparent subsequent compensation to give a 6% reduction over 0 6 h Published online August 13,

7 Arms Baseline HbA 1c (%) HbA 1c change (%)* Baseline weight (kg) Weight change* Devineni et al 72 Baseline treatment: insulin±ad Duration: 28 days (n=29) Rosenstock et al 70 Baseline treatment: metformin Duration: 12 weeks (n=451) Stenlof et al 73 Duration: 26 weeks (n=584) Schernthaner et al 74 Baseline treatment: metformin+ sulfonylurea Duration: 52 weeks (n=755) Canagliflozin 100 mg once daily Canagliflozin 300 mg twice daily Canagliflozin 50 mg Canagliflozin 100 mg Canagliflozin 200 mg Canagliflozin 300 mg Canagliflozin 600 mg Sitagliflozin 100 mg Canagliflozin 100 mg Canagliflozin 300 mg Canagliflozin 300 mg Sitagliflozin 100 mg 8 4 (0 88) 8 4 (1 02) 8 3 (0 83) 8 0 (0 99) 7 83 (0 96) 7 61 (0 80) 7 69 (1 02) 7 73 (0 89) 7 64 (0 95) 7 75 (0 83) 8 0 (1 0) 8 1 (1 0) 8 0 (1 0) p<0 05 vs placebo p<0 001 vs placebo 0 91 ( 1 1 to 0 7) 1 16 ( 1 3 to 1 0) (23 34) 94 1 (16 17) 95 1 (13 96) 87 6± ± ± ± ± (18 0) 85 9 (19 5) 85 8 (21 4) 86 9 (20 5) 87 6 (19 5) 0 68 ( 1 62 to 0 25) 1 24( 2 15 to 0 33) 0 03 (0 61) p<0 05 vs placebo p<0 001 vs placebo 2 2 ( 2 9 to 1 6) 3 3 ( 4 0 to 2 6) 0 5 Based on information provided at the Food and Drug Administration advisory committee, January, Data are mean (95% CI) or mean (SD). HbA 1c =glycated haemoglobin A 1c. AD=oral antidiabetic drugs. Table 4: Summary of randomised controlled trials with canagliflozin of >4 weeks duration 52,64,68 71 Empagliflozin at daily doses of mg given for 28 days reduced FPG compared with placebo ( 29 to 44 mg/dl). 47 In a 12-week randomised controlled trial, empagliflozin 5 25 mg daily reduced FPG ( 1 3 to 1 7 vs 0 04 mm), HbA 1c ( 0 4 to 0 7% vs +0 1 for placebo), and bodyweight compared with placebo. 75 Similarly, ipragliflozin reduced HbA 1c, FPG, and bodyweight compared with placebo when used as monotherapy or add-on to metformin in patients with type 2 diabetes. 76,77 The dual SGLT1/SGLT2 inhibitor LX4211 increased urinary glucose excretion, and lowered FPG, PPG, and HbA 1c in a 28-day randomised controlled trial. 51 A combination of sitagliptin and LX4221 also reduced PPG and increased active GLP1 synergistically when compared with each drug alone. 78 Effect on cardiovascular risk factors The potential microvascular and macrovascular benefits of early and sustained glycaemic control together with reduced adiposity are reviewed elsewhere, 2 and the fact that long-term clinical use of SGLT2 inhibitors should help to achieve these benefits is recognised. 79 In addition to improved glycaemic control and bodyweight loss, the increased glucosuria created by SGLT2 inhibition results in a mild osmotic diuresis, typically about 300 ml over 24 h. 56 This diuresis might account, at least in part, for a favourable effect on blood pressure control. Dapagliflozin has consistently reduced systolic blood pressure by 3 5 mm Hg in individuals with diabetes with and without hypertension when used as monotherapy or in combination with other glucose-lowering drugs, including insulin. A smaller and less consistent reduction in diastolic blood pressure has also been noted during clinical trials ther SGLT inhibitors have also produced reductions in systolic blood pressure not dissimilar to those produced by a mild diuretic, and without causing hypotension. 41,73,76 Although SGLT inhibitors do not seem to directly affect lipid metabolism, preliminary accounts note small decreases in circulating triglycerides, decreased LDL cholesterol and increased HDL cholesterol, but without change to the LDL HDL ratio. 41,73 Whether this represents a clinically meaningful effect, and whether SGLT1 and SGLT2 inhibition contribute differently to such an effect is unknown, but adjustments to the glucose fatty acid (Randle) cycle and haemoconcentration could be involved. 41,73 Analyses of major adverse cardiovascular events (MACE: cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke) during randomised phase 2 and 3 trials of new glucose-lowering drugs, as required by the US Food and Drug Administration, have shown a reduction in the number of events with dapaglifloxin and canagliflozin. 35,41 The glucose reduction, weight loss, or blood pressure decrease could each contribute to this reduction of cardiovascular events. Although neither of these SGLT inhibitors has shown any cardiovascular safety signal in the pre-approval development programme, both are involved in long-term Published online August 13,

8 vascular outcome studies. 80 The CANVAS study with canagliflozin as add-on to normal care was started preapproval. CANVAS is following about 4400 patients with type 2 diabetes for more than 4 years, primarily to capture MACE events. The DECLARE study with dapagliflozin as add-on to normal care will investigate MACE events in about patients and is planned to continue for about 6 years. 81 Safety In clinical trials, use of an SGLT inhibitor as monotherapy or in combination with metformin or pioglitazone has not increased reported symptoms of hypoglycaemia, and no severe adverse events have been noted. In combination with sulfonylureas or insulin, SGLT inhibition can increase the risk of hypoglycaemic episodes, although this has not increased severe events. 34,40 As a precaution, consideration of reduction of the dose of insulin or sulfonylurea is suggested when adding an SGLT2 inhibitor. The glucose-lowering effect of SGLT2 inhibition seems to be self-limiting such that when the blood glucose concentration (and therefore the glucose concentration of the glomerular filtrate) decreases to concentrations at which hypoglycaemic symptoms are experienced (eg, below about 4 mmol/l in most patients with diabetes), the remaining SGLT2 activity plus the SGLT1 activity can reabsorb almost all of the filtered glucose, preventing further loss of glucose. Thus the activity of SGLT1 is a safety net for glucose loss below normoglycaemia. Mild suppression of renal SGLT1 activity with some agents under investigation does not seem to have compromised this ability to counter hypoglycaemia. 41,72 74 The self-limiting efficacy of SGLT2 inhibition as glucose concentrations decrease also precludes misuse of these drugs. The excess urinary glucose excretion accompanying SGLT inhibition might be anticipated to increase genitourinary infections, and the fluid loss through osmotic diuresis might cause hypovolaemia, hypotension, and dehydration. Results of extensive published studies with dapagliflozin (table 5) and experience of canagliflozin, empagliflozin, and ipragliflozin use indicate an increased (approximately doubled) incidence of genital infection (particularly in women), although these infections were mostly self-treated or responded to standard anti-fungal intervention. 35,41 The occurrence of these infections seems to be reduced with time, possibly because the early symptoms are recognised and treated prophylactically. The occurrence of urinary tract infections was inconsistent among trials but overall incidence rates were increased by about a third. 35,41 Asymptomatic bacteriuria is not uncommon in patients with poorly controlled diabetes, and the distribution of organisms in the urinary tract infections studied with dapagliflozin was similar to that in the general population. 82 Patients responded to standard therapy, and risk of severe infection or pyelonephritis was not increased. 35,83,84 Evidence of hypovolaemia and hypo tension was rarely encountered and not severely so in the trials with dapagliflozin. The osmotic diuresis effect of dapagliflozin might be helpful to counter peripheral oedema in patients treated with pioglitazone, although this combination has been excluded because of bladder caution. 35 Although dapagliflozin was not mutagenic or carcinogenic in preclinical trials and no overall imbalance in malignancies during the development programme was noted, occurrence of breast, prostate, and bladder tumours was higher. 81 When patients receive frequent and thorough attention during a clinical trial, rapid weight loss can enable early detection of breast tumours, urination difficulties can signal prostate problems, and unresolved haematuria prompts investigation for bladder cancer. These cancers were mostly identified early in the trials and were too advanced to have arisen after treatment randomisation. The possibility that continual high glucose exposure could damage the urothelium or promote tumour growth was not seen in long-term preclinical studies with large drug exposures, and patients with familial renal glucosuria have not shown adverse urinary tract events. 19 Place in therapy Because the inhibition of SGLT1/2 reduces hyperglycaemia in an insulin-independent way, this therapeutic approach should be suitable for all stages in the natural history of any type of diabetes provided that insulinisation (endogenous or exogenous) and renal function are adequate. That SGLT1/2 inhibition treats hyperglycaemia but does not directly address the underlying endocrinopathies of diabetes is reiterated, although a reduction in glucotoxicity is expected to benefit those endocrinopathies and complications that are aggravated or caused by the hyperglycaemia, notably insulin resistance, β-cell damage, and microvascular disease. 23 Practical experience exists of dapagliflozin in type 2 diabetes as monotherapy and as add-on to other glucoselowering therapies including insulin. Although the glucose-lowering efficacy of dapagliflozin has been confirmed as monotherapy in type 2 diabetes, 60,67 the recognised advantages of metformin as initial pharmacotherapy in most patients with type 2 diabetes suggest that monotherapy with an SGLT1/2 inhibitor might only be considered when metformin is not tolerated. 35,85 SGLT2 inhibition is unlikely to be suitable if metformin is contraindicated because of renal impairment. A more likely scenario is use of SGLT1/2 inhibition as add-on to metformin or other drugs for inadequately controlled overweight or obese patients, especially when hypoglycaemia or obesity-related comorbidities such as sleep apnoea or severe hypertension are particular concerns. 35,57,58,64,85 As previously mentioned, when hypoglycaemia is a particular risk, reduction of the dose of a sulfonylurea or insulin if adding dapagliflozin might be appropriate. Addition of dapagliflozin to insulin 8 Published online August 13,

9 Arms Hypoglycaemia Urinary tract infection Genitourinary infections Volume depletion/ hypotension List et al 56 Duration: 12 weeks (n=389) Dapagliflozin 50 mg Metformin Wilding et al 59 Baseline treatment: ADs+insulin (but no sulfonylurea) Duration: 12 weeks (n=71) Dapagliflozin 20 mg Dapagliflozin 10 mg % % 20 8% 4 3% 4 Ferrannini et al 60 (n=485) Bailey et al 57 Baseline treatment: metformin (n=546) Strojek et al 61 Baseline treatment: glimepiride (n=597) Nauck et al 58 Baseline treatment: metformin Duration: 52 weeks (n=814) Henry et al 63 (n=641) Wilding et al 64 Baseline treatment: insulin±ad Duration: 48 weeks (n=808) Rosenstock et al 62 Baseline treatment: pioglitazone±ad Duration: 48 weeks (n=420) Dapagliflozin (max 10 mg) Glipizide (max 20 mg) Dapagliflozin 10 mg+metformin XR Dapagliflozin 10 mg Metformin XR Dapagliflozin 5 mg Dapagliflozin 10 mg 1 5% 2 9% 2 7% % 6 9% 7 9% 4 8% 3 4% 39 7% 3 3% 0 9% 2 9% 60 4% 55 7% 53 6% 51 8% 12 5% 4 6% 5 7% % 6 9% 5 3% 6 2% 5 9% 7 6% 2 8% 7 8% 1 9% 5 4% 7 5% 7 1% 4 1% 5 8 5% 7 9% 7 8% 7 7% 12 9% 1 3% % 6 2% 6 6% 0 7% 12 3% 2 7% 8 5% 12 8% 2 4% 6 4% 9 9% 10 7% 2 5% 8 6% 9 2% 2 9% 1 4% 1 3% 1 <1 0 6% 0 7% 1 5% 0 7% 0 9% 2 5% 2 4% 1 5% 1 Values are percentages of patients reporting or showing symptoms or receiving a confirmed diagnosis. ADs=oral antidiabetic drugs. XR=extended release. Table 5: Summary of adverse events in randomised controlled trials of dapagliflozin of >12 weeks duration reduces insulin dose escalation and offsets weight gain. 64 Use of an SGLT1/2 inhibitor can also be included as part of a triple therapy regimen with or without insulin, again if renal function is sufficient. 35 The present indication for dapagliflozin excludes combination with pioglitazone to avoid any complications associated with risk and attribution of bladder tumours. 35 However, in principle, inhibition of SGLT2 should counter the weight gain and the propensity for oedema with a PPAR-γ agonist. Experience with dapagliflozin as add-on to incretin therapy is low but not precluded, and use in the elderly (patients older than 75 years) is restricted, as efficacy is compromised with decreasing renal competence. 35 Because impaired renal function is a common complication of diabetes, 86 the absence of evidence that SGLT inhibitors cause damage to kidneys is emphasised. Improved glycaemic control and lower blood pressure should reduce glomerular damage, and the results of longterm studies are awaited. As with a reduction in extracellular volume during initiation of diuretic therapy, the osmotic diuresis with renal SGLT inhibition could temporarily reduce glomerular filtration rate, and potential effects on sodium excretion mean caution should be exercised if inhibitors are used with a loop diuretic. 35 Conclusions By decreasing renal glucose reabsorption, SGLT2 inhibition can reduce hyperglycaemia in an insulinindependent manner and assist weight loss and blood pressure control. Slight inhibition of SGLT1 can further decrease renal glucose reabsorption and delay intestinal glucose absorption, although these effects should not be too potent to avoid susceptibility to hypoglycaemia or Published online August 13,

10 Search strategy and selection criteria We searched PubMed, Medline, and Google Scholar for articles published in English, and the conference proceedings websites of the American Diabetes Association and European Association for the Study of Diabetes meetings for abstracts of non-published trials. We searched for articles published between 2003 and We used the following terms for our search: SGLT, SGLT inhibitor, and individual names of the SGLT inhibitors in development. We also consulted the websites of the European Medicines Agency and the US Food and Drug Administration. transfer of glucose into the large intestine. Glucosuria can increase rates of genital and urinary tract infections, but overall tolerability has been good. Randomised trials have consistently confirmed the antihyperglycaemic efficacy of SGLT2 inhibition, with and without significant SGLT1 inhibition in type 2 diabetes as monotherapy or add-on to other glucose-lowering therapies, including insulin. In patients with adequate renal function, this approach can improve glycaemic control in diabetic states. Contributors All authors contributed equally Conflicts of interest AAT has received travel or accommodation reimbursement from Bristol-Myers Squibb, Eli Lilly, Novo-Nordisk, and Sanofi-Aventis. AHB has received honoraria for advisory work and lectures from Bristol-Myers Squibb, AstraZeneca, Jannsen, Boehringer-Ingelheim, Novartis, Merck Sharp & Dohme, Roche, Takeda, Sanofi-Aventis, Eli Lilly, and Novo-Nordisk. CJB has consulted for Bristol-Myers Squibb, AstraZeneca, Merck Sharp & Dohme, Novo-Nordisk, Sanofi-Aventis, Janssen, Eli Lilly, Roche, and Takeda; delivered continuing medical education programmes sponsored by Bristol-Myers Squibb, AstraZeneca, GlaxoSmithKline, Merck Serono, Merck Sharp & Dohme, Eli Lilly, and Boehringer Ingelheim; and received travel or accommodation reimbursement from AstraZeneca and Bristol-Myers Squibb. References 1 DeFronzo RA. 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