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Discovery and development of gliflozins

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SGLT-2 inhibitors is a new class of drugs in the treatment of type 2 diabetes (T2D). The efficacy of the drug is dependent on renal excretion and prevents glucose from going into blood circulation by promoting glucosuria.

Introduction

Kidneys play an important role in glucose homeostasis

There are at least four members of SLC-5 gene family, which is secondary active glucose transporters. The sodium glucose transporters proteins SGLT-1 and SGLT-2 are the two premier members of the family. These two members are found in the kidneys, among other transporters, and are the main co-transporters there related to the blood sugar, they play a role in renal glucose reabsorption and also in intestinal glucose absorption.[1][2]

Blood glucose is freely filtered by the glomeruli and SGLT-1 and SGLT-2 reabsorb glucose in the kidneys and put it back into the circulation cells. SGLT-2 is responsible for 90% of the reabsorption but SGLT-1 for 10%.[3][1]

The SGLT-2 protein

Sodium glucose co-transporter (SGLT) proteins are proteins that are bound to the cell membrane and have the role of transporting glucose through the membrane into the cells, against the concentration gradient of glucose. This is done by using the sodium gradient, produced by sodium/potassium ATPase pumps, so at the same time glucose is transported into the cells, the Na+ is too. Since it is against the gradient, it requires energy to work. SGLT proteins cause the glucose reabsorption from the glomerular filtrate, independent of insulin.[1][4][3]

SGLT-2 is a member of the glucose transporter family and is a low-affinity, high-capacity glucose transporter. SGLT-2 is mainly expressed in the S-1 and S-2 segments of the proximal renal tubules where the majority of filtered glucose is absorbed. So SGLT-2 has a role in regulation of glucose and is responsible for most glucose reabsorption in the kidneys.[5][1]

In diabetes extracellular glucose concentration increases, this high glucose level leads to up-regulation of SGLT-2 that leads to more absorption of glucose in the kidneys. That is not good, since these effects cause maintenance of hyperglycemia.[6] Because Na+ is absorbed at the same time as glucose via SGLT-2, the up-regulation of SGLT-2 probably leads to development or maintenance of hypertension. In study where rats were given either ramipril or losartan, levels of SGLT-2 protein and mRNA significantly reduced. In patients with diabetes, hypertension is a common problem so this may have relevance in this disease.[1]

Drugs that inhibit sodium glucose cotransporter 2, inhibit renal glucose reabsorption that leads to enhanced urinary glucose excretion leading to lower glucose in blood. The good thing about them is that they work independently of insulin and can reduce glucose levels without causing hypoglycemia or weight gain.[1][7]

Drug discovery

Originally it was thought that diabetes mellitus was a renal disorder because of the glucose found in the urine. But after insulin was discovered the focus of diabetes management was on the pancreas. Traditional focus of therapeutic strategies for diabetes have been to enhance endogenous insulin secretion and/or to improve insulin sensitivity. In the previous decade the role of the kidney in the development and maintenance of high glucose levels, has been examined. The role of the kidney led to the development of drugs that inhibit sodium glucose transporter 2 (SGLT-2) protein. Every day approximately 180 grams of glucose are filtered through the glomeruli and lost into the primary urine in healthy adults but more than 90% of the glucose that is initially filtered is reabsorbed of high capacity system controlled by SGLT-2 in the early convoulted segment of the proximal tubules. Almost all remaining filtered glucose is reabsorbed by high capacity system called sodium glucose transporter 1 (SGLT-1) so under normal circumstances less than 0,1g of glucose that are reabsorbed will never find its way into the urine of non-diabetic individuals.[8][9]

Phlorizin

Phlorizin

Phlorizin is a compound that has been known for over a century. It is a naturally occurring botanical glucoside that produces renal glycosuria and blocks intestinal glucose absorption through inhibition of the sodium-glucose symporters located in the proximal renal tubule and mucosa of the small intestine. Phlorizin was first isolated in 1835 and was subsequently found to be potent but rather non-selective inhibitor of both SGLT-1 and SGLT-2 proteins.[10][11][12]

Phlorizin seemed to have very interesting properties and the results in animal studies were encouraging, it improved insulin sensitivity and in diabetic rat models it seemed to increase glucose levels in urine and also normal glucose concentration in plasma occurred without hypoglycemia. Unfortunately, in spite of these properties, phlorizin was not suitable enough for clinical development for several reasons. Phlorizin has very poor oral bioavailability, it is broken down in the gastrointestinal tract, so it had to be given parenterally. Phloretin, the active metabolite in phlorizin, is a potent inhibitor of facilitative glucose transporters and also, phlorizin seem to lead to serious adverse events in the gastrointestinal tract like diarrhea and dehydration. Because of these reasons, phlorizin was never pursued in humans.[10][12][13]

Although phlorizin was not suitable for further clinical trials, it served an important role in the development of a new class of drugs, SGLT-2 inhibitors. It served a basis for the recognition of SGLT inhibitors with improved safety and tolerability profiles. For an example the SGLT inhibitors are not associated with gastrointestinal adverse events and the bioavailability is much greater in the SGLT inhibitors.[4][12][13]

Inhibition of SGLT-2 result as better control of glucose level, lower insulin, lower blood pressure and uric acid levels and augment calorie wasting. Some data also supports that SGLT-2 inhibition may have direct renoprotective effects, including actions to attenuate tubular hypertrophy and hyperfiltration associated with diabetes as well as reduce the tubular toxicity of glucose. Inhibition of SGLT-2 following treatment with dapagliflozin reduces the capacity for tubular glucose reabsorption by approximately 30–50%.[8]

Drug development

Phlorizin consist of glucose moiety and two aromatic rings (aglycone moiety) joined by an alkyl spacer. In first, phlorizin was isolated for treatment of fever and infectious diseases, particularly malaria. According to Michael Nauck and his partners, studies were made in the 1950s on phlorizin that showed that phlorizin blocks sugar transport in the kidney, small intestine and few other tissues. In the early 1990s sodium glucose co-transporter 2 was fully characterized so at that time the mechanism of phlorizin was real interest. In later studies it was said that sugar blocking effects of phlorizin was due to inhibition of the sodium glucose cotransport proteins.[4][1][9][11]

Most of the reported SGLT-2 inhibitors are glucosides analogs that can be tracked to the o-aryl glucoside found in the nature. The problem about o-glucosides as SGLT-2 inhibitors is instability that can be tracked to degradation by β-glucosidase in the small intestine. Because of that, o-glucosides given orally have to be prodrug esters. These prodrugs go through changes in the body leading to carbon-carbon bond between the glucose and the aglycone moiety so c-glucoside are formed from the o-glucosides. C-glucosides have a different pharmacokinetic profile than o-glucosides (e.g. half life and duration of action) and are not degraded by the β-glucosidase. The first discovered c-glucoside is the drug Dapagliflozin ((1S)-1,5-anhydro-1-C-{4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl}-D-glucitol).[1][14][15] Dapagliflozin was the first highly selective SGLT2-inhibitor approved by the European Medicine Agency.[16] All SGLT-2 inhibitors in clinical development are prodrugs that have to be converted to its active ‘A’ form for activity.[9]

T-1095

The structure of T-1095

Phlorizin is a nonselective inhibitor with poor oral bioavailability so it is unsuitable as a drug for treatment of diabetes, therefore phlorizin derivative was synthesised and called T-1095. T-1095 is a methyl carbonate prodrug that is absorbed into the circulation when given orally and is rapidly converted to the active metabolite, T-1095A, in the liver.[1][9] By inhibiting SGLT-1 and SGLT-2, urinary glucose excretion increased in diabetic animals. T-1095 did not proceed in clinical development, probably because of the inhibition of SGLT-1 [1] but non-selective SGLT inhibitors may also block glucose transporter 1 (GLUT-1). About 90% of filtered glucose is reabsorbed through SGLT-2 so research has focused specifically on SGLT-2. Inhibition of SGLT-1 may also lead to the genetic disease called Glucose Galactose Malabsorption syndrome, characterized by a severe diarrhea.[9][17]

ISIS 388626

According to preliminary findings of a novel method of SGLT-2 inhibition, the antisense oligonucleotide ISIS 388626 improved plasma glucose in rodents and dogs by reducing mRNA expression in the proximal renal tubules by up to 80% if it was given once a week. It did not affect SGLT-1. A study results on long-term use of ISIS 388626 in nonhuman primates observed more than 1000 fold increase in glucosuria without any associated hypoglycemia. This increase in glucosuria can be attributed to dose-dependent reduction in expression of SGLT-2, where the highest dose led to more than 75% reduction. In 2010, ISIS Pharmaceuticals recently announced that ISIS-SGLT-2RX, which is a 12-nucleotide antisense oligonucleotide, was about to commence human phase 1 studies.[9]

The activity of SGLT-2 inhibitors in glycemic control.

Michael Nauck recounts that meta-analyses of studies about the activity of SGLT-2 inhibitors in glycemic control in type 2 diabetes mellitus patients, shows improvement in the control of glucose, compared with placebo, metformin, sulfonylurea, thiazolidinediones, insulin and more. The HbA1c was examined after SGLT-2 inhibitors were given alone (as monotherapy) or as an add-on therapy to the other diabetes medicines. The SGLT-2 inhibitors that were used were dapagliflozin and canagliflozin among others in that same drug class. The meta-analysis was taken together from studies ranging from period of few weeks up to more than 100 weeks. [4]

The results, summed up, were that 10 mg of Dapagliflozin showed more effect than placebo in the control of glucose, when given for 24 weeks. However, no inferior efficacy of 10 mg Dapagliflozin were shown when used as an add-on therapy to metformin, compared with glipizide after use for 52 weeks. 10 mg of Dapagliflozin did neither show inferior efficacy compared with metformin when both of the medicines were given as monotherapy for 24 weeks.[4]

The results from meta-analysis when Canagliflozin was examined, showed that compared to placebo, canagliflozin effect the HbA1c. Meta-analysis studies also showed that 10 mg and 25 mg of Empagliflozin, improved HbA1c compared with placebo.[4]

Structure-activity relationship (SAR)

When we look at the aglycones of phlorizin and dapagliflozin, both of them have weak inhibition effects on SGLT-1 and SGLT-2. According to this, two synergistic forces are involved in binding of inhibitors to SGLTs. Different sugars on the aglycone will affect and change the orientation of it in the access vestibule because one of the forces involved in the binding is the binding of sugar to the glucose site. The other force affects the binding affinity of the entire inhibitor and that is the binding of the aglycone.[14]

The discovery of T-1095 led to investigation of how to enhance potency, selectivity and oral bioavailability by adding various substituents to the glycoside core. As an example we can take the change of o-glycosides to c-glycosides by creating a carbon-carbon bond between the glucose and the aglycone moiety. C-glucosides are more stable than o-glucosides which leads to modified half life and duration of action. The modifications has also led to more specificity to SGLT-2.[9] C-glucosides that have heterocyclic ring at the distal ring or proximal ring are better when it comes to anti-diabetic effect and physicochemical features all together. [3][18] C-glucoside bearing thiazole at the distal ring on dapagliflozin has shown good physicochemical properties that can lead to a clinical development, but still has the same antidiabetic activity as Dapagliflozin. This is shown in tables 1 and 2.

Song and his partners did preparate thiazole compound by starting with carboxyl acid. Working with that, it took them three steps to get compound like dapagliflozin with thiazole ring. Inhibitory effects on SGLT-2 of the compounds were tested by Song and partners. In table 1, table 2 and table 3 you can see how the IC50 value changes depending on what compound is in the ring position, in the C-4 region of the proximal phenyl ring, and how the thiazole ring relates.[3]

Many compounds gave different IC50 value in the ring position in an in vitro activity. For an example there was a big difference if there was an n-pentyl group (IC50 = 13,3 nM), n-butyl (IC50 = 119 nM), phenyl with 2-furyl (IC50 = 0,720) or 3-thiophenyl (IC50 = 0,772). As seen in table 1, the in vitro activity increases depending on what compound is bonded to the distal ring (given that in the C-4 region of the proximal phenyl ring is a Cl atom).[3]

Table 1: Skrifa smá texta um hvað er í töflunni

R IC50 (nM)[3] Activity[3]
0.720 in vitro activity improved*
1.14 in vitro activity improved*
13.3 As the number of carbons increases, the IC-50 value fluctuates
19.6 in vitro activity decreased*
21.2 in vitro activity decreased*

* comparator to ethyl group (IC50 = 16,7)

In table 2 it is shown how the in vitro activity changes depending on the compound in the C-4 region of the proximal phenyl ring (X). Small methyl groups or other halogen atoms in the C-4 position gave IC50 ranging from 0,72 - 36,7 (given that the phenyl with 2-furyl is in the ring position).[3]

Table 2: Skrifa smá texta hér hvað er í töflunni

X [3] IC50 (nM) [3]
Cl 0.720
Me 1.43
F 6.11
H 22.6
CN 36.7

Table 3: The difference in the IC-50 value depending on how the thiazole ring relates (nothing else is changed in the structure (X = Cl, R = phenyl with 2-furyl).

Compound IC50 (nM) [3]
0.720
1.11

Mechanism of action

Kidney Nephron

SGLTs are responsible for mediating glucose reabsorption in the kidneys, as well as in the gut and the heart. SGLT-2 is primarily expressed in the kidney on the epithelial cells lining the S1 segment of the proximal convoluted tubule. It is the major transport protein that promotes reabsorption from the glomerular filtration glucose back into circulation and is responsible for approximately 90% of renal glucose reabsorption. By inhibiting SGLT-2 it prevents renal reuptake from the glomerular filtrate and subsequently lowers the glucose level in the blood and promotes glucosuria.[19][20]

Dapagliflozin is an example of SGLT-2 inhibitor, it is a competitive, highly selective inhibitor of SGLT. It acts via selective and potent inhibition of SGLT-2, and it’s activity is based on each patient’s underlying glycemic control and renal function. The results are decreased renal reabsorption of glucose, glucosuria effect increases with higher level of glucose in the blood circulation. Thereby dapagliflozin reduces the blood glucose concentration with a mechanism that is independent of insulin secretion and sensitivity, unlike many other antidiabetic drugs. Functional β-cells are not necessary for the activity of the drug so it is convenient for patients with diminished β-cell function.[20][19]

Sodium and glucose is co-transported by the SGLT-2 protein into the tubular epithelial cells across the brush-border membrane of the proximal renal tubule. This happens because of the sodium gradient between the tubule and the cell, thereby it provides a secondary active transport of glucose. Glucose is later reabsorbed by passive transfer of endothelial cells into the interstitial glucose transporter protein.[21][20][19]

The use of dapagliflozin with other oral antidiabetic agents act synergistically with virtually no increased risk of hypoglycaemia.[20][19]

Pharmacology

Three SGLT-2 inhibitors have been approved by the FDA; dapagliflozin, canagliflozin and empagliflozin. The elimination half-life, bioavailability and protein binding is various between the drugs as seen in table 4. These drugs are excreted in the urine as inactive metabolites.[22][23][24][21]

Drug Bioavailability (%) tmax (hours) Protein Binding (%) t1/2
Canagliflozin 65[24] 1-2[24] 99[24] 100mg = 10.6 hours, 300mg = 13.1 hours[24]
Dapagliflozin 78[23] 1-2[23] 91[23] 10mg = 12.9 hours[23]
Empagliflozin 85[25] 1.5[22] 86.2[22] 10mg = 12.4[22]

tmax: Time to achieve maximum plasma concentration t1/2: Elimination half-life

Dapagliflozin

In studies that were made on healthy people and people with diabetes type 2, who were given dapagliflozin in either single ascending dose (SAD) or multiple ascending dose (MAD) showed results that confirmed a pharmacokinetic profile of the drug. With dose-dependent cencentrations the half-life is about 12-13 hours, Tmax 1-2 hours and it is protein-bounded, so the drug has a rapid absorption and minimal renal excretion.[13]

Dapagliflozin disposition is not evidently affected by BMI or body weight, therefore the pharmacokinetic findings are expected to be applicable to patients with a higher BMI. Dapagliflozin resulted in dose-dependent increases excretions in urinary glucose, up to 47g/d following single-dose administration, which can be expected from its mechanism of action, dapagliflozin. [26]

In some long term clinical studies that have been made on dapagliflozin, dapagliflozin was associated with a decrease in body weight which was statistically superior compared to placebo or other active comparators. It is primarily associated with caloric rather than fluid loss.[26][21]

Adverse Events

Until recently, dapagliflozin was not approved by the Food and Drug Administration (FDA) because of safety issues. The reason FDA didn’t approve the drug right away, was because of these safety issues that were associated to an increased risk for infections in the urinary tract and genitals. Increased risk for breast cancer as well as bladder cancer were also associated to dapagliflozin. But in January 2014, dapagliflozin was approved by the FDA.[16]

Drug-Drug Interaction

Interactions are very important for SGLT2 inhibitors because most T2DM patients are taking many other medications. There is low risk of clinically relevant pharmacokinetics drug drug interactions because of the metabolic pathway of SGLT2.[27] According to Bhartia and his co-workers, it is safe to consume dapagliflozin along with pioglitazone, metformin, glimepiride, or sitagliptin and dose adjustment is unnecessary for either drug.[13] It is unlikely that food intake has clinical meaningful impact on the efficacy of dapagliflozin, therefore it can be administered without regard to meals.[26][13]

References

  1. ^ a b c d e f g h i j Nair, S.; Wilding, J.P.H. (2010). "Sodium Glucose Cotransporter 2 Inhibitors as a New Treatment for Diabetes Mellitus". Journal of Clinical Endocrinology & Metabolism. 95 (1): 34–42.
  2. ^ Wright, E.M.; Hirayama, B.A.; Loo, D.F. (2007). "Active sugar transport in health and disease". Journal of Internal Medicine. 261 (1): 32–43.
  3. ^ a b c d e f g h i j k Song, Kwang-Seop; Lee, Suk Ho; Kim, Min Ju; Seo, Hee Jeong; Lee, Junwon; Lee, Sung-Han; Jung, Myung Eun; Son, Eun-Jung; Lee, MinWoo; Kim, Jeongmin; Lee, Jinhwa (10 February 2011). "Synthesis and SAR of Thiazolylmethylphenyl Glucoside as Novel-Aryl Glucoside SGLT2 Inhibitors". ACS Medicinal Chemistry Letters. 2 (2): 182–187. doi:10.1021/Ml100256c.
  4. ^ a b c d e f Nauck, Michael (2014). "Update on developments with SGLT2 inhibitors in the management of type 2 diabetes". Drug Design, Development and Therapy: 1335–1380. doi:10.2147/DDDT.S50773.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  5. ^ Kasichayanula, Sreeneeranj; Liu, Xiaoni; Pe Benito, Melanie; Yao, Ming; Pfister, Marc; LaCreta, Frank P.; Humphreys, William Griffith; Boulton, David W. (2013). "The influence of kidney function on dapagliflozin exposure, metabolism and pharmacodynamics in healthy subjects and in patients with type 2 diabetes mellitus". British Journal of Clinical Pharmacology. 76 (3): 432–444. doi:10.1111/bcp.12056.
  6. ^ Mediavilla Bravo, J.J. (July 2014). "Aportaciones de los SGLT-2 y nuevos fármacos en investigación". SEMERGEN - Medicina de Familia. 40: 34–40. doi:10.1016/S1138-3593(14)74388-6.
  7. ^ Whaley, Jean; Tirmenstein; Reilly; Poucher; Saye; Parikh; List (2012). "Targeting the kidney and glucose excretion with dapagliflozin: preclinical and clinical evidence for SGLT2 inhibition as a new option for treatment of type 2 diabetes mellitus". Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy: 135. doi:10.2147/DMSO.S22503.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  8. ^ a b Thomas, M. C. (24 July 2014). "Renal effects of dapagliflozin in patients with type 2 diabetes". Therapeutic Advances in Endocrinology and Metabolism. 5 (3): 53–61. doi:10.1177/2042018814544153.
  9. ^ a b c d e f g Idris, Iskandar; Donnelly, Richard (2009). "Sodium-glucose co-transporter-2 inhibitors: an emerging new class of oral antidiabetic drug". Diabetes, Obesity and Metabolism. 11 (2): 79–88. doi:10.1111/j.1463-1326.2008.00982.x.
  10. ^ a b Ehrenkranz, Joel R. L.; Lewis, Norman G.; Ronald Kahn, C.; Roth, Jesse (2005). "Phlorizin: a review". Diabetes/Metabolism Research and Reviews. 21 (1): 31–38. doi:10.1002/dmrr.532.
  11. ^ a b Chao, Edward C.; Henry, Robert R. (28 May 2010). "SGLT2 inhibition — a novel strategy for diabetes treatment". Nature Reviews Drug Discovery. 9 (7): 551–559. doi:10.1038/nrd3180.
  12. ^ a b c McGill, Janet B. (12 April 2014). "The SGLT2 Inhibitor Empagliflozin for the Treatment of Type 2 Diabetes Mellitus: a Bench to Bedside Review". Diabetes Therapy. 5 (1): 43–63. doi:10.1007/s13300-014-0063-1.
  13. ^ a b c d e Bhartia, Mithun; Tahrani, Abd A.; Barnett, Anthony H. (2011). "SGLT-2 Inhibitors in Development for Type 2 Diabetes Treatment". The Review of Diabetic Studies. 8 (3): 348–354. doi:10.1900/RDS.2011.8.348.
  14. ^ a b Hummel, C. S.; Lu, C.; Liu, J.; Ghezzi, C.; Hirayama, B. A.; Loo, D. D. F.; Kepe, V.; Barrio, J. R.; Wright, E. M. (21 September 2011). "Structural selectivity of human SGLT inhibitors". AJP: Cell Physiology. 302 (2): C373 – C382. doi:10.1152/ajpcell.00328.2011.
  15. ^ Li, An-Rong; Zhang, Jian; Greenberg, Joanne; Lee, TaeWeon; Liu, Jiwen (2011). "Discovery of non-glucoside SGLT2 inhibitors". Bioorganic & Medicinal Chemistry Letters. 21 (8): 2472–2475. doi:10.1016/j.bmcl.2011.02.056.
  16. ^ a b Cuypers, J; Mathieu, C; Benhalima, K (2013). "SGLT2-inhibitors: a novel class for the treatment of type 2 diabetes introduction of SGLT-2-inhibitors in clinical practice". Acta clinica Belgica. 68 (4): 287–93. PMID 24455799.
  17. ^ Lv, Binhua; Xu, Baihua; Feng, Yan; Peng, Kun; Xu, Ge; Du, Jiyan; Zhang, Lili; Zhang, Wenbin; Zhang, Ting; Zhu, Liangcheng; Ding, Haifeng; Sheng, Zelin; Welihinda, Ajith; Seed, Brian; Chen, Yuanwei (December 2009). "Exploration of O-spiroketal C-arylglucosides as novel and selective renal sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors". Bioorganic & Medicinal Chemistry Letters. 19 (24): 6877–6881. doi:10.1016/j.bmcl.2009.10.088.
  18. ^ Park, Eun-Jung; Kong, Younggyu; Lee, Jun Sung; Lee, Sung-Han; Lee, Jinhwa (January 2011). "Exploration of SAR regarding glucose moiety in novel C-aryl glucoside inhibitors of SGLT2". Bioorganic & Medicinal Chemistry Letters. 21 (2): 742–746. doi:10.1016/J.Bmcl.2010.11.115.
  19. ^ a b c d Anderson, S. L.; Marrs, J. C. (20 March 2012). "Dapagliflozin for the Treatment of Type 2 Diabetes". Annals of Pharmacotherapy. 46 (4): 590–598. doi:10.1345/aph.1Q538.
  20. ^ a b c d Li, An-Rong; Zhang, Jian; Greenberg, Joanne; Lee, TaeWeon; Liu, Jiwen (April 2011). "Discovery of non-glucoside SGLT2 inhibitors". Bioorganic & Medicinal Chemistry Letters. 21 (8): 2472–2475. doi:10.1016/j.bmcl.2011.02.056.
  21. ^ a b c Plosker, Greg L. (December 2012). "Dapagliflozin". Drugs. 72 (17): 2289–2312. doi:10.2165/11209910-000000000-00000.
  22. ^ a b c d "Jardiance". drugs.com. Drugs.com. Retrieved 31 October 2014.
  23. ^ a b c d e "Farxiga". drugs.com. Drugs.com. Retrieved 31 October 2014.
  24. ^ a b c d e "Invokana". drugs.com. Drugs.com. Retrieved 31 October 2014.
  25. ^ Nisly, S. A.; Kolanczyk, D. M.; Walton, A. M. (31 January 2013). "Canagliflozin, a new sodium-glucose cotransporter 2 inhibitor, in the treatment of diabetes". American Journal of Health-System Pharmacy. 70 (4): 311–319. doi:10.2146/ajhp110514.
  26. ^ a b c Yang, Li; Li, Haiyan; Li, Hongmei; Bui, Anh; Chang, Ming; Liu, Xiaoni; Kasichayanula, Sreeneeranj; Griffen, Steven C.; LaCreta, Frank P.; Boulton, David W. (August 2013). "Pharmacokinetic and Pharmacodynamic Properties of Single- and Multiple-Dose of Dapagliflozin, a Selective Inhibitor of SGLT2, in Healthy Chinese Subjects". Clinical Therapeutics. 35 (8): 1211–1222.e2. doi:10.1016/J.Clinthera.2013.06.017.
  27. ^ Scheen, André J. (14 January 2014). "Drug–Drug Interactions with Sodium-Glucose Cotransporters Type 2 (SGLT2) Inhibitors, New Oral Glucose-Lowering Agents for the Management of Type 2 Diabetes Mellitus". Clinical Pharmacokinetics. 53 (4): 295–304. doi:10.1007/s40262-013-0128-8.
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