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 Table of Contents  
REVIEW ARTICLE
Year : 2014  |  Volume : 6  |  Issue : 3  |  Page : 107-113

Canagliflozin: A novel SGLT2 inhibitor for type 2 diabetes mellitus


1 Quantum Solutions India, DLF building, Chandigarh Technology Park, Chandigarh, India
2 Department of Pharmacology, AIIMS, New Delhi, India
3 Central Leprosy Teaching and Research Institute, Chengalpattu, Tamilnadu, India
4 Department of Pharmacology, Govt. Medical College Patiala, Punjab, India

Date of Web Publication11-Mar-2014

Correspondence Address:
Harmanjit Singh
Department of Pharmacology, AIIMS, New Delhi
India
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Source of Support: This article received no specifi c grant from any funding agency in the public, commercial, or not for-profi t sectors., Conflict of Interest: None


DOI: 10.4103/1947-2714.128471

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  Abstract 

Diabetes Mellitus continues to be a major non- communicable disease with global burden of 366 million at present and projected to increase to 439 to 552 million by 2030, India being the hub of diabetes. Sodium glucose transporter 2 (SGLT2) inhibitors presents a new class of anti-diabetic drugs having an insulin-independent mechanism that offers a considerable advantage of increasing urinary glucose excretion without inducing hypoglycemia and promoting weight loss due to loss of 300 to 400kcal/day, Canagliflozin being the 1 st successful candidate of this group and became the first SGLT2 inhibitor to be FDA approved on March 29, 2013. In various clinical trials, it has shown promising results in controlling glycemia, causing weight loss, reducing systolic and diastolic BP and cardiovascular risk. There are some safety concerns associated with its use e.g. genital mycotic infections, increased urination, urinary tract infection and hyperkalemia, which need to be carefully addressed while using this drug.

Keywords: Canagliflozin, Diabetes Mellitus, HbA1C, Inhibitors, SGLT2


How to cite this article:
Kaushal S, Singh H, Thangaraju P, Singh J. Canagliflozin: A novel SGLT2 inhibitor for type 2 diabetes mellitus. North Am J Med Sci 2014;6:107-13

How to cite this URL:
Kaushal S, Singh H, Thangaraju P, Singh J. Canagliflozin: A novel SGLT2 inhibitor for type 2 diabetes mellitus. North Am J Med Sci [serial online] 2014 [cited 2019 Dec 10];6:107-13. Available from: http://www.najms.org/text.asp?2014/6/3/107/128471


  Introduction Top


Diabetes Mellitus, one of the most common non-communicable diseases with the present global burden of 366 million is projected to increase to 439 to 552 million by the year 2030. [1],[2] Present prevalence in India is 61.3 million and will be 101.2 million by 2030. [3]

People with Type 2 diabetes are at increased risk for microvascular (neuropathy, nephropathy, and retinopathy) and macrovascular (peripheral vascular disease, cerebrovascular disease, and cardiovascular disease) complications in addition to metabolic syndrome, which further increases risk of cardiovascular manifestations, including stroke and myocardial infarction. [4] Cardiovascular disease is attributable to ~65% of deaths in diabetic patients [5] and this is expected to rise to 75% by 2030, leading to premature deaths. [6]

Many studies have proved the benefits of intensive glycemic control (fasting blood glucose less than 6 mmol/L [108mg/dL]) in reducing all-cause death, including microvascular and macrovascular complications from diabetes. [7],[8],[9],[10]

Commonly used antidiabetic agents for the treatment of type 2 diabetes act by increasing insulin release, increasing insulin sensitivity, restraining glucagon secretion, controlling hepatic glucose release, or inhibiting intestinal glucose absorption. [11],[12] Pertaining to the progressive dysfunction of the pancreatic β-cells and increasing insulin resistance over time, there is constant need for newer treatments with different mechanisms. Moreover, commonly used agents have multiple drawbacks e.g. thiazolidinediones and sulfonylurea contribute to weight gain during the therapeutic process, [13] due to which achievement of long-term glucose control becomes difficult. [14] Likewise, rosiglitazone was linked to increased incidence of MI and death in diabetics leading to complete withdrawal of the drug. [15] Even different sulphonylureas like tolbutamide, glyburide, glipizide and glimepiride are associated with widely variable CVD risk and mortality outcomes. [16],[17]

Among the newer FDA approved agents, GLP- 1 analogues are associated with reports of pancreatitis and gastroparesis, [18],[19] and more recently there are concerns about thyroid cancer risk in rat models. [18] Also, being primarily eliminated through kidneys, these drugs are not recommended in patients with renal insufficiency (creatinine clearance, CrCl <30mL/min) or end-stage renal disease. [20] The FDA approved DPP-4 inhibitors reportedly cause nasopharyngitis (5.2 to 6.3%), upper respiratory tract infection (4.5 to 6.2%), headache (1.1 to 5.9%), and rare cases of hypoglycemia. They also carry the same pancreatitis risk as associated with GLP-1 agonists. [21] and must be dose reduced with moderate to severe renal dysfunction. [22]

Therefore, the current focus of research is an anti-diabetic agent that can improve glycemic control without increasing hypoglycemia, can promote weight loss, improve β- cell function, while reducing complications and mortality associated with the disease and which is safe enough to be used in renal or hepatic compromise. [23]

Sodium glucose transporter-2 (SGLT-2) inhibitors

Recently, kidneys have emerged as a new target for diabetes therapy. Patients with high blood glucose levels usually experience glycosuria and nocturia, which has been used as a diagnostic feature for diabetes and indicates poor glycaemic control. [23] Actually, this glucose load excreted by the body is what is left after glucose has passed through the renal nephron. Glucosuria is now recognized as a feasible insulin-independent mechanism that reduces blood glucose without causing hypoglycemia and facilitating weight loss.

SGLTs belong to a large family of sodium glucose cotransporter SLC5. [24] SGLT1 are expressed primarily in small intestines, proximal tubule of nephrons and in myocardium, whereas SGLT2 are exclusively present in the brush border of epithelial cells in S1 and S2 segments of proximal renal tubules. Their expression and activity is elevated by raised plasma glucose concentration [25] but is unrelated to renal gluconeogensis, which may be increased in diabetes. [26]

In healthy individuals, kidneys reabsorb all of the glomerullary filtered glucose [27] through high capacity SGLT2 in the early proximal tubule, which reabsorb most of the glucose load, and the low capacity SGLT1 in more distal regions of the tubule reabsorbing the remainder. These co-transporters are secondary active as they depend on Na+ to K+ATPase activity in the basolateral membrane for the active removal of sodium. GLUT2 and GLUT1 respectively facilitate glucose transport across the basolateral membrane in the early and more distal regions of the proximal tubule. [26],[28] In healthy individuals, about 180g of glucose is filtered and reabsorbed daily through the kidneys and maximal transport rate (Tmax) is 300mg/min. This rate is about 20% higher i.e. 352 mg/min (19.5mmol/l/min) to 419mg/min (23.3mmol/l/min) [29],[30] in patients with poorly controlled T2DM. This pertains to the increased expression of SGLTs in persons with diabetes which represents a physiological response to increased glucose delivery to the nephrons that is ultimately maladaptive. [31]

Antagonizing these transporters with SGLT2 inhibitors is an insulin-independent mechanism that offers a considerable advantage of increasing urinary glucose excretion without inducing hypoglycemia [4],[14] and promoting weight loss due to loss of 300-400 kcal/day. [32],[33]

A look into history

A naturally occurring inhibitor of both SGLT1 and SGLT2 called phlorizin was isolated from apple tree bark by French chemists in 1835. [34] In early 1900s phlorizin administered to normal animals was noted to cause glucosuria, polydipsia and weight loss, [35] and in the 1980s it was shown to normalize glycaemia in 90% pancreatectomised animals, arousing interest in its potential to treat diabetes. [36] Since; phlorizin was a non-specific SGLT inhibitor, poorly absorbed from the gastrointestinal tract and not sufficiently stable for clinical use, it was not suited to clinical development [37] but dapagliflozin, canagliflozin (TA7264), empagliflozin, remogliflozin, sergliflozin, ipragliflozin, luseogliflozin, tofogliflozin, ertugliflozin and desoxyrhaponticin and other agents progressed in clinical development. Canagliflozin lowered renal threshold for glucose (RTG), increased urinary glucose excretion, improved glycemic control and beta-cell function in rodent models of T2DM, and reduced body weight gain in rodent models of obesity. [38],[39]

Canagliflozin

It was discovered that C-glucosides bearing a heteroaromatic ring are metabolically more stable SGLT-2 inhibitors than O-glucosides. A novel thiophene derivative 4b-3 (canagliflozin) was a highly potent and selective SGLT-2 inhibitor showing pronounced anti-hyperglycemic effects in high-fat diet fed KK (HF-KK) mice. [38]

Canagliflozin lowered renal threshold for glucose (RTG), increased urinary glucose excretion, improved glycemic control and beta-cell function in rodent models of T2DM, and reduced body weight gain in rodent models of obesity. [39] Canagliflozin became the first SGLT2 inhibitor to be FDA approved on March 29, 2013. [40]

Beneficial effects

Glycemic control

0It is quite evident from multiple studies that early effective glycaemic control defers or prevents the onset and reduce the severity of microvascular complications. [8],[10],[41] Canagliflozin has been reported to reduce fasting glucose ranging from 0.9 to 2.1mmol/L with daily doses between 50mg and 600mg. The corresponding reduction in HbA1c was 0.9% at a dose of 300mg daily. [42],[43],[44] Canagliflozin has an additional advantage of showing moderate but sustained efficacy even in patients with moderately impaired renal function (eGFR in the range 30 to 50ml/min/1.73m2). [45]

Body weight reduction

Early weight reduction during canagliflozin use owes to its osmotic diuretic effect, whereas incremental weight loss over subsequent weeks is likely due to caloric loss. [43] With an average of 200 to 400 calories loss per day, weight loss of 2.4 to 4.7kg has been demonstrated in 12 weeks trial of canagliflozin. [33],[43]

Blood pressure

Because of the chronic osmotic diuresis caused by glycosuria with increases in 24 hours urinary volumes of between 107 and 470mL [42],[46] canagliflozin is associated with small but consistent reductions in systolic and diastolic blood pressure, eg. 6/2mmHg. [47] This continually controlled blood pressure provides a further advantage, considering the high prevalence of hypertension among persons with diabetes [48] and ultimately rendering a favorable effect on cardiovascular risk.

Cardiovascular effects

On the basis of meta-analyses of randomized trials, 0.8% reduction in HbA1c is anticipated to reduce coronary risk by about 8% [49] and the same level of protection is provided by a 4mmHg reduction in systolic blood pressure. [50] Jointly, these effects would be expected to reduce vascular risk by about 15%. A series of large ongoing trials will accrue a significant number of cardiovascular safety outcomes for canagliflozin for the next few years. One such phase 3 trial, (CANVAS) CANagli- flozin cardioVascular Assessment Study [51] is a major CV outcome study started in 2009 with 4411 participants and is estimated to primary completion in June 2018. It will evaluate the effects of canagliflozin compared to placebo on CV events including CV death, myocardial infarction and stroke in patients with T2DM.

Major clinical trials involving canagliflozin

Some of the major clinical trials are tabulated in [Table 1]
Table 1: Major trials involving canaglifl ozin

Click here to view


Pharmacokinetics of canagliflozin

The pharmacokinetics properties are almost similar in healthy subjects and patients with diabetes.

Following single-dose oral administration of 100 mg and300 mg, peak plasma concentrations (median Tmax) of canagliflozin occurs within 1 to 2 hours post-dose. Plasma Cmax and AUC of canagliflozin increases in a dose-proportional manners from 50mg to 300mg. The half-life (t1/2): 10.6 h and 13.1 h for the 100mg and 300mg doses, respectively and time to reach Steady-state concentration: 4 to 5 days of once-daily dosing with canagliflozin 100mg to 300mg. [55],[56]

Absorption

The mean absolute oral bioavailability: 65% (may be taken with or without food). However, based on the potential to cause hypoglycemia, it is recommended it should be taken before the first meal. [55],[56]

Distribution

The volume of distribution of canagliflozin following a single intravenous infusion in healthy subjects was found to be around 119 L, suggesting extensive tissue distribution. It is extensively bound (nearly 99%) to plasma proteins, mainly albumin. [55],[57]

Metabolism and excretion

O- glucuronidation is the major metabolic elimination pathway for canagliflozin,. It is glucuronidated by UGT1A9 and UGT2B4 to two inactive O-glucuronide metabolites.

CYP3A4-mediated metabolism of canagliflozin is minimal in humans, so it is least likely to result in significant drug interactions. The two major metabolites are the inactive M5 and M7 O - glucuronide conjugates of unchanged drug Canagliflozin, M5, and M7 concentrations rose in a dose - dependent fashion over the canagliflozin dose range. Less than 1% of the administered canagliflozin dose was excreted unchanged in urine; approximately 7 to 10% was excreted in urine as M5 and approximately 21 to 32% was excreted as M7. Renal clearance of canagliflozin ranges from 1.30 to 1.55mL/min. [55],[56],[57]

Prescribing information

The initial dose of canagliflozin is 100mg daily taken before breakfast. Patients requiring additional glycemic control may be incremented to 300mg, but those with an eGFR 45 to <60mL/min/1.73 m 2 be restricted to maximum of 100mg/day. Dose adjustment may also be recommended in elderly and those on loop diuretics, and the use is contraindicated with eGFR <30mL/min/1.73m 2 . Since canagliflozin is metabolized by O-glucuronidation primarily through uridine diphosphate-glucuronosyl transferase (UPD-GT), its use is not recommended with UPD-GT inducers, such as rifampin and phenytoin. [55] Canagliflozin is effective as monotherapy as well as in combination with other anti-hyperglycaemic drugs including insulin. [55],[56],[ 58],[59]

Individuals with a history of dehydration or recurrent urinary and genital infections would not be recommended. The need for adequate renal function is recognized, noting that the mode of action on the proximal tubule SGLT2 transporters should not aggravate existing damage at the glomerulus, and may offer benefit through reduced glucotoxicity, lower systolic blood pressure and reduced proteinuruia. [55],[58]

Adverse effects

Generally, it is a well tolerated drug. Common side effects are genital mycotic infections in both females and uncircumcised males, increased urination, urinary tract infection and hyperkalemia. [57],[60] Mycotic infections secondary to canagliflozin use are mild to moderate in nature and respond to treatment with antifungals. [56] Consequent to osmotic diuresis effect, orthostatic hypotension, increased thirst, and hypotension may also occur. [55],[61]

A small increase of 4% in LDL cholesterol can also occur but this is associated with also a similar increase in HDL-Cholesterol and significant drop in triglycerides.

Future of SGLT2 inhibitors

Non-phlorizin-based molecules targeting SGLT2 are also being developed, such as ISIS-SGLT2Rx, an antisense inhibitory microRNA molecule, to reduce the expression of SGLT2. [62] SGLT1 and 2 inhibitors are also being developed (Lexicon Pharmaceuticals).


  Conclusion Top


SGLT2 inhibitors offer an entirely novel, insulin-independent approach for treatment of diabetes by blocking the reabsorption of glucose in the renal nephron resulting in markedly increased glycosuria and reduced blood glucose concentrations. Since this mechanism is not constrained by the extent of insulin resistance or beta-cell dysfunction, these drugs are ideal candidates to be used at any stage in the natural history of diabetes- from newly diagnosed to long-standing disease, including extremes of insulin resistance and β-cell dysfunction, as well as in type 1 diabetes (not approved but studied). Their prospective use is further enhanced by the fact that these can be used as monotherapy for patients seeking different treatment options and in complementary manner with other antidiabetic agents or insulin. Furthermore, at low plasma glucose concentrations, SGLT1 is free to reabsorb the filtered glucose load providing for an automatic cushion against additional risk of severe hypoglycaemia. [12] Since canagliflozin significantly improves blood pressure and weight in addition to glycaemic indicators (HbA1C, fasting and postprandial plasma glucose), there is a strong rationale for expecting that it will protect against microvascular and macrovascular complications of the disease. [46] However, concrete evidences regarding this are still to be determined from the ongoing CV trials. [51] It is generally well tolerated in subjects with T2DM and Stage 3 chronic kidney disease (CKD). Possible side effects include increased risk of urinary or genital infection, headache, hypotension, and increased thirst. However, severe side effects such as hypoglycemia are rare.

 
  References Top

1.Whiting DR, Guariguata L, Weil C, Shaw J. IDF Diabetes Atlas: Global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Res Clin Pract 2011;94:311-21.   Back to cited text no. 1
    
2.Shaw JE, Sicree RA, Zimmet PZ. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract 2010;87:4-14.  Back to cited text no. 2
    
3.IDF Diabetes Atlas Update 2012. (Accessed October 3, 2013, at http://www.idf.org/diabetesatlas/5e/Update2012).   Back to cited text no. 3
    
4.Tahrani A, Bailey C, Del Prato S, Barnett AH. Management of type 2 diabetes: New and future developments in treatment. Lancet 2011;378:182-97.  Back to cited text no. 4
    
5.Grundy SM, Benjamin IJ, Burke GL, Chait A, Eckel RH, Howard BV, et al. Diabetes and cardiovascular disease: A statement for healthcare professionals from the American Heart Association. Circulation 1999;100:1134-46.  Back to cited text no. 5
    
6.Ford ES. Trends in the risk for coronary heart disease among adults with diagnosed diabetes in the U.S.: Findings from the National Health and Nutrition Examination Survey, 1999-2008. Diabetes Care 2011;34:1337-43.  Back to cited text no. 6
    
7.American Diabetes Association. Standards of medical care in diabetes-2012. Diabetes Care 2012;35:S11-63.   Back to cited text no. 7
    
8.UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:854-65.  Back to cited text no. 8
    
9.Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, et al. Medical management of hyperglycemia in type 2 diabetes: A consensus algorithm for the initiation and adjustment of therapy: A consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2009;32:193-203.  Back to cited text no. 9
    
10.Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes (UKPDS 80). N Engl J Med 2008;359:1577-89.  Back to cited text no. 10
    
11.Wagman AS, Nuss JM. Current therapies and emerging targets for the treatment of diabetes. Curr Pharm Des 2001;7:417-50.  Back to cited text no. 11
    
12.Bailey CJ, Day C. SGLT2 inhibitors: Glucuretic treatment for type 2 diabetes. Br J Diabetes Vasc Dis 2010;10:193.  Back to cited text no. 12
    
13.Wilding J. Thiazolidinediones, insulin resistance and obesity: Finding a balance. Int J Clin Pract 2006;60:1272-80.  Back to cited text no. 13
    
14.Katsuno K, Fujimori Y, Ishikawa-Takemura Y, Isaji M. Long-term treatment with sergliflozin etabonate improves disturbed glucose metabolism in KK-A(y) mice. Eur J Pharmacol 2009;618:98-104.  Back to cited text no. 14
    
15.Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007;356:2457-71.  Back to cited text no. 15
    
16.Schramm TK, Gislason GH, Vaag A, Rasmussen JN, Folke F, Hansen ML, et al. Mortality and cardiovascular risk associated with different insulin secretagogues compared with metformin in type 2 diabetes, with or without a previous myocardial infarction: A nationwide study. Eur Heart J 2011;32:1900-8.   Back to cited text no. 16
    
17.Gore MO, McGuire DK. Resolving drug effects from class effects among drugs for type 2 diabetes mellitus: More support for cardiovascular outcome assessments. Eur Heart J 2011;32:1832-4.  Back to cited text no. 17
    
18.DeYoung MB, MacConell L, Sarin V, Trautmann M, Herbert P. Encapsulation of exenatide in poly-(d,l-lactide-co-glycolide) microspheres produced an investigational long-acting once-weekly formulation for type-2 diabetes. Diabetes Technol Ther 2011;13:1145-54.  Back to cited text no. 18
    
19.Zinman B, Schmidt WE, Moses A, Lund N, Gough S. Achieving a clinically relevant composite outcome of an HbA1C of <7% without weight gain or hypoglycemia in type 2 diabetes: A meta-analysis of the liraglutide clinical trial program. Diabetes Obes Metab 2012;14:77-82.  Back to cited text no. 19
    
20.Byetta (exenatide injection) prescribing information. (Accessed October 4, 2013, at http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=751747da-7c1f-41ad-b1a6-a6d920f70599).   Back to cited text no. 20
    
21.Januvia (sitagliptin). (Accessed October 4, 2013, at http://www.drugs.com/monograph/januvia.html).   Back to cited text no. 21
    
22.Chan JC, Scott R, Arjona Ferreira JC, Sheng D, Gonzalez E, Davies MJ, et al. Safety and efficacy of sitagliptin in patients with type 2 diabetes and chronic renal insufficiency. Diabetes Obes Metab 2008;10:545-55.  Back to cited text no. 22
    
23.Mathers MC, Zarbock SD, Sutton EE. New and Future Medications for the Treatment of Type 2 Diabetes Mellitus. Am J Lifestyle Med 2013. [Published online before print]  Back to cited text no. 23
    
24.Wright EM, Turk E. The sodium/glucose cotransport family SLC5. Pflugers Arch 2004;447:510-8.  Back to cited text no. 24
    
25.Patel AK, Fonseca V. Turning glucosuria into a therapy: Efficacy and safety with SGLT2 inhibitors. Curr Diab Rep 2010;10:101-7.  Back to cited text no. 25
    
26.Gerich JE, Meyer C, Woerle HJ, Stumvoll M. Renal gluconeogenesis: Its importance in human glucose homeostasis. Diabetes Care 2001;24:382-91.  Back to cited text no. 26
    
27.Wright EM, Hirayama BA, Loo DF. Active sugar transport in health and disease. J Intern Med 2007;261:32-43.  Back to cited text no. 27
    
28.Song J. Dapagliflozin: An emerging treatment option for type 2 diabetes mellitus. Formulary 2011;46:412-31.  Back to cited text no. 28
    
29.DeFronzo RA, Davidson JA, Del Prato S. The role of the kidneys in glucose homeostasis: A new path towards normalizing glycaemia. Diabetes Obes Metab 2012;14:5-14.  Back to cited text no. 29
    
30.Mogensen CE. Maximum tubular reabsorption capacity for glucose and renal hemodynamcis during rapid hypertonic glucose infusion in normal and diabetic subjects. Scand J Clin Lab Invest 1971;28:101-9.   Back to cited text no. 30
    
31.Bakris GL, Fonseca VA, Sharma K, Wright EM. Renal sodium-glucose transport: Role in diabetes mellitus and potential clinical implications. Kidney Int 2009;75:1272-7.  Back to cited text no. 31
    
32.Komoroski B, Vachharajani N, Boulton D, Kornhauser D, Geraldes M, Li L, et al. Dapagliflozin, a novel SGLT2 inhibitor, induces dose-dependent glucosuria in healthy subjects. Clin Pharmacol Ther 2009;85:520-6.   Back to cited text no. 32
    
33.Sha S, Devineni D, Ghosh A, Polidori D, Chien S, Wexler D, et al. Canagliflozin, a novel inhibitor of sodium glucose co-transporter 2, dose dependently reduces calculated renal threshold for glucose excretion and increases urinary glucose excretion in healthy subjects. Diabetes Obes Metab 2011;13:669-72.  Back to cited text no. 33
    
34.Ehrenkranz JR, Lewis NG, Kahn CR, Roth J. Phlorizin: A review. Diabetes Metab Res Rev 2005;21:31-8.  Back to cited text no. 34
    
35.Stiles PG, Lusk G. On the action of phlorizin. Am J Physiol 1903;10:61-79.  Back to cited text no. 35
    
36.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 1987;79:1510-5.  Back to cited text no. 36
    
37.Fujimori Y, Katsuno K, Ojima K, Nakashima I, Nakano S, Ishikawa-Takemura Y, et al. Sergliflozin etabonate, a selective SGLT2 inhibitor, improves glycemic control in streptozotocin-induced diabetic rats and Zucker fatty rats. Eur J Pharmacol 2009;609:148-54.  Back to cited text no. 37
    
38.Nomura S, Sakamaki S, Hongu M, Kawanishi E, Koga Y, Sakamoto T, et al. Discovery of canagliflozin, a novel C-glucoside with thiophene ring, as sodium-dependent glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes mellitus. J Med Chem 2010;53:6355-60.   Back to cited text no. 38
    
39.Liang Y, Arakawa K, Ueta K, Matsushita Y, Kuriyama C, Martin T, et al. Effect of canagliflozin on renal threshold for glucose, glycemia, and body weight in normal and diabetic animal models. Plos One 2012;7:e30555.  Back to cited text no. 39
    
40.New Drugs at FDA. (Accessed October 4, 2013, at http://www.fda.gov/drugs/developmentapprovalprocess /druginnovation/ default.htm).  Back to cited text no. 40
    
41.UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin sompared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;353:837-53.  Back to cited text no. 41
    
42.Inagaki N, Kondo K, Iwasaki T. Canagliflozin, a novel inhibitor of sodium glucose co-transporter 2 (SGLT2) improves glycemic control and reduces body weight in Japanese type 2 diabetes mellitus (T2DM). Diabetes 2011;60:abstract 0999-P.   Back to cited text no. 42
    
43.Rosenstock J, Arbit D, Usiskin K, Capuano G, Canovatchel W. Canagliflozin, an inhibitor of sodium glucose co-transporter 2 (SGLT2), improves glycemic control and lowers body weight in subjects with type 2 diabetes (T2D) on metformin. Orlando: American Diabetes Association; 2010, abstract 77.  Back to cited text no. 43
    
44.Rosenstock J, Polidori D, Zhao Y, Sha S, Arbit D, Usiskin K, et al. Canagliflozin, an inhibitor of sodium glucose co-transporter 2 (SGLT2), improves glycemic control, lowers body weight and improves beta cell function in subjects with type 2 diabetes on back- ground metformin (T2D) on metformin. Diabetologia 2010;53:S1-556.   Back to cited text no. 44
    
45.Yale JF, Bakris G, Xi L, Figueroa K, Wajs E, Usiskin K, et al. Canagliflozin, a SGLT2 inhibitor, improves glycemia and is well tolerated in type 2 diabetes mellitus subjects with moderate renal impairment. Abstracts. Can J Diabetes 2012;36:S24-76.  Back to cited text no. 45
    
46.List JF, Whaley JM. Glucose dynamics and mechanistic implications of SGLT2 inhibitors in animals and humans. Kidney Int Suppl 2011:120:S20-7.  Back to cited text no. 46
    
47.Yale JF, Bakris G, Cariou B, Yue D, David-Neto E, Xi L, et al. Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease. Diabetes Obes Metab 2013;15:463-73.  Back to cited text no. 47
    
48.Holman RR, Paul SK, Bethel A, Neil HA, Matthews DR. Long-term follow-up after tight control of blood pressure in type 2 diabetes. N Engl J Med 2008;359:1565-76.  Back to cited text no. 48
    
49.Turnbull F, Abraira C, Anderson R, Byington RP, Chalmers JP, Duckworth WC, et al. Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia 2009;52:2288-98.   Back to cited text no. 49
    
50.Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: Metaanalysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. BMJ 2009;338:b1665.  Back to cited text no. 50
    
51.CANVAS. Canagliflozin Cardiovascula Assessment Study. (Accessed October 4, 2013, at http://clinicaltrials.gov/show/NCT01032629).   Back to cited text no. 51
    
52.Stenlof K, Cefalu WT, Kim KA, Alba M, Usiskin K, Tong C, et al. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab 2013;15:372-82.  Back to cited text no. 52
    
53.Stenlof K, Cefalu WT, Tong C. Canagliflozin, a sodium glucose co-transporter 2 inhibitor, improves glycaemic control in subjects with type 2 diabetes inadequately controlled with diet and exercise (Abstract 760). Diabetologia 2012;55 Suppl 1:S312-3.  Back to cited text no. 53
    
54.Cefalu WT, Leiter LA, Yoon KH, Arias P, Niskanen L, Xie J, et al. Ecacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial. Lancet 2013;382:941-50.  Back to cited text no. 54
    
55.Invokana (canagliflozin). Prescribing information. (Accessed October 4, 2013, at http: //www .invokanahcp.c om/prescribing- information.pdf).  Back to cited text no. 55
    
56.Invokana. (Accessed October 5, 2013, at http://www.drugs.com/invokana.html).   Back to cited text no. 56
    
57.Devineni D, Curtin CR, Polidori D, Gutierrez MJ, Murphy J, Rusch S, et al. Pharmacokinetics and pharmacodynamics of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in subjects with type 2 diabetes mellitus. J Clin Pharmacol 2013;53:601-10.   Back to cited text no. 57
    
58.Devineni D, Morrow L, Hompesch M, Skee D, Vandebosch A, Murphy J, et al. Canagliflozin improves glycemic control over 28 days in subjects with type 2 diabetes not optimally controlled on insulin. Diabetes Obes Metab 2012;14:539-45.  Back to cited text no. 58
    
59.Rosenstock J, Aggarwal N, Polidori D, Alba M, Usiskin K, Tong C, et al. Dose-ranging effects of Canagliflozin, a Sodium-Glucose Cotransporter 2 Inhibitor, as add- on to metformin in subjects with type 2 diabetes. Diabetes Care 2012;35:1232-8.  Back to cited text no. 59
    
60.Janssen Research and Development to Present Results from Five Phase 3 Studies Evaluating Investigational Canagliflozin for the Treatment of Type 2 Diabetes. Janssen Research and Development, LLC, June 5, 2012. (Accessed October 4, 2013, at http://www.prnewswire.com/news- releases/janssen-research).  Back to cited text no. 60
    
61.Schernthaner G, Gross JL, Rosenstock J, Guarisco M, Fu M, Yee J, et al. Canagliflozin compared with sitagliptin for patients with type 2 Diabetes who do not have adequate glycemic control with metformin plus sulfonylurea- a 52-week randomized trial. Diabetes Care 2013;36:2508-15.  Back to cited text no. 61
    
62.Calado J, Sznajer Y, Metzger D, Rita A, Hogan MC, Kattamis A, et al. Twenty-one additional cases of familial renal glucosuria: Absence of genetic heterogeneity, high prevalence of private mutations and further evidence of volume depletion. Nephrol Dial Transplant 2008;23:3874-9.  Back to cited text no. 62
    



 
 
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