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REVIEW ARTICLE
Year : 2014  |  Volume : 5  |  Issue : 2  |  Page : 166-173

SGLT2 inhibitors for treatment of Type 2 diabetes mellitus: Focus on Canagliflozin


Department of Pharmacology, Armed Forces Medical College, Pune, Maharashtra, India

Date of Web Publication1-Jul-2014

Correspondence Address:
Santosh Kumar Singh
Department of Pharmacology, Armed Forces Medical College, Sholapur Road, Pune - 411 040, Maharashtra
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0975-9727.135761

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  Abstract 

The incidence of type 2 diabetes mellitus (T2DM) is increasing worldwide. The existing therapeutic classes of antidiabetic drugs are not adequately effective in maintaining long-term glycemic control in most patients, even when used in combination. Many marketed compounds do not address relevant aspects of the disease. In addition, side effects for established therapies such as hypoglycemia and weight gain have to be controlled. One emerging novel therapeutic class of antidiabetic drugs is sodium glucose co-transporter 2 (SGLT2) inhibitors. SGLT2 accounts for 90% of the glucose reabsorption in the kidney. The SGLT2 inhibitors increase urinary excretion of glucose and lower plasma glucose levels in an insulin-independent manner. This article discusses the role of novel SGLT2 inhibitor canagliflozin in the treatment of T2DM.

Keywords: Hypoglycaemia, SGLT2 inhibitors, type 2 DM


How to cite this article:
Singh SK, Gupta A K. SGLT2 inhibitors for treatment of Type 2 diabetes mellitus: Focus on Canagliflozin. Muller J Med Sci Res 2014;5:166-73

How to cite this URL:
Singh SK, Gupta A K. SGLT2 inhibitors for treatment of Type 2 diabetes mellitus: Focus on Canagliflozin. Muller J Med Sci Res [serial online] 2014 [cited 2019 Jul 22];5:166-73. Available from: http://www.mjmsr.net/text.asp?2014/5/2/166/135761


  Introduction Top


Diabetes is a highly prevalent disease affecting more than 150 million people worldwide. [1] The number of people with T2DM is increasing in every country. Three-hundred and sixty-six million people have diabetes in 2011 worldwide which is expected to rise to 552 million by 2030. Eighty percent of people with diabetes live in low- and middle-income countries age group. Commonly affected age group is between 40 and 59 years, with 183 million people (50%) remaining undiagnosed. In India, 61.3 million persons effected with diabetes in 2011 and it will be 101.2 million by 2030. Diabetes caused 4.6 million deaths in 2011 worldwide and is associated with significant mortality and morbidity due to associated complications. [2] The Chennai Urban Population Study (CUPS) and Chennai Urban Rural Epidemiology Study (CURES) show that there is a huge burden due to diabetes-related complications in India. [3] T2DM is characterized by disturbed insulin secretion from pancreatic β-cells and/or insufficient action of insulin in peripheral organs. High blood glucose (hyperglycemia) is the main pathogenic factor for the development of diabetic complications including coronary heart disease, retinopathy, nephropathy, and neuropathy. Various antidiabetic agents used for treatment of T2DM includes increasing insulin release, increasing insulin sensitivity, controlling hepatic glucose release, or inhibiting intestinal glucose absorption. [4] Treatment of T2DM is often complicated by coexistent obesity, which further impairs insulin action and aggravates hypertension, dyslipidemia, inflammation, and other pathogenic factors that promote cardiovascular risk. [5] Although existing glucose-lowering therapies address many of the endocrine and metabolic derangements of diabetes, they often cannot reinstate or maintain long-term glycemic control in many patients. [6]


  Role of Sodium Glucose Cotransporter (SGLT) Top


SGLTs are secondary-active cell-membrane symporters (electrochemical gradient which allows sodium to enter into 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) 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. [7] SGLTs are encoded by a subfamily of solute carrier genes which are members of the sodium substrate symporter family. Two types of sodium glucose co transporters mediate glucose reabsorption. The low affinity sodium glucose cotransporter (SGLT2) is found almost exclusively in the kidney, the high-affinity sodium glucose co transporter (SGLT1) is mainly expressed in the small intestine where it facilitates glucose absorption. [3],[8]


  Glucose Handling in the Kidney Top


The kidneys contribute significantly to glucose homoeostasis mainly by reabsorbing filtered glucose from the renal tubule and by gluconeogenesis which occurs in the renal cortex, and mostly used by the renal medulla. In diabetic states, the kidneys (like the liver) have increased gluconeogenesis. [9],[10] Patients with T2DM have been shown to experience hyperglycemia without resultant glycosuria, and the maximal glucose reabsorptive capacity in these patients has been shown to increase from a normal level of 352 to 419 mg/min). [11] The renal tubule operates an electrochemical gradient generated by the Na + /K + -ATPase located in the basolateral membrane. [11],[12] SGLT2, situated in the S1 segment, is a low-affinity high-capacity transporter reabsorbing up to 90% of filtered glucose. SGLT1, situated in the S3 segment, is a high-affinity low-transporter capacity reabsorbing the remaining 10% [Figure 1]. In patients with type 2DM, overall glucose production increases by as much as 300%, this increased production contributes not only to increase in fasting glucose in T2DM patients but also to raises postprandial glucose, as glucose ingestion increases renal gluconeogenesis. In T2DM there is increased expression and activity of SGLT2 and GLUT2 in the proximal tubules, which will further contribute to hyperglycemia. [13],[14]
Figure 1: Glucose reabsorption from the kidneys is mediated by SGLT2 (90%) and SGLT1 (10%); inhibitors of SGLT2 increase urinary glucose excretion, therefore reducing circulatory glucose levels

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  Development of SGLT Inhibitors Top


In the 1980s, Rossetti introduced the concept of normalization of glucose concentrations in the body by an increase in urinary glucose excretion. [15] It was found that phlorizin (a naturally occurring phenolic glycoside first isolated from apple tree bark in 1835) increased urinary glucose and lowered blood glucose in partly pancreatectomized rats. [15] Although several potent selective SGLT2 inhibitors such as T1095, sergliflozin, and remogliflozin were developed, they were vulnerable to degradation by intestinal glucosidases at their O-glucoside linkage and have not progressed in clinical development. Oral SGLT inhibitors that are approved or in advanced clinical development that have prevented this glucosidase degradation by replacement of the O-glucoside linkage with a C-aryl linkage. [16],[17] The US Food and Drug Administration have approved canagliflozin (Invokana, Janssen Pharmaceuticals, Beerse, Belgium) on March 29, 2013 for the treatment of adults with type 2 diabetes. It is first approved oral inhibitor of SGLT2. [18],[19]

Mechanism of Action

Canagliflozin is a selective SGLT-2 inhibitor which blocks the reabsorption of glucose in the kidneys and promotes excretion of excess glucose in the urine. It transports filtered glucose from the proximal renal tubule into tubular epithelial cells. By inhibiting SGLT2, canagliflozin decreases glucose reabsorption, increases urinary glucose excretion, and lowers blood glucose levels, as well as weight loss due to 300-400 kcal/day loss. The structure of canagliflozin is described in [Figure 2]. [20]
Figure 2: Structure of canagliflozin

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Clinical Trials

Canagliflozin was studied in over 10,300 patients in nine global, randomized and double-blind placebo- or active comparator-controlled trials as monotherapy and in combination with other agents (metformin, sulfonylurea, metformin and sulfonylurea, metformin and TZD and insulin). [21],[22],[23]

The Media Fact Sheet from Janssen Research and Development, LLC, 2012 provides the following explanation of the phase 3 program:
"CANTATA (CANagliflozin Treatment and Trial Analysis) studied the glucose-lowering efficacy and safety of canagliflozin in adult patients diagnosed with T2DM failing to achieve glycemic control on diet and exercise and on the background of a variety of commonly used oral antihyperglycemic agents or insulin.

CANVAS (CANagliflozin cardiovascular Assessment Study) assessed the general safety, tolerability and cardiovascular safety of canagliflozin in approximately 4,300 adult patients with T2DM, who also have either a history or high risk of cardiovascular disease, [22] various clinical trials and their results are summarized in [Table 1]. [24],[25],[26],[27],[28],[29]
Table 1: Various clinical trials for canagliflozin

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Drug Interactions [30]

Canagliflozin is metabolized primarily by UDP-glucuronosyltransferase (UGT) 1A9 and 2B4; concurrent use of UGT inducers such as rifampin, phenobarbital, ritonavir or phenytoin can decrease serum concentrations of the drug and may require an increase in the dose. Canagliflozin can increase serum concentrations of digoxin; a decrease in the dose of digoxin may be necessary. There appear to be no significant interactions between canagliflozin and CYP450 enzymes.

Indication and Dosage

Canagliflozin is approved for adults with type-2 diabetes mellitus who require improved glycemic control in addition to diet and exercise. Canagliflozin should be taken orally before the first meal of the day. The initial dose of 100 mg once daily can be increased to 300 mg once daily if needed for glycemic control. In patients with moderate renal impairment (eGFR 45-59 mL/min/1.73 m 2 ), the dose should not exceed 100 mg.

Contraindication

Canagliflozin is contraindicated in patients with a severe hypersensitivity reaction to the drug, in individuals with severe renal impairment (an eGFR below 30 mL/minute/1.732), in those with endstage renal disease, and in patients on dialysis.

Precautions and Warnings

Volume status should be assessed and corrected before canagliflozin is initiated in patients with low BP, in those using diuretics or drugs that interfere with the renin-angiotensin-aldosterone system (RAS), or in those with impaired renal function. Monitoring of serum potassium levels is also recommended upon the initiation of canagliflozin therapy in patients with renal impairment and in those taking medications that can interfere with potassium secretion to avoid the risk of hyperkalemia. Dose adjustments of the insulin or insulin secretagogues may be needed to avoid hypoglycemia. Patients taking canagliflozin should be informed about and monitored for signs and symptoms of genital mycotic infections. It is also recommended that LDL-C levels be monitored, as dose-related increases in LDL-C levels have been observed with this medication. Canagliflozin has been designated as a Pregnancy Category C drug. Well-controlled studies have not been conducted in pregnant women, and it is unknown whether this medication is excreted in human milk. There is no evidence to support its use in lactation.

Other Drugs

Clinical trials are underway to assess the efficacy and safety of other investigational SGLT2 inhibitors like ipragliflozin, Dapagliflozin (Forxiga) is already available in Europe (November 2012). Dapaglifozin approved status of empaglifozin uncertain


  Conclusion Top


Recovery of glucose from the glomerulus filtrate represents an important mechanism in maintaining glucose homeostasis and represents a novel target for the management of Type 2 diabetes. SGLT2 inhibitors introduce a new mode to the control of T2DM by promoting an 'escape' mechanism for glucose. The expected favorable safety profile and insulin-independent mechanism of action appear to support the use of SGLT2 inhibitors in combination with other anti-diabetic drugs. Canagliflozin has been shown to be modestly effective in lowering HbA1c, and it has a low risk of hypoglycemia. It has also been shown to cause weight loss, reduced FPG and BP, increased HDL, and reduced uric acid. Due to canagliflozin's reductions in blood pressure, body weight, A1C, and uric acid, it may have a favorable overall effect which may benefit obese patients with high CV risk. [31],[32] However, the increase in LDL-C and other potential unknown effects may have the opposite effect. Notable side-effects include increased urinary and genital mycotic infections (which were not severe and resolved with simple treatment. [33],[34] Concerns regarding CV and fracture risks and risks in patients with renal impairment were highlighted by the FDA. A long-term cardiovascular outcomes study and 4 other post marketing studies (an enhanced pharmacovigilance program, a bone safety study, and two pediatric studies) were required as a condition of approval. [34] Long-term data on the effects of canagliflozin (and other SGLT2 inhibitors) on cardiovascular outcomes in T2DM patients are not yet available. The findings of the canagliflozin phase 3 study in T2DM patients with chronic kidney disease suggests that it may be an appropriate option in this patient population, but efficacy is attenuated with declining renal function and additional studies are needed to assess its efficacy and safety. [27]

 
  References Top

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