Summary

• By inhibiting sodium-glucose cotransporter-2 (SGLT2), canagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose (RT_G), and thereby increases urinary glucose excretion (UGE). Canagliflozin is an orally active, competitive, reversible inhibitor of SGLT2.¹
• A multimedia reply providing a brief overview of the glycemic control mechanism of action of canagliflozin is available and can be accessed by clicking on the link below or typing it into your browser. Please note that it should be used in conjunction with the accompanying written reply document. Select the link below: https://www.janssenscience.com/products/invokana/medical-content/video-invokana-mechanism-of-action
• Following single and multiple oral doses of canagliflozin in patients with type 2 diabetes, dose-dependent decreases in the RT_G and increases in urinary glucose excretion were observed. From a starting RT_G value of approximately 240 mg/dL, canagliflozin at 100 mg and 300 mg once daily suppressed RT_G throughout the 24-hour period. Maximal suppression of mean RT_G over the 24-hour period was seen with the 300 mg daily dose to approximately 70 to 90 mg/dL in patients with type 2 diabetes mellitus (T2DM) in phase 1 studies.²
• The reductions in RTG led to increases in mean UGE of approximately 100 g/day in subjects with T2DM treated with either 100 mg or 300 mg of canagliflozin,^2-6 equivalent to ~400 kcal/day (calculated based on 1 g glucose = 4 kcal).^7,8
• Several phase 1 studies reported that canagliflozinincreased UGE, leading to improved glycemic control and reduced body weight in healthy volunteers and in patients with T2DM. Reductions in body weight in diabetic and nondiabetic obese subjects were also reported.^6,9-11
• In phase 1 studies, canagliflozin300 mg also lowered postprandial plasma glucose by increasing UGE (due to renal SGLT2 inhibition) and by delaying oral glucose absorption (potentially due to transient intestinal sodium-glucose cotransporter-1 [SGLT1] inhibition). Glucose malabsorption was not reported.^12,13
• Reduction in plasma glucose with canagliflozin has also been associated with decreases in plasma insulin, increases in endogenous glucose production (EGP) in healthy subjects and plasma glucagon, and improvement in measures of β-cell function and insulin sensitivity.^12-14
• The mechanism of action behind the reduction in the risk of major adverse cardiovascular events (MACE) with canagliflozin is unknown.¹⁵
• There are several established effects of SGLT2 inhibitors on intermediate outcomes that may contribute to cardiovascular protection. Although pleiotropic effects have been inferred, improved glycemic control, lowering of blood pressure, decrease in intraglomerular pressure, reduction in albuminuria, and amelioration of volume overload are all plausible protective mechanisms.¹⁵

MULTIMEDIA REPLY

• A multimedia reply providing a brief overview of the mechanism of action of canagliflozinis available and can be accessed by clicking on the link below or typing it into your browser. Please note that it should be used in conjunction with the accompanying written reply document. See Figure: Mechanism of Action or select the following link: https://www.janssenscience.com/products/invokana/medical-content/video-invokana-mechanism-of-action

BACKGROUND

The kidneys play an essential role in maintaining glucose balance. Glucose is filtered in the glomerulus and, as plasma glucose levels increase, the amount of glucose in the glomerular filtrate increases linearly. Reabsorption of filtered glucose also increases linearly until the maximal reabsorptive capacity is exceeded. Glucose filtered from the blood by the glomeruli in the kidney is mainly reabsorbed into the blood stream by the sodium-glucose cotransporters (SGLTs), primarily by the SGLT2 type, located on the on the apical membrane on the luminal side in the early proximal tubular system of the kidney.¹⁶ When the capacity of these transporters is exceeded, glucose appears in urine.^10,16-19 Inhibition of SGLT-2 receptors is believed to take place on the luminal side, however tubular luminal concentrations cannot be measured in humans.²⁰ When adjusted for protein binding the renal clearance of CANA is similar to estimated glomerular filtration rate (eGFR), which suggests unbound canagliflozin may be freely filtered and that CANA concentrations in the lumen of the proximal tubule may be equal to the unbound concentrations in the plasma. Adjusting the estimated in vivo EC₅₀ values for protein binding (∼99%) gives estimated in vivo EC₅₀ values based on unbound drug concentrations of 0.32 – 0.35 ng/mL (0.7 – 0.8 nM). When compared to in vitro values, these values are modestly lower than the values for human SGLT2 determined under serum‐free conditions reported for canagliflozin (2.4 –4.4 nM). The data are generally compatible with the concept that unbound canagliflozin is freely filtered and acts on the luminal side of the proximal tubule.²¹

In healthy individuals, the rate of glucose reabsorption in the kidneys by SGLTs, mainly SGLT2, matches the filtration rate for plasma glucose levels up to ≈180-200 mg/dL (10.0-11.1 mmol/L), the RT_G. At the RT_G, the maximal reabsorptive capacity for glucose of the proximal tubule transport maximum (Tm) has been reached. Any increase in plasma glucose levels above the RT_G results in progressive glucosuria. RT_G in type 2 diabetes patients is increased (~248 mg/dL [13.8 mmol/L]) compared to the commonly reported values in healthy individuals.^10,17-19

Inhibition of the SGLT2  cotransporter results in a decreased threshold for renal glucose, which allows excess glucose to be excreted in the urine.^7,10,18 The caloric loss arising from glucose excretion may lead to weight loss; 1 g of glucose excreted in the urine equates to approximately 4 kcal of energy.⁸

CANAGLIFLOZIN - Mechanism of Action

Glycemic Control

• Canagliflozin is an orally active, competitive, reversible inhibitor of SGLT2.¹
• Inhibition of SGLT-2 receptors is believed to take place on the luminal side, however tubular luminal concentrations cannot be measured in humans.²⁰ The low expected renal secretion of canagliflozin is expected to be due to extensive (~99%) protein binding.  When adjusted for protein binding, the renal clearance is similar to eGFR, suggesting that the unbo0075nd canagliflozin is freely filtered.  The available data based on in vivo concentrations opposed to in vitro, serum-free conditions, suggest that unbound drug in the proximal tubule may be equal to unbound concentrations in the plasma.³
• Canagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose (RT_G), and thereby increases UGE.¹
• The affinity of canagliflozin for SGLTs was demonstrated to be approximately 150-fold more potent on human SGLT2 inhibition than on SGLT1.^22-24
• Nomura et al (2010),²³ Liang et al (2012),²² and Grempler et al (2012)²⁴ showed in cells overexpressing either human SGLT1 or SGLT2 that canagliflozin inhibits sodium-dependent 14C-α-methylglucoside uptake with a lower inhibitory concentration (IC₅₀) against SGLT2 than SGLT1 (see Table: Canagliflozin IC₅₀ of SGLT1 and SGLT2 in Humans).
• In vitro study results predicted that canagliflozin would not inhibit other members of the SGLT family (i.e. SGLT4, SGLT6) or facilitated transporters (i.e. GLUT1, GLUT2 and GLUT4).²⁵

• Preclinical studies demonstrated that canagliflozin lowers the renal glucose threshold (RT_G) while preserving the threshold nature of the UGE.^10,22
• Canagliflozin phase 1 studies showed a dose-dependent, 24-hour maximal mean reduction in RT_G  to approximately 70-90 mg/dL in patients with T2DM.^{3,6,9,10,26,27}
• The reductions in RTG led to increases in mean UGE of ~100 g/day in patients with T2DM treated with either 100 mg or 300 mg of canagliflozin in phase 1 studies,^2-6 equivalent to ~400 kcal/day (calculated based on 1 g glucose = 4 kcal).^7,8
• In phase 1 studies, canagliflozin 300 mg also lowered postprandial plasma glucose by increasing UGE (due to renal SGLT2 inhibition) and by delaying oral glucose absorption (potentially due to transient intestinal SGLT1 inhibition). Glucose malabsorption was not reported.^12,13
• Several phase 1 studies reported that canagliflozin increased UGE, leading to improved glycemic control and reduced body weight in healthy volunteers and in patients with T2DM. Reductions in body weight in diabetic and nondiabetic obese subjects were also reported.^6,9-11

Cardiovascular Outcomes

• The mechanism of action behind the reduction in the risk of MACE events with canagliflozin is unknown.¹⁵
• There are several established effects of SGLT2 inhibitors on intermediate outcomes that may contribute to cardiovascular protection. Although pleiotropic effects have been inferred, improved glycemic control, lowering of blood pressure, decrease in intraglomerular pressure, reduction in albuminuria, and amelioration of volume overload are all plausible protective mechanisms.¹⁵

ADDITIONAL INFORMATION

SGLT2 Upregulation

• In T2DM, renal glucose reabsorption is increased potentially due to upregulation of SGLT2/GLUT2 transporter expression and activity.^19,28,29  By inhibiting SGLT2, canagliflozin reduces reabsorption of filtered glucose and lowers RTG, and thereby increases UGE.¹
• The long-term effect of canagliflozin on SGLT2 upregulation (transporter expression or activity) with the use of canagliflozin has not been studied.

LITERATURE SEARCH

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 13 November 2024.