1. SGLT-2 Inhibitors : Mechanism of Action
Dr. Jordan Weinstein, MD
Division of Nephrology, St. Michael's Hospital
Assistant Professor of Medicine
University of Toronto

2. Disclosure
I am receiving an honorarium as compensation for delivering this presentation
Statements made during this presentation might be deemed ‘off-label’

3. Learning Objectives Brief review of kidney anatomy
Understand glucose metabolism
The role of SGLT2 co transporters

4. The Nephron and Collecting System
Glomerulus Filters:
Water
Glucose
Salts
Small metabolites from
plasma into Bowman’s space
Collecting Duct
Final Water reabsorption
(Vasopressin)
Renal tubule
Reabsorption of water and ion
Proximal convoluted tubule
Reabsorption of potassium,
bicarbonate, chloride, glucose,
amino acids, sodium, water
(Angiotensin)
Distal convoluted tubule
Final sodium reabsorption
(Aldosterone)
Loop of Henle
This shows a depiction of the kidney glomerular and tubular collecting system.
The glomerulus is the major filtering area. Water, glucose, salt, and a number of metabolites are filtered (including a small amount of protein).
Water and ions get absorbed in the renal tubule.
The proximal convoluted tubule is responsible for reabsorption of glucose, chloride, phosphate, bicarbonate and potassium; some sodium and water also reabsorbed here.
The distal convoluted tubule is responsible for any final reabsorption of sodium, and this is mediated via aldosterone.
Finally, in the loop of Henle, which is the collecting duct, water is reabsorbed as a result of vasopressin action.
References:
Adapted from:
Guyton AC & Hall JE. Textbook of Medical Physiology. 11th ed. Philadelphia, PA: Elsevier Saunders; 2006
Silverman M, et al. In: Windhager EE, ed. Handbook of Physiology: a Critical, Comprehensive Presentation of Physiological Knowledge and Concepts. New York, NY: Oxford; 1992:
Adapted from:
Guyton AC & Hall JE. Textbook of Medical Physiology. 11th ed. Philadelphia, PA: Elsevier Saunders; 2006
Silverman M, et al. In: Windhager EE, ed. Handbook of Physiology: a Critical, Comprehensive Presentation of Physiological Knowledge and Concepts. New York, NY: Oxford; 1992:

5. Glucose Metabolism
The kidneys play an important role in glucose homeostasis through the following major mechanisms:
Release of glucose into circulation via gluconeogenesis
Uptake of circulating glucose to satisfy the kidneys’ energy needs
Reabsorption of glucose at the proximal tubule
The kidneys play an important role in glucose homeostasis through the following major mechanisms:
Release of glucose into circulation via gluconeogenesis.
Uptake of circulating glucose to satisfy the kidneys’ energy needs.
Reabsorption of glucose at the proximal tubule.
Glucose balance is important to avoid the consequences of hypo- and hyperglycemia:
Long-term hyperglycemia leads to increased risk of cardiovascular disease, retinopathy, neuropathy, nephropathy.
Hypoglycemia can lead to physical morbidity and symptoms of confusion, behavioural changes, feeling fatigued, hot or cold.
Reference:
Mather A & Pollock C. Glucose handling by the kidney. Kidney Int 2011;79 (Suppl 120):S1-S6.
CDA Clinical Practice Guidelines Expert Committee. Can J Diabetes 2008; 32(Suppl 1):S1-S201.
Mather A & Pollock C. Kidney Int 2011;79 (Suppl 120);S1-S6.
CDA Clinical Practice Guidelines Expert Committee. Can J Diabetes 2008; 32(suppl 1):S1-S201.

6. Role of Kidneys in Glucose Handling
In subjects with normal kidney function and glucose tolerance
Glucose homeostasis in the body
Net ~ 0 g/day
Glucose input ~ 250 g/day
Glucose uptake ~ 250 g/day
• Dietary intake ~ 180 g/day
• Glucose production ~ 70 g/day
– gluconeogenesis
– glycogenolysis
• Brain ~ 125 g/day
• Rest of the body ~ 125 g/day
The kidney reabsorbs and recirculates glucose
Glucose reabsorbed ~ 180 g/day
Glucose filtered ~ 180 g/day
The human body tightly maintains glucose levels, even when food consumption and physical activity fluctuate. The importance of the kidney in normal glucose homeostasis is well recognized; it has a major part in maintaining the overall metabolic balance of the body.
Glucose production, which is a combination of gluconeogenesis and glycogenolysis, accounts for about 70 g of glucose per day. Dietary intake accounts for the about 180 g/day.
Each day the kidney filters about 180 liters of plasma containing 180 grams of glucose. Nearly all plasma glucose that is filtered by the renal glomerulus is reabsorbed into the blood stream; only about 500 mg of glucose is excreted in urine every day.
Glucose utilization occurs in a number of tissues, with the brain being a major user. About 50% of glucose is used by the brain and the rest of the body uses the remaining 50%.
References:
Adapted from:
Wright EM, et al. Active sugar transport in health and disease. J Intern Med 2007; 261(1):32-43.
Marsenic O. Glucose control by the kidney: An emerging target in diabetes. Am J Kidney Dis. 2009;53(5):
Adapted from:
Wright EM, et al. J Intern Med 2007;261:32-43.
Marsenic O. Am J Kidney Dis 2009;53:

7. Renal handling of glucose in non-diabetic individuals
Glucose filtration
(180 L/day) (1000 mg/L) =180 g/day
Glomerulus
Loop of Henle
Distal tubule
Collecting duct
Proximal tubule
Glucose reabsorption S3
~10% S1
~90%
No/minimal glucose excretion
This slide provides a closer look at the functional unit of the kidney - the nephron.
In normal glucose-tolerant subjects, virtually all filtered glucose is reabsorbed back into the bloodstream in the proximal tubule, and a minimal amount of glucose is excreted in the urine.
The majority of renal glucose reabsorption takes place in the convoluted segment (S1) of the proximal tubule where the high-capacity, low-affinity sodium-glucose transporter (SGLT) 2 and facilitative glucose transporter (GLUT) 2 are located.
The remaining 10% is reabsorbed in the distal straight segment (S3) of the proximal tubule where the high-affinity, low-capacity SGLT1 transporter, and GLUT1, are located.
This variation is thought to allow the majority of glucose to be reabsorbed in the S1 segment of the proximal tubule, whereas any glucose that is left in the ultrafiltrate by the time it reaches S3 is avidly reabsorbed.
Reference:
Adapted from:
Bailey CJ. Renal glucose reabsorption inhibitors to treat diabetes. Trends in Pharamcol Sci 2011;32:63-71.
Chao EC. Dapagliflozin: an evidence-based review of its potential in the treatment of type-2 diabetes. Core Evidence 2012;7:21-28.
S1 segment of proximal tubule
~90% glucose reabsorbed
Facilitated by SGLT2
S3 segment of proximal tubule
~10% glucose reabsorbed
Facilitated by SGLT1
Adapted from:
Bailey CJ. Trends in Pharmacol Sci 2011;32:63-71.
Chao EC. Core Evidence 2012;7:21-28.
SGLT = Sodium-dependent glucose transporter

8. SGLT Family of Transporters
Distribution
Function
SGLT1
Small intestine, heart, trachea, kidney
Active cotransport of sodium, glucose, and galactose across the brush border of intestine and proximal tubule of kidney
SGLT2
Kidney
Active cotransport of sodium and glucose in the S1 segment of the proximal tubule of kidney
SGLT3
Small intestine, uterus, lungs, thyroid, and testis
Active transport of sodium (not glucose)
SGLT4
Small intestine, kidney, liver, stomach, lung
Transport of glucose and mannose
SGLT5
Unknown
SGLT6
Spinal cord, kidney, brain, and small intestine
Transport of myo-inositol and glucose
This slide shows the distribution and function of the various sodium-glucose cotransporters (SGLT) in the body.
While some SGLTs only transport sodium, others actively co-transport both sodium and glucose across cell membranes. SGLT1 and SGLT2 are the best characterized co- transporter SGLTs.
SGLT1 is the main intestinal glucose transporter, it is also expresses in the kidney.
SGLT2 is almost exclusively expresses in the proximal tubules of the kidney.
References:
Adapted from:
Bays H. From victim to ally: the kidney as an emerging target for the treatment of diabetes mellitus. Curr Med Res Opin. 2009;25(3):
SGLT = Sodium-dependent glucose transporter
Adapted from:
Bays H. Curr Med Res Opin. 2009;25:

9. SGLT1 and SGLT2 SGLT1 SGLT2 Site Intestine, kidney Kidney
Sugar specificity
Glucose or galactose
Glucose
Glucose affinity
High
Km=0.4 mM
Low
Km=2 mM
Glucose transport capacity
Role
Dietary absorption of glucose and galactose
Renal glucose reabsorption
This slide describes the differences between the 2 sodium-glucose transport proteins.
SGLT1 is a high-affinity, low-capacity transport protein that resides in both the gut and the proximal tubule in the kidney. It plays a role in both dietary absorption and renal reabsorption of glucose. Inhibition of SGLT1 can result in malabsorption of glucose and other nutrients from the intestine, leading to osmotic diarrhea. For example, in glucose-galactose malabsorption syndrome, mutations in the gene for SGLT1 result in impaired absorption of glucose and galactose and severe diarrhea.
In contrast, SGLT2 is a low-affinity, high-capacity transport protein that resides in the proximal tubule alone. Specific inhibition of SGLT2 as a rational target of therapy for type 2 diabetes is based on familial renal glucosuria. Patients with this benign, inherited condition have a defective SGLT2 protein and excrete large amounts of glucose in their urine, with few if any adverse effects.
References:
From:
Wright EM, et al. Active sugar transport in health and disease. J Intern Med ;261:32-43.
Marsenic O. Glucose control by the kidney: An emerging target in diabetes. Am J Kidney Dis. 2009;53(5):
Chao EC & Henry RR. SGLT2 inhibition — a novel strategy for diabetes treatment. Nature Reviews Drug Discovery 2010;9:
From:
Wright EM, et al. J Intern Med. 2007;261:32-43.
Marsenic O. Am J Kidney Dis 2009;53:
Chao EC & Henry RR. Nature Reviews Drug Discovery 2010;9:
SGLT = Sodium-dependent glucose transporter

10. SGLT2 Mediates Glucose Reabsorption in the Kidney
Lumen
Blood
Na+ K+
ATPase
Glucose
SGLT2
Na+
Na+ and glucose
at 1:1 stoichiometry
S1 Proximal Tubule
Glucose
GLUT2
This slide shows the basic mechanism of SGLT2.
On the luminal side of the early proximal tubule S1 segment, absorption of sodium across the cell membrane creates an energy gradient that in turn allows glucose to be absorbed. On the other side of the cell, sodium is reabsorbed through an ATPase-mediated sodium-potassium pump into the bloodstream in order to maintain intravascular volume. This exchange alters the concentration gradient within the cell so that glucose is reabsorbed into the bloodstream via the GLUT2 transporter.
Reference:
Chao EC & Henry RR. SGLT2 inhibition — a novel strategy for diabetes treatment. Nature Reviews Drug Discovery 2010;9:
Major transporter of glucose in the kidney
Low affinity, high capacity for glucose
Nearly exclusively expressed in the kidney
Responsible for ~90% of renal glucose reabsorption in the proximal tubule
SGLT = Sodium-dependent glucose transporter
GLUT = Glucose transporter
Chao EC & Henry RR. Nature Reviews Drug Discovery 2010;9:

11. Renal SGLT2 Inhibition A Novel Approach to Type 2 Diabetes
Patients with type 2 diabetes
Type 2 diabetes with SGLT2 inhibition
Excess glucose
Excess glucose
Glomerulus
Glomerulus
Renal proximal tubule
Reduced blood glucose levels resulting from less glucose reabsorption
Renal proximal tubule
Glucose reabsorption
Glucose
Glucose excretion enabled through SGLT2 inhibition
Plasma glucose filtered in the kidney glomeruli, is reabsorbed into the systemic circulation by sodium glucose transporters (SGLTs) in the proximal tubule.
In patients with type 2 diabetes, the reabsorption of glucose helps sustain hyperglycemia.
By redirecting excess glucose via urinary excretion, SGLT2 inhibition represents a novel approach to type 2 diabetes.
SGLT2 inhibitors block glucose reabsorption, increasing urinary glucose excretion. There is substantive decrease in net glucose entering the system plasma glucose is lowered.
Glucosuria leads to loss of ~ g of glucose/day (~3-4 g/h) in subjects with type 2 diabetes mellitus.
References:
Adapted from:
Chao EC & Henry RR. SGLT2 inhibition — a novel strategy for diabetes treatment. Nature Reviews Drug Discovery 2010;9:
DeFronzo RA, et al. The role of the kidneys in glucose homeostasis: a new path towards normalizing glycemia. Diab Obes Metab 2012;14:5-14.
Washburn WN. Development of the renal glucose reabsorption inhibitors: a new mechanism for the pharmacotherapy of diabetes mellitus type 2. J Med Chem ;52(7):
Urinary excretion
Glucose excretion
Adapted from:
Chao EC & Henry RR. Nature Reviews Drug Discovery 2010;9:
DeFronzo RA, et al. Diab Obes Metab 2012;14:5-14.
Washburn WN. J Med Chem 2009;52:

12. SGLT2 As A Drug Target in Diabetes
Kidney as a major site of glucose flux
Upregulated in diabetes
Sodium-glucose cotransporter 2 (SGLT2) plays a role in renal glucose reabsorption in proximal tubule
Renal glucose reabsorption is increased in type 2 diabetes
Selective inhibition of SGLT2 increases urinary glucose excretion, reducing blood glucose
Approach based upon benign autosomal genetic disorder resulting from mutations in genes encoding SGLT2 (familial renal glucosuria)
Potential for weight loss
Low risk for hypoglycemia
Inhibition of sodium-glucose cotransporter 2 (SGLT2) protein is a rational approach to therapy for type 2 diabetes for the reasons listed on this slide.
SGLT2 inhibitors reduce glucose reabsorption in the renal proximal tubule, resulting in glucosuria. This decreases plasma glucose levels and reverses glucotoxicity.
This approach to therapy is simple and nonspecific, and thereby would complement the action of all other antidiabetic agents, including insulin. As a result, even refractory type 2 diabetes will respond.
Increased glucose excretion in the urine has the potential for weight loss
There is low risk for hypoglycemia with SGLT2 inhibitors.
References:
From:
Nair S & Wilding JPH. Sodium glucose cotransporter 2 inhibitors as a new treatment for diabetes mellitus. J Clin Endocrinol Metab 2010:95:34-42.
Bailey CJ. Renal glucose reabsorption inhibitors to treat diabetes. Trends in Pharamcol Sci 2011;32:63-71.
DeFronzo RA, et al. The role of the kidneys in glucose homeostasis: a new path towards normalizing glycemia. Diab Obes Metab 2012;14:5-14.
Abdul-Ghani MA, et al. Role of sodium-glucose cotransporter 2 (SGLT 2) inhibitors in the treatment of type 2 diabetes. Endo Review 2011;32:
From:
Nair S & Wilding PH. J Clin Endocrinol Metab 2010;95:34-42.
Bailey CJ. Trends in Pharmacol Sci 2011;32:63-71.
DeFronzo RA et al. Diab Obes Metab 2012;14:5-14.
Abdul-Ghani MA, et al. Endo Rev 2011:32

13. The Renal Glucose Threshold (RTG) Concept in Healthy Subjects
Urinary Glucose Excretion (g/d)
Below RTG
Minimal Glucosuria Occurs
Above RTG
Glucosuria Occurs
Healthy
RTG
~10 mmol/L
Urinary glucose excretion is commonly described as a threshold relationship.
Glucose is filtered by the kidneys and the vast majority is reabsorbed through the sodium- dependent glucose transporters SGLT2 and SGLT1.
The renal glucose transporters are able to reabsorb virtually all glucose when plasma glucose concentrations are in the normal range.
When plasma glucose increases and filtered glucose load exceeds the maximal renal reabsorption capacity, glucose is excreted into urine in direct proportion to the plasma glucose level.
The lowest plasma glucose concentration at which appreciable urinary glucose excretion occurs is termed the renal threshold for glucose excretion (RTG). This is commonly quoted to be mmol/L in normoglycemic, healthy subjects.
The true relationship between the renal threshold for glucose excretion and urinary glucose excretion is not a perfect threshold as shown on the slide; there is some splay in the relationship.
References:
Adapted from:
Guyton AC, Hall JE. Textbook of Medical Physiology. 11th ed. Philadelphia, PA: Elsevier Saunders; 2006
DeFronzo RA, et al. The role of the kidneys in glucose homeostasis: a new path towards normalizing glycemia. Diab Obes Metab 2012;14:5-14. 2 4 6 8 10 12 14 16
Plasma Glucose (mmol/L)
Adapted from:
Guyton AC, Hall JE. Textbook of Medical Physiology. 11th ed. Philadelphia, PA: Elsevier Saunders; 2006.
DeFronzo RA, et al. Diab Obes Metab 2012;14:5-14.

14. RTG is Elevated in Subjects With Type 2 Diabetes*
In subjects with type 2 diabetes, mean RTG in is about 13.8 mmol/L, compared with mmol/L in healthy subjects (each dot represents an individual subject - about 120 subjects).
Elevated RTG consistent with reports of elevated glucose transporter expression (SLGT2 and GLUT2) in subjects with type 2 diabetes.
These data suggest that an adaptation occurs in which high PG levels lead to an increase in RTG that could contribute to further increases in PG levels.
Renal Threshold (mmol/L)
In a study of a novel method, the renal threshold for glucose excretion was shown to be increased in patients with type 2 diabetes. The new methodology involved using measured plasma glucose, glomerular filtration rates, and urinary glucose excretion collected over several time intervals. This method solves for the unique value of the renal glucose threshold that makes the calculated urinary glucose excretion equal to the measured urinary glucose excretion.
Each dot shown in the graph represents an individual subject (about 120 subjects).
Note the inter-subject variability in the relationship between renal threshold for glucose excretion and plasma glucose.
If you calculate how much extra glucose is reabsorbed due to the elevated renal threshold for glucose excretion, the magnitude of this flux is as big or bigger than the reported increases in hepatic glucose production in subjects with type 2 diabetes.
Chronically high glucose may result in an adaptation that raises the renal threshold for glucose excretion. By increasing glucose reabsorption, elevations in the renal threshold for glucose excretion could contribute to further increases in plasma glucose levels, which is likely to contribute to disease progression.
References:
Adapted from:
Polidori D, et al Abstract 2186-PO. ADA. June 25-29, 2010; Orlando, Florida.
Polidori D, et al Abstract# 546 EASD. September 20-24, 2010; Stockholm, Sweden
24-Hour Average Plasma Glucose (mmol/L)
*Subjects with type 2 diabetes who were naïve to antihyperglycemic therapy or following washout of antihyperglycemic therapy.
RTG = Renal threshold for glucose excretion; SGLT = Sodium-dependent glucose transporter; GLUT = Glucose transporter
Adapted from:
Polidori D, et al Abstract 2186-PO. ADA. June 25-29, 2010; Orlando, Florida.
Polidori D, et al Abstract# 546 EASD. September 20-24, 2010; Stockholm, Sweden.

15. Upregulation of SGLT2 Transporter and Enhanced Cellular Glucose Uptake in Type 2 Diabetes
Glucose Uptake by Tubular Cells
Normalized Glucose Transporter Levels (mean ±SE)
P<0.05
Protein Expression
AMG* Uptake (CPM; mean ±SE)
P<0.05
Limited data (in 4 people) suggest patients with type 2 diabetes mellitus experience increased reabsorption of glucose.
Exfoliated proximal tubule epithelial cells from urine of 50 healthy patients and 50 patients with type 2 diabetes were placed into cell culture and examined for renal glucose transporter expression. In parallel, they were also examined for cellular glucose uptake.
Subjects with type 2 diabetes showed significantly increased amounts of SGLT2 and GLUT2, compared with healthy subjects. In addition, subjects with diabetes also demonstrated increased cellular uptake of glucose (up to 3 times greater) than healthy volunteers. A radio-labelled glucose substitute was used for this determination.
.Note that as these are only in vitro data, results still need to be confirmed by in vivo/clinical studies before definite conclusions can be made about increased glucose reabsorption in patients with type 2 diabetes.
Several preclinical studies show that expression of SGLT1, SGLT2, and GLUT2 in the kidney is upregulated in experimentally-induced and genetic forms of diabetes in rats.
References:
Rahmoune H, Thompson PW, Ward JM, Smith CD, Hong G, Brown J. Glucose transporters in human renal proximal tubular cells isolated from the urine of patients with non-insulin-dependent diabetes. Diabetes. 2005;54:
*Uptake of AMG is Na+ dependent and is a measure of transport by SGLTs rather than GLUTs.
AMG=methyl-α-D-[U-14C]-glucopyranoside; CPM=counts per minute.
Rahmoune H, et al. Diabetes 2005;54(12):

16. The Renal Glucose Threshold (RTG) Concept in Patients with Type 2 Diabetes
Below RTG minimal glucosuria occurs
Urinary Glucose Excretion (g/d)
Above RTG
Glucosuria Occurs
Type 2 diabetes
RTG
~13.8 mmol/L
Healthy
RTG
~10 mmol/L
Urinary glucose excretion is commonly described as a threshold relationship.
Glucose is filtered by the kidneys and the vast majority is reabsorbed through the sodium- dependent glucose transporters SGLT2 and SGLT1.
The renal glucose transporters are able to reabsorb virtually all glucose when plasma glucose concentrations are in the normal range.
When plasma glucose increases and filtered glucose load exceeds the maximal renal reabsorption capacity, glucose is excreted into urine in direct proportion to the plasma glucose level.
The lowest plasma glucose concentration at which appreciable urinary glucose excretion occurs is termed the renal threshold for glucose excretion (RTG). This is commonly quoted to be mmol/L in normoglycemic, healthy subjects.
The true relationship between the renal threshold for glucose excretion and urinary glucose excretion is not a perfect threshold as shown on the slide; there is some splay in the relationship.
References:
Adapted from:
Guyton AC, Hall JE. Textbook of Medical Physiology. 11th ed. Philadelphia, PA: Elsevier Saunders; 2006
DeFronzo RA, et al. The role of the kidneys in glucose homeostasis: a new path towards normalizing glycemia. Diab Obes Metab 2012;14:5-14. 2 4 6 8 10 12 14 16
Plasma Glucose (mmol/L)
Adapted from:
Guyton AC, Hall JE. Textbook of Medical Physiology. 11th ed. Philadelphia, PA: Elsevier Saunders; 2006.
DeFronzo RA, et al. Diab Obes Metab 2012;14:5-14.

17. Renal Glucose Handling Before and After Inhibition of SGLT222
Tmax
Pre-inhibition of SGLT2 21 =
Post-inhibition
of SGLT2 11
Pre-inhibition
of SGLT2
Rate of glucose filtration/reabsoprtion/excretion
(mmol per min)
Re-absorption
Post-inhibition
of SGLT2
5.5
Excretion
This slide shows a schematic of renal glucose reabsorption (purple line) and excretion (green line) in normal individuals. The amount of glucose reabsorbed by the kidneys is essentially equivalent to the amount entering the system, with reabsorption increasing with glucose concentrations up to approximately 11 mmol/L. At this threshold, the system becomes saturated and the maximal resabsorption rate, or glucose transport maximum (TmG), is reached. No more glucose can be absorbed, and instead the kidneys begin excreting it in the urine.
Although 11 mmol/L represents the theoretical threshold glucose concentration, the actual concentration varies due to nephron heterogeneity, resulting in slight differences in actual glucose reabsorption levels and TmG values between individual tubules. Thus, the actual threshold is not a single point but a curve, where excretion begins to occur at plasma glucose levels of ~10 mmol/L, and increases more gradually than sharply.
Likewise, as reabsorption approaches the TmG, it tails off in parallel to the glucose concentration threshold. The difference between the actual and theoretical TmG is known as splay.
In diabetes due to up-regulation of SGLT2, the reabsorption curve is shifted to the right.
SGLT2 inhibition may reduce plasma glucose levels by decreasing TmG, increasing the glucose excretion rate, or both.
In normal individuals, SGLT2 inhibition has no effect on plasma glucose concentration, because the liver increases glucose production to compensate for glycosuria.
In diabetes however, administration of an SGLT2 inhibitor produces both dose-dependent glucosuria and a significant reduction in plasma glucose concentrations. SGLT2 inhibitors lower both the saturation threshold and the transport maximum (Tmax) for glucose. This results in increased glucosuria for a given plasma glucose level, shown here as a left shift of the glucosuria curve.
In essence, SGLT2 inhibition “resets” the system by lowering the threshold for glucosuria; consequently, plasma glucose levels decrease and glucotoxicity declines.
References:
Adapted from:
Chao EC & Henry RR. SGLT2 inhibition — a novel strategy for diabetes treatment. Nature Reviews Drug Discovery 2010;9:
Guyton AC, Hall JE. Textbook of Medical Physiology. 11th ed. Philadelphia, PA: Elsevier Saunders; 2006
Theoretical threshold = =
Actual threshold 10 11
16.65
Plasma Glucose (mmol/L)
Adapted from:
Chao EC & Henry RR. Nature Reviews Drug Discovery 2010;9:
Guyton AC & Hall JE. Textbook of Medical Physiology. 11th ed. Philadelphia, PA: Elsevier Saunders; 2006.

18. RTG Reduction With Canagliflozin, an SGLT2 Inhibitor, in Subjects With Type 2 Diabetes Mellitus
RTG After Multiple-Dose SGLT2 Inhibitor (Canagliflozin) Treatment on Day 16, Mean (SE)
RTG (mmol/L)
Renal threshold for glucose excretion (RTG) of ~10-11 mmol/l commonly is cited as “normal” for healthy subjects.
RTG was calculated from measured plasma glucose (PG) concentration-time profiles, urinary glucose excretion (UGE), and estimated glomerular filtration rate (estimated from measured 24-h creatinine clearance) by assuming that UGE is well described by a threshold correlation in which there is insignificant UGE when PG is below RTG and that UGE increases with increasing PG when PG exceeds RTG.
Canagliflozin lowered RTG in a dose-dependent manner.
Canagliflozin lowered RTG maximally to ~5 mmol/l.
Canagliflozin doses ≥200 mg provide near-maximal lowering of RTG over 24 h. As in healthy subjects, maximally effective doses lowered RTG by about 65%.
With maximal inhibition of renal sodium glucose co-transporter 2, RTG is reduced to about 5 mmol/l, which suggests a low potential for hypoglycemia.
The 100-mg dose of CANA provided near-maximal suppression of RTG during most of the day, with a slight waning of the effect in the overnight period.
References:
Adapted from:
Sha S et al Abstract 568-P, ADA June 25-29, 2010; Orlando, Florida.
Rothenberg PL, et al. Abstract 876, EASD, September 20-24, 2010; Stockholm, Sweden.
Dose (mg)
Baseline RTG: group means ranged from mmol/l
Canagliflozin lowered RTG in a dose-dependent manner with near maximal effect (to ~5 mmol/l) at doses ≥200 mg
Adapted from:
Sha S et al Abstract 568-P, ADA June 25-29, 2010; Orlando, Florida.
Rothenberg PL, et al. Abstract 876, EASD, September 20-24, 2010; Stockholm, Sweden.

19. Conclusions
SGLT2 inhibition represents a novel approach to the treatment of type 2 diabetes.
SGLT2 is a low-affinity, high-capacity glucose transporter located in the proximal tubule and is responsible for 90% of glucose reabsorption.
Inhibition of SGLT2 in patients with diabetes results in decreased glucose reabsorption and increased glucosuria.
Lowering the renal threshold for glucose provides an insulin-independent mechanism for correction of hyperglycemia.
SGLT2 inhibition represents a novel approach to the treatment of type 2 diabetes.
SGLT2 is a low-affinity, high-capacity glucose transporter located in the proximal tubule and is responsible for 90% of glucose reabsorption.
Inhibition of SGLT2 in patients with diabetes results in decreased glucose reabsorption and increased glucosuria.
Lowering the renal threshold for glucose provides an insulin-independent mechanism for correction of hyperglycemia.