This document provides an overview of canagliflozin, an SGLT2 inhibitor used to treat type 2 diabetes. It discusses the pathogenesis of type 2 diabetes, progressive beta cell dysfunction, and the kidney's role in glucose regulation. It then reviews canagliflozin's mechanism of action as an SGLT2 inhibitor, increasing urinary glucose excretion and reducing blood glucose levels. The document summarizes canagliflozin's clinical trials, pharmacokinetics, efficacy, safety profile, and effects on renal function and lipids.

1. Canagliflozin : SGLT2 inhibitor
Review of its Clinical Efficacy and
Safety in T2DM
DR A P NAVEEN KUMAR
Chief Specialist ( Gen. Med. )
Visakha Steel General Hospital

2. Pathogenesis of type 2 diabetes - The Ominous Octet
Adapted from De Fronzo RA. Diabetes. 2009;58:773-95.
Hyperglycaemia
Decreased Insulin
Secretion
Increased
Glucagon
Secretion
Neurotransmitter
Dysfunction
Decreased Incretin Effect
Increased Hepatic
Glucose Production
Decreased
Glucose Uptake
Increased
Glucose
Reabsorption
Increased
Lipolysis
Islet-α cell

3. Progressive β Cell Dysfunction and Effect of Weight on Glycemic Control in
T2DM
Every 3 kg weight gain offsets benefits of 1%
A1c reduction in terms of QALY.*
* P. McEwan, M. Evans, H. Kan; Diabetes, Obesity and Metabolism 12: 431–436, 2010.
“50% of β cells are dead at diagnosis”
- UKPDS

4. Adapted from De Fronzo RA. Diabetes. 2009;58:773-95.
Hyperglycaemia
Decreased Insulin
Secretion
Increased
Glucagon
Secretion
Neurotransmitter
Dysfunction
Decreased Incretin Effect
Increased Hepatic
Glucose Production
Decreased
Glucose Uptake
Increased
Glucose
Reabsorption
Increased
Lipolysis
Islet-α cell
New Dimension: Targeting Kidney

5. Plasma glucose
Blood pressure
The kidney as glucose
regulator
Nephropathy
Microalbuminuria
Marker of CV risk
The kidney contributes to glucose
homeostasis through:
1. Glucose release (gluconeogenesis)
~ 25 % of total glucose release
2. Glucose utilisation for energy needs
~ 10 % of dietary glucose
3. Glucose filtration and reabsorption
~ 180 g/day of glucose
Kidney Int. 2011; 79 (Suppl. 120): S1–S6.
Kidney and Diabetes
Structural and functional
damage of Kidneys

12. SGLT: Sodium Glucose Linked Transporter
Key Renal Transporter Reabsorbing Filtered Glucose
• SGLT2: Low Affinity/High Capacity
– Primarily expressed in kidney
– Responsible for majority of renal
glucose reabsorption (90%)
• SGLT1: High Affinity/Low Capacity
– Responsible for small portion of
renal glucose reabsorption (10%)
– Prominent role in intestinal
glucose absorption
SGLT2
SGLT1

13. Canagliflozin -Mechanism of Action
Inhibition of Glucose Reabsorption in the PCT
• Filtered Glucose is reabsorbed in the PCT
by SGLT2 (90%) and SGLT1 (10%)
contributing to Hyperglycaemia in T2DM
Glucose
SGLT2
SGLT1
P
C
T
↑ Blood
Glucose

14. Glucose
SGLT2
SGLT1
CANA
P
C
T
Canagliflozin -Mechanism of Action
Inhibition of Glucose Reabsorption in the PCT
• Filtered Glucose is reabsorbed in the PCT
by SGLT2 (90%) and SGLT1 (10%)
contributing to Hyperglycaemia in T2DM.
• Canagliflozin blocks the SGLT2
transporters
• Inhibits reabsorption of Glucose via SGLT2
transporters and decrease blood glucose
level and HbA1c.
↓ Blood
Glucose
Glucosuria

21. Familial Renal Glucosuria: A Genetic Model of SGLT2 Inhibition
Presentation
• Glucosuria: 1-170 g/day
• Asymptomatic
Blood
• Normal glucose concentration
• No hypoglycemia or hypovolemia
Kidney / bladder
• No tubular dysfunction
• Normal histology and function
Complications
• No increased incidence of
– Chronic kidney disease
– Urinary tract infection
Santer R, et al. J Am Soc Nephrol. 2003;14:2873-2882;
Wright EM, et al. J Intern Med. 2007;261:32-43.

23. History of SGLT Inhibitors : From Phlorizin to Gliflozins1,2
• 1835, French chemists isolated a substance, phlorizin, from the
bark of apple trees.
• 1886, German physician and diabetes pioneer Joseph von
Mering demonstrated glucosuria at high doses of phlorizin.
• Early 1970s – 1990s, research with phlorizin revealed the
location and characterization SGLT receptors.
• 1999, first phlorizin derivative, T-1095 was reported as novel
approach to treat diabetes.
• 2012 - Dapagliflozin; 2013 – Canagliflozin; 2014 - Empagliflozin
approved for treatment of T2DM.
1. White, John R. "Apple trees to sodium glucose co-transporter inhibitors: a review of SGLT2 inhibition.’’ Clinical Diabetes 28.1 (2010): 5-10.
2. Oku, Akira, et al. "T-1095, an inhibitor of renal Na+-glucose cotransporters, may provide a novel approach to treating diabetes." Diabetes 48.9 (1999): 1794-
1800.

42. Canagliflozin – Introduction
• CANA is an orally active
inhibitor of SGLT2, a
transporter responsible for
reabsorbing the majority of
glucose in the kidney.
• CANA’s affinity for SGLT2 is
approximately 150 times
greater than for SGLT1
Canagliflozin Chemical
Structure

43. Canagliflozin – Mechanism of Action
• By inhibiting renal SGLT2, CANA
lowers Renal threshold for
glucose (RTG )
• Decrease in RTG results in
increased Urinary
Glucose Excretion
(UGE) upto 80–120
g/day.
• Mechanism of Action is
Independent of Insulin
1. Nomura S, et al. J Med Chem. 2010; 53(17):6355-6360.
2. Sha S, et al. Diabetes Obes Metab. 2011;13(7):669-672.
3. Liang Y, et al. PLoS One. 2012; 7(2):e30555.
4. Devineni D, et al. Diabetes Obes Metab. 2012.
5. Rosenstock J, et al. Diabetes Care. 2012
Till PG ~ 180mg/dL,
no glycosuria.
Till PG ~ 240mg/dL,
no glycosuria.
At PG >70-90mg/dL,
there is glycosuria.
Leading to increased
Urinary Glucose
Excretion and decreased
HbA1c
PG: Plasma Glucose
Healthy T2DM CANA

44. Canagliflozin - Pharmacokinetics (ADME Profile)
Absorption
• Rapid and good oral absorption [Bioavailability 65%]
• Tmax 1 to 2 hours, Steady state in 4 to 5 days
Distribution • Plasma protein binding: 98 - 99%
Metabolism
• O-Glucuronidation is major metabolic pathway
• No clinically relevant active metabolites
Elimination
• Excretion: 51.7% in feces and 33% in urine (<1% unchanged in urine)
• Terminal half life (t1/2) 10.6 hrs (100 mg) and 13.1 hrs (300 mg)
Food, Gender, Age, Body weight, and Race do not alter the pharmacokinetics of Canagliflozin to a
clinically relevant extent
Plosker, Greg L. "Canagliflozin: A Review of Its Use in Patients with Type 2 Diabetes Mellitus." Drugs 74.7 (2014): 807-824.

46. The CANagliflozin Treatment And Trial Analysis (CANTATA) Program
Robust phase 3 Clinical development program with >10,000 subjects enrolled
globally
3 active controlled trials at the time of FDA submission

47. Distribution of Subjects in Phase 3
North America
Canada, Mexico
3743 (36%)
EU/EEA/EFTA6
2681 (26%)
Central/South
America
795 (8%)
India (11%)
• 49 countries
• Provided greater total subject exposure than other recent registration programs for antidiabetic drugs
• Broad T2DM patient population
- including early-stage T2DM & more advanced stage treated with ≥1 AHAs (dual and triple
combination therapy studies) and/or insulin
Asia/Australia/Africa
3082 (30%)

48. Trial Description & Baseline Characteristics
Characteristic
Worldwide
N=10301 (100%)
Age, y
Mean (SD) 59.5 (9.46)
Sex, n (%)
Male 5965 (58)
Female 4336 (42)
Race, n (%)
White 7411 (72)
Black or African-
American
452 (4)
Asian 1643 (16)
Other 795 (8)
Ethnicity, n (%)
Hispanic or Latino 1699 (16)
Not Hispanic or Latino 8563 (83)
Not provided 39 (<1)
Study Description
Duration
Core/Ext
Monotherapy vs PBO (DIA3005)
CANTATA-M
26/26 week
Add-on to MET vs PBO & SITA
(DIA3006) CANTATA-D
26/26 week
Add-on to MET vs GLIM (DIA3009)
CANTATA-SU
52/52 week
Add-on to MET + SU vs PBO
(DIA3002) CANTATA-MSU
26/26 week
Add-on to MET + TZD (PIO) vs PBO
(DIA3012) CANTATA-MP
26/26 week
Add-on to MET + SU vs SITA
(DIA3015) CANTATA-D2
52 week
CV Outcomes (DIA3008) CANVAS
(Insulin Substudy)
(SU Substudy)
4-8 years
(18 week)
(18 week)
Moderate Renal Impairment Study
(DIA3004)
26/26 week
Study in Older subjects
(DIA3010)
26/78 week

58. Tolerability and Safety of Canagliflozin
• Review of specific Adverse Drug Reactions
• AEs Related to Osmotic Diuresis & Reduced Intravascular
• Renal safety (eGFR and ACR)
• Review of changes to lipid profile
• CV safety

59. Summary of Adverse Drug Reactions
≥2% and >Placebo in the Placebo-controlled Studies Dataset
Placebo
N=646
n (%)
CANA 100 mg
N=833
n (%)
CANA 300 mg
N=834
n (%)
Gastrointestinal Disorders
Constipation 6 (0.9) 15 (1.8) 19 (2.3)
Thirst 1 (0.2) 23 (2.8) 19 (2.3)
Renal and Urinary Disorders
Polyuria or pollakiuria 5 (0.8) 44 (5.3) 38 (4.6)
Urinary tract infection 26 (4.0) 48 (5.8) 36 (4.3)
Genital Tract Infections
Balanitis or balanoposthitis 2 (0.6) 17 (4.2) 15 (3.7)
Vulvovaginal candidiasis 10 (3.2) 44 (10.4) 49 (11.4)
Other ADR’s: Hypotension, Impaired renal function, Hypoglycemia with concomitant insulin or insulin secretatgoues, Hypersensitivty
reactions, Increased LDL-C, Pancreatitis, Bone fractures
Increases in: Potassium, Magnesium, Phosphate, and Hemoglobin

60. Incidence of Urinary Tract Infection Adverse Events
Non-CANA
N=3262
n (%)
CANA 100 mg
N=3092
n (%)
CANA 300 mg
N=3085
n (%)
All CANA
N=6177
n (%)
Any UTI adverse events 218 (6.7) 254 (8.2) 250 (8.1) 504 (8.2)
Upper UTI AE 11 (0.3) 20 (0.6) 10 (0.3) 30 (0.5)
AEs leading to
discontinuation
4 (0.1) 11 (0.4) 6 (0.2) 17 (0.3)
Serious AEs 12 (0.4) 16 (0.5) 8 (0.3) 24 (0.4)
• UTI AEs in subjects treated with CANA were generally mild to moderate in severity
- similar duration to those occurring in PBO-treated subjects
- recurrent in a similar proportion of subjects as seen with PBO
- led to few study discontinuations
• No meaningful increases in upper UTIs or serious events were observed with CANA

61. AEs Related to Osmotic Diuresis & Reduced Intravascular Volume (4 Pooled
PBO-controlled, 26-week Studies)*
Subjects, n (%)
PBO
(n = 646)
CANA 100 mg
(n = 833)
CANA 300 mg
(n = 834)
Osmotic diuresis-related AEs†
Any AE
AEs leading to discontinuation
AEs related to study drug‡
Serious AEs
Specific terms§
Pollakiuria|
Polyuria¶
Thirst
5 (0.8)
0
5 (0.8)
0
4 (0.6)
0
1 (0.2)
56 (6.7)
1 (0.1)
41 (4.9)
0
35 (4.2)
6 (0.7)
11 (1.3)
47 (5.6)
2 (0.2)
41 (4.9)
0
26 (3.1)
12 (1.4)
16 (1.9)
Volume-related AEs#
Any AE
AEs leading to discontinuation
AEs related to study drug‡
Serious AEs
Specific terms§
Hypotension
Orthostatic hypotension
Postural dizziness
7 (1.1)
1 (0.2)
2 (0.3)
1 (0.2)
4 (0.6)
1 (0.2)
2 (0.3)
10 (1.2)
0
4 (0.5)
0
6 (0.7)
0
3 (0.4)
11 (1.3)
0
6 (0.7)
0
2 (0.2)
4 (0.5)
4 (0.5)
*All AEs are reported for regardless of rescue medication.
†
Reported terms included micturition urgency, nocturia, pollakiuria, polyuria, urine output increased, dry mouth, polydipsia, and
thirst. ‡
Possibly, probably, or very likely related to study drug. §
The 3 most common terms are shown.|
Increased urine frequency.
¶
Increased urine volume. #
Reported terms included dehydration, dizziness postural, hypotension, orthostatic hypotension, and
syncope.
Weir M et al. Poster presented at the 73rd Scientific sessions of the American Diabetes Association (ADA), 2013; Jun. 21-25; Chicago, Illinois, (P1077).

62. eGFR Mean Change from Baseline Over Time
Wk 104Wk 78Wk 52Wk 260
eGFR(mL/min/1.73m2
)
MeanChange±SE
Wk 52Wk 42Wk 34Wk 26Wk 18Wk 60
-7
-6
-5
-4
-3
-2
-1
0
eGFR(mL/min/1.73m2
)
MeanChange±SE
Wk 12
SITA 100 mg (BL: 87.76) CANA 300 mg (BL: 87.17)DIA3015
0
-4
-8
Leiter LA et al. Diabetes Care 2014 Sep 9
Scherthaner G et al. Diabetes Care 2013 (supplementary Data)

63. Change from Baseline in Albumin/Creatinine Ratio
Data from CV Safety Study (DIA3008)
CANA 300 mg
CANA 100 mg
Placebo
Week 52Week 12BaselineN
768927946Placebo
837948971CANA 100 mg
813927961CANA 300 mg
Subjects with Normo-albuminuria
MeanChange±SE
0
5
10
15
25
30
Week 52Week 12BaselineN
769496Placebo
637172CANA 100 mg
697983CANA 300 mg
Subjects with Macro-albuminuria
-600
-500
-400
-300
-200
-100
0
100
200
300
Week 52Week 12BaselineN
222284289Placebo
269311320CANA 100 mg
234282288CANA 300 mg
Subjects with Micro-albuminuria
-50
-40
-30
-20
-10
0
10
20
30
40
50
60
70
20
Baseline Mean (SD) –
10.0 (6.45) µg/mg
Baseline Mean (SD) –
95.6 (67.8) µg/mg
Baseline Mean (SD) –
1023.2 (1000.38) µg/mg
MeanChange±SE
MeanChange±SE
Proportion Progressing ≥ 1-step
%ofSubjects

64. Change in HbA1c in the Overall Population and Indian Subgroup
n 1,191 1,404 1,419 99 112 115
–0.96%
(95% CI: –1.18, –0.74)
Baseline (%)
Overall population Indian subgroup
8.1 8.1 8.1 8.4 8.2 8.3
–0.69%
(95% CI: –0.75, –0.63)
–0.83%
(95% CI: –0.89, –0.77)
–0.87%
(95% CI: –1.10, –0.65)
LS, least squares; SE, standard error; CI, confidence
interval.
–1.0
–1.2
–0.6
–0.8
0
0.2
–0.4
–0.2
Kumar et al. Poster presented at IDF 2014
Efficacy and Safety of Canagliflozin in Patients With Type 2 Diabetes Mellitus From
India

65. Percent Change in Body Weight in the Overall Population & Indian
Subgroup
n 1,230 1,425 1,435 105 112 117
–2.0%
(95% CI: –2.8, –1.1)
Baseline (kg)
Overall population Indian subgroup
92.9 92.4 91.6 72.1 71.3 69.3
–2.0%
(95% CI: –2.3, –1.8)
–2.7%
(95% CI: –2.9, –2.4)
–3.0%
(95% CI: –3.8, –2.1)
–0.5
–1.0
–1.5
–2.0
–2.5
–3.0
0.5
0
–3.5
Kumar et al. Poster presented at IDF 2014

66. –8
–2
–6
–4
Change in SBP in the Overall Population & Indian Subgroup
n 1,230 1,425 1,437 105 112 117
–3.9 mmHg
(95% CI: –7.1, –0.7)
Baseline (mmHg)
Overall population Indian subgroup
133.1 131.8 132.7 130.8 131.1 131.8
–3.3 mmHg
(95% CI: –4.2, –2.4)
–4.5 mmHg
(95% CI: –5.4, –3.6)
–3.5 mmHg
(95% CI: –6.6, –0.3)
–10
0
Kumar et al. Poster presented at IDF 2014

67. Summary of Overall AEs and Selected AEs in the Overall Population and
Indian Subgroup (Safety Population)
Patients, n (%)
Overall population Indian subgroup
Non-CANA
(n = 3,262)
CANA
100 mg
(n = 3,092)
CANA
300 mg
(n = 3,085)
Non-CANA (n =
349)
CANA
100 mg
(n = 342)
CANA
300 mg
(n = 347)
Any AE 2,160 (66.2) 2,083 (67.4) 2,133 (69.1) 206 (59.0) 206 (60.2) 219 (63.1)
AEs leading to discontinuation 121 (3.7) 129 (4.2) 173 (5.6) 5 (1.4) 6 (1.8) 14 (4.0)
AEs related to study drug* 585 (17.9) 765 (24.7) 912 (29.6) 54 (15.5) 53 (15.5) 68 (19.6)
Serious AEs 271 (8.3) 239 (7.7) 249 (8.1) 24 (6.9) 24 (7.0) 16 (4.6)
Deaths 18 (0.6) 12 (0.4) 13 (0.4) 2 (0.6) 2 (0.6) 2 (0.6)
Selected AEs
UTI
Genital mycotic infection
Male†
Female‡
Osmotic diuresis–related AEs§
Volume depletion–related AEs||
141 (4.3)
20 (0.6)
31 (1.0)
48 (1.5)
49 (1.5)
171 (5.5)
104 (3.4)
161 (5.2)
174 (5.6)
71 (2.3)
175 (5.7)
140 (4.5)
162 (5.3)
177 (5.7)
105 (3.4)
13 (3.7)
0
1 (0.3)
1 (0.3)
0
21 (6.1)
4 (1.2)
6 (1.8)
2 (0.6)
3 (0.9)
20 (5.8)
11 (3.2)
7 (2.0)
5 (1.4)
5 (1.4)
*Possibly, probably, or very likely related to study drug, as assessed by investigators.
†
Including balanitis, balanoposthitis, genital infection fungal, and posthitis.
‡
Including genital infection fungal, vaginal infection, vulvovaginal candidiasis, vulvovaginal mycotic infection, vulvovaginal pruritus, and
vulvovaginitis.
§
Including dry mouth, dry throat, micturition disorder, micturition urgency, nocturia, pollakiuria, polydipsia, polyuria, thirst, tongue dry,
and urine output increased.
||
Including dehydration, dizziness postural, hypotension, orthostatic hypotension, orthostatic intolerance, presyncope, and syncope.

68. ADA/EASD Position Statement - 2015
Silvio E. Inzucchi et al. Diabetes Care Volume 38, January 2015

69. Summary of Canagliflozin Clinical data
• Novel ß-Cell Independent MOA
• Consistent and sustained improvements in glucose control.
• CANA 100 mg demonstrated non-inferior to Glimepiride and Sitagliptin and
CANA 300 mg superior to both agents.
• Greater proportion of patients achieving HbA1c goals.
• Significant reduction of Fasting and Post-meal glucose.
• Significant reductions in Systolic blood pressure and sustained Body Weight loss.
• Hypoglycemia comparable to placebo
• Side effects includes genital mycotic infections, which can be managed with
standard treatment.
• Recommended by ADA, EASD and AACE for management of T2DM

70. Which weight-related counseling advice is appropriate for
patients like this who are treated with SGLT2 inhibitors?
• SGLT2-related weight changes are similar to those of DPP-
4 inhibitors
• Significant weight loss is seen only in about 25% of SGLT2-
treated patients
• Weight gain is frequently associated with SGLT2s when
used in combination with insulin
• Weight loss stabilizes after a few weeks but there is no
rebound weight gain

71. Which of the following is the main contraindication
with SGLT2 inhibitor therapy present in this
patient?
• The patient's nonadherence to insulin therapy
• The patient has a history of urinary tract infections
• The patient has known kidney disease
• The patient had kidney stones

72. This patient inquires about the relationship between
SGLT2 therapy and fungal infections. Which statement
represents an appropriate response?
• These drugs are contraindicated in patients with a history of
fungal infections
• Fungal infections reflect poor personal hygiene
• More than 20% of patients in clinical trials had to discontinue
treatment due to fungal infections
• Related fungal infections are usually treatable using standard
treatment with good efficacy

73. Prior to initiating SGLT2 inhibitor therapy, which
counseling advice related to adverse effects is
correct?
• SGLT2s are associated with a decrease in LDL-C
• SGLT2s have a neutral effect on LDL-Cl
• SGLT2s significantly increase LDL-C and are associated with
cardiovascular risk
• SGLT2s are associated with a small increase in LDL-C

74. This patient is a 60-year-old man who was diagnosed with type 2
diabetes 8 years ago. He has no serious comorbidities, but is
prone to hypoglycemia, most likely due to erratic eating habits.
He has had previous experience with the following medications:
(1) metformin 1 g twice daily, which gave him diarrhea and was discontinued;
(2) glipizide 10 mg twice daily, which contributed to episodes of hypoglycemia
and was discontinued;
(3) sitagliptin 100 mg daily, which he tolerated but did not get his HbA1c below
7.9% and was discontinued;
(4) liraglutide 1.2 mg daily, which caused nausea and vomiting and was
discontinued;
(5) pioglitazone 30 mg daily, which caused swelling of his legs and weight gain
and was discontinued; and
(6) insulin (glargine and aspart), which was not preferred by the patient, caused
hypoglycemia, and was discontinued.

75. What is the most important diabetes-related
pathophysiological maladaptation in this
patient?
• Leptin deficiency
• Insulin secretory deficiency
• Deficiency of glucose-dependent insulinotropic
peptide (GIP)
• Maladaptation in the kidneys to hyperglycemia
and glycosuria

76. What agent would you use to advance
treatment in this patient?
• An SGLT2 inhibitor
• Colesevelam
• Neutral protamine Hagedorn (NPH) insulin
• Pioglitazone 45 mg daily

77. Thank You
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