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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
Pathogenesis of type 2 diabetes - The Ominous Octet
Adapted from De Fronzo RA. Diabetes. 2009;58:773-95.
Hyperglycaemia
Decreased InsulinSecretion
IncreasedGlucagonSecretion
NeurotransmitterDysfunction
Decreased Incretin Effect
Increased HepaticGlucose Production
DecreasedGlucose Uptake
IncreasedGlucoseReabsorption
Increased Lipolysis
Islet- cell
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
Adapted from De Fronzo RA. Diabetes. 2009;58:773-95.
Hyperglycaemia
Decreased InsulinSecretion
IncreasedGlucagonSecretion
NeurotransmitterDysfunction
Decreased Incretin Effect
Increased HepaticGlucose Production
DecreasedGlucose Uptake
IncreasedGlucoseReabsorption
Increased Lipolysis
Islet- cell
New Dimension: Targeting Kidney
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 glucose3. 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
SGLT: Sodium Glucose Linked TransporterKey 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
Canagliflozin -Mechanism of ActionInhibition 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
PCT
↑ Blood Glucose
Glucose
SGLT2
SGLT1
CANA
PCT
Canagliflozin -Mechanism of ActionInhibition 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
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.
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.
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
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 Insulin1. 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
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.
The CANagliflozin Treatment And Trial Analysis (CANTATA) ProgramRobust phase 3 Clinical development program with >10,000 subjects enrolled
globally
3 active controlled trials at the time of FDA submission
Distribution of Subjects in Phase 3
North AmericaCanada, Mexico
3743 (36%)
EU/EEA/EFTA62681 (26%)
Central/South America795 (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/Africa3082 (30%)
Trial Description & Baseline Characteristics
Characteristic WorldwideN=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 DurationCore/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
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
Summary of Adverse Drug Reactions≥2% and >Placebo in the Placebo-controlled Studies Dataset
PlaceboN=646n (%)
CANA 100 mgN=833n (%)
CANA 300 mgN=834n (%)
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
Incidence of Urinary Tract Infection Adverse Events
Non-CANAN=3262
n (%)
CANA 100 mgN=3092
n (%)
CANA 300 mg N=3085
n (%)
All CANAN=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
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).
eGFR Mean Change from Baseline Over Time
Wk 104Wk 78Wk 52Wk 260
eGFR
(mL/
min
/1.7
3m2 )
Mea
n C
hang
e ±
SE
Wk 52Wk 42Wk 34Wk 26Wk 18Wk 60-7-6-5-4-3-2-10
eGFR
(mL/
min
/1.7
3m2 )
Mea
n C
hang
e ±
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 9Scherthaner G et al. Diabetes Care 2013 (supplementary Data)
Change from Baseline in Albumin/Creatinine Ratio Data from CV Safety Study (DIA3008)
CANA 300 mgCANA 100 mgPlacebo
Week 52Week 12BaselineN768927946Placebo837948971CANA 100 mg813927961CANA 300 mg
Subjects with Normo-albuminuria
Mea
n Ch
ange
± S
E
0
5
10
15
25
30
Week 52Week 12BaselineN769496Placebo637172CANA 100 mg697983CANA 300 mg
Subjects with Macro-albuminuria
-600-500-400-300-200-100
0100200300
Week 52Week 12BaselineN222284289Placebo269311320CANA 100 mg234282288CANA 300 mg
Subjects with Micro-albuminuria
-50-40-30-20-10
010203040506070
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
Mea
n Ch
ange
± S
E
Mea
n Ch
ange
± S
E
Proportion Progressing ≥ 1-step11.2%
9.0%
6.8%
0.0%
2.0%
4.0%
6.0%
8.0%
10.0%
12.0%
Placebo (N=1087) CANA 100 mg (N=1184) CANA 300 mg (N=1131)
% o
f Sub
ject
s
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
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
–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
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)
CANA300 mg
(n = 3,085)Non-CANA (n =
349)
CANA 100 mg
(n = 342)
CANA300 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)
01 (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.
ADA/EASD Position Statement - 2015
Silvio E. Inzucchi et al. Diabetes Care Volume 38, January 2015
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
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
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
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
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
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.
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
What agent would you use to advance treatment in this patient?
• An SGLT2 inhibitor• Colesevelam• Neutral protamine Hagedorn (NPH) insulin• Pioglitazone 45 mg daily
Thank You
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