The Role of SGLT-2 Inhibitors in the Management of Patients with

Report
The Role of SGLT-2 Inhibitors in the
Management of Patients
with Type 2 Diabetes
Lawrence Blonde, MD
Director, Ochsner Diabetes Clinical Research Unit,
Department of Endocrinology, Diabetes, and Metabolic Diseases
Ochsner Medical Center, New Orleans, LA
Disclosures: Lawrence Blonde, MD
•
Clinical research: Boehringer Ingelheim , Eli Lilly, Johnson & Johnson, Novo
Nordisk, Roche, Sanofi-aventis
•
Advisor or consultant: Amylin, AstraZeneca, Boehringer Ingelheim, Bristol-Myers
Squibb, Daiichi Sankyo, GlaxoSmithKline, Halozyme Therapeutics, Johnson &
Johnson, MannKind Corporation, Merck, Novo Nordisk, Orexigen Therapeutics,
Roche, Sanofi-aventis, Santarus, VeroScience
•
Speaker/speakers bureau: AstraZeneca, Boehringer Ingelheim, Bristol-Myers
Squibb, Daiichi Sankyo, Merck, Novo Nordisk, Santarus, VeroScience
The Role of SGLT-2 Inhibitors in the
Management of Patients with Type 2 Diabetes
This CME activity is supported by an educational
grant from:
The Role of SGLT-2 Inhibitors in the
Management of Patients with Type 2 Diabetes
Please complete the questionnaire/evaluation
form located in your program books.
Case Presentation
• 48-year-old African American man with 12 month history of
type 2 diabetes
• Hypertension for past 6 years treated with lisinopril 10 mg daily
– Most recent blood pressure was 138/84 mm Hg
• Increased LDL-C treated with simvastatin 40 mg qd;
– Most recent LDL-C 98 mg/dL
• Diabetes treated with lifestyle intervention (increased physical
activity, medical nutritional therapy) and metformin 1000 mg
bid
– Weight 240 pounds, height 6’ (BMI = 32.5)
• A1C = 7.5 %
Natural History of T2D
and β-cell Function
Bergenstal R, et al. Endocrinology. Philadelphia, PA: WB Saunders Co;2001:821-835.
Ominous Octet
DeFronzo RA. Diabetes. 2009;58:773-795.
Survival as a Function of A1C in Patients Type 2
Diabetes: A Retrospective Cohort Study*
Oral Agents
Currie CJ, et al. Lancet. 2010;6(375):481-9.
Insulin +/- Oral Agents
*28,000 patients 50 years and older
ABCs of Type 2 Diabetes:
AACE/ACE 2011 and ADA 2011
Target
Treatment
Goals
AACE/ACE 2011
ADA 2011
A1C
≤ 6.5%
< 7.0%
Blood
pressure
<130/80 mm Hg
<130/80 mm Hg
Cholesterol
(lipids)
• LDL-C < 100 mg/dL
• LDL-C < 100 mg/dL
(< 70 mg/dL for patients
(< 70 mg/dL for patients
with diabetes and
with diabetes and
coronary artery disease)
coronary artery disease)
• HDL-C > 40 mg/dL in men; • HDL-C > 40 mg/dL in men;
> 50 mg/dL in women
> 50 mg/dL in women;
• Triglycerides <150 mg/dL
• Triglycerides < 150 mg/dL
*In individuals with overt cardiovascluar disease, a lower LDL-cholesterol goal of <70 mg/dL (1.8 mmol/L), using high-dose of a statin, is an
option.
Handelsman Y, et al. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for
AACE
Diabetes Mellitus
ClinicalMellitus
Practice Guidelines
Task Force.
Endocr
2007;13(suppl
1):1-68.
Developing
a Diabetes
Comprehensive
Care
Plan.Pract.
Endocr
Pract. 2011;17(Suppl
2):1-53.
"Standards
of Medical
Care inCare
Diabetes—2011."
Diabetes Diabetes
Care 34(Supplement
1): S11-S61. 1): S11-S61.
Standards
of Medical
in Diabetes—2011.
Care. 34(Supplement
Glycemic Control Recommendations
for Type 2 Diabetes:
AACE/ACE 2011 and ADA 2011
Target
Treatment
Goals
AACE/ACE 2011
ADA 2011
A1C
≤ 6.5%
< 7.0%
Fasting
glucose
Fasting plasma glucose:
< 110 mg/dL
2-hr postprandial glucose:
< 140 mg/dL
Preprandial capillary plasma
glucose: 70 – 130 mg/dL
Postprandial
glucose
Peak postprandial capillary
plasma glucose: < 180 mg/dL
*InHandelsman
individuals with
disease, a lower
LDL-cholesterol
goal of <70Medical
mg/dL (1.8
mmol/L), using
high-dose
of a statin,
Y, overt
et al.cardiovascluar
American Association
of Clinical
Endocrinologists
Guidelines
for Clinical
Practice
foris an
option.
Developing a Diabetes Mellitus Comprehensive Care Plan. Endocr Pract. 2011;17(Suppl 2):1-53.
AACE Diabetes Mellitus Clinical Practice Guidelines Task Force. Endocr Pract. 2007;13(suppl 1):1-68.
Standards of Medical Care in Diabetes—2011. Diabetes Care. 34(Supplement 1): S11-S61.
"Standards of Medical Care in Diabetes—2011." Diabetes Care 34(Supplement 1): S11-S61.
ADA/AHA/ACC Consensus Recommendations
From ACCORD, ADVANCE, & VA Diabetes Trials
• A1C goal for non-pregnant adults in general = < 7.0%
– Lowering A1C to ≈7.0% has been shown to reduce microvascular and
neuropathic complications
• For selected individual patients, lower A1C goals may be recommended if
goal can be achieved without significant hypoglycemia or other adverse
events, eg, patients with
– Short duration of diabetes
– Long life expectancy
– No significant cardiovascular disease
• For some patients, less stringent A1C goals may be appropriate,
eg, patients with
–
–
–
–
–
History of severe hypoglycemia
Limited life expectancy
Advanced microvascular or macrovascular complications
Extensive co-morbid conditions
Long-standing diabetes where goals have not been achieved despite optimal
Rx
Skyler J, et al. Diabetes Care. 2009;32:187–192.
Challenges in Type 2 Diabetes
• Large number of patients
– Diabetes affects 25.8 million people (8.3 % of the US population)
• DIAGNOSED- 18.8 million people
• UNDIAGNOSED- 7.0 million people
• PREDIABETES – 79 million people
• Progressive worsening of insulin secretory deficit requiring
increased number of antihyperglycemic medications over time
• Risk for hypoglycemia with some therapies
• Risk for weight gain with some therapies
• Difficulty controlling postprandial glucose and glucose fluctuations
• Preventing and managing complications and co-morbidities
• Difficulty attaining and sustaining optimal long-term glycemic
control
CDC 2010. National Diabetes Fact Sheet. US Department of Health and Human Services.
Cefalu, WT. Am J Med. 2012;343(1):21-26.
http://ndep.nih.gov/resources/diabetes-healthsense/
ADA/EASD Writing Goup Consensus Algorithm
Nathan DM, et al. Diabetes Care. 2009:32:193-203.
*Validation based on clinical trials and clinical judgment
†Sulfonylureas other than glybenclamide (glyburide) or
chlorpropamide
AACE/ACE Diabetes Algorithm
for Glycemic Control
American Association of Clinical Endocrinologists. AACE/ACE Diabetes Algorithm for Glycemic Control.
Available at https://www.aace.com/publications. Accessed January 2012.
Summary of Key Benefits and Risks of Medications
Metformin
DPP-4
Inhibitor
GLP-1
Agonist
Sulfonylure
a
Glinide
TZD
Colesevelam
AGI
Insulin
Pramlintid
e
Benefits
PPG - lowering
FPG - lowering
Nonalcoholic fatty
liver disease (NAFLD)
Mild
Moderate
Moderate
to Marked
Moderate
Moderate
Mild
Mild
Moderate
Moderate
to Marked
Moderate to
Marked
Moderate
Mild
Mild
Moderate
Mild
Moderate
Mild
Neutral
Moderate
to Marked
Mild
Mild
Neutral
Mild
Neutral
Neutral
Moderate
Neutral
Neutral
Neutral
Neutral
Risks
Hypoglycemia
Neutral
Neutral
Neutral
Moderate
Mild
Neutral
Neutral
Neutral
Moderate
to Severe
Neutral
GI Symptoms
Moderate
Neutral
Moderate
Neutral
Neutral
Neutral
Moderate
Moderate
Neutral
Moderate
Risk of use with
renal
insufficiency
Severe
Reduce
Dosage
Moderate
Moderate
Neutral
Mild
Neutral
Neutral
Moderate
Neutral
Contraindicated if
liver failure or
predisposition to
lactic acidosis
Severe
Neutral
Neutral
Moderate
Moderate
Moderate
Neutral
Neutral
Neutral
Neutral
Heart
failure/Edema
Contraindicted
in CHF
Neutral
Neutral
Neutral
Neutral
Mild/
Moderate
Neutral
Neutral
Neutral
Unless
with TZD
Neutral
Weight Gain
Benefit
Neutral
Benefit
Mild
Mild
Moderate
Neutral
Neutral
Mild to
Moderate
Benefit
Fractures
Neutral
Neutral
Neutral
Neutral
Neutral
Moderate
Neutral
Neutral
Neutral
Neutral
Drug-Drug
Neutral
Neutral
Neutral
Moderate
Moderate
Neutral
Neutral
Neutral
Neutral
Neutral
Contraindicted in
class 1, 4
CHF
Interactions
American
Association of Clinical Endocrinologists. AACE/ACE Diabetes Algorithm for Glycemic Control. Available at https://www.aace.com/publications. Accessed January 2012.
Unmet Needs With Conventional
Antihyperglycemic Therapies
• Many therapies are associated with weight gain
• Insulin and non incretin oral insulin secretagogue
therapies are associated with significant risk for
hypoglycemia
• Other AEs with some therapies include GI side effects
and edema
• Many therapies fail to adequately control postprandial
hyperglycemia
• Therapies often fail to maintain long-term glycemic
control
Blonde L. Am J Manag Care. 2007;13:S36-S40.
Blonde L, et al. J Manag Care Pharm. 2006;12(suppl):S2-S12.
Unmet Needs
Type 2 DM Control is Not Durable
3
6
9
12
15 18 21 24 27 30 33 36 39
Time (months)
Bloomgarden, ZT. Diabtes Care. 2007;30(1):174-180.
42
45 48
New Classes Presently in Development
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Long-acting GLP-1 receptor agonists
Ranolazine
Dual & Pan PPAR agonists
11 Hydroxysteroid Dehydrogenase (HSD)- 1 inhibitors
Fructose 1,6-bisphosphatase inhibitors
Glucokinase activators
G protein-coupled Receptor (GPR)- 40 & -119 agonists
Protein Tyrosine Phosphatase (PTB)- 1b inhibitors
Camitine- Palmitoyltransferase (CPT)- 1 inhibitors
Acetyl COA Carboxylase (ACC)- 1 & -2 inhibitors
Glucagon receptor antagonists
Salicylate derivatives
Immunomodulatory drugs
Sodium- Glucose Cotransporter (SGLT) {-1} & -2 inhibitors
The Kidneys Play an Important
Role in Glucose Control
Normal Renal Glucose Physiology
• 180 g of glucose is filtered each day
• Virtually all glucose reabsorbed in the proximal
tubules & reenters the circulation
• SGLT2 reabsorbs about 90% of the glucose
• SGLT1 reabsorbs about 10% of the glucose
• Virtually no glucose excreted in urine
Mather, A & Pollock, C. Kidney International. 2011;79:S1-S6.
Sodium- Glucose Cotransporters
SGLT1
SGLT2
Site
Mostly intestine with some Almost exclusively kidney
kidney
Sugar Specificity
Glucose or galactose
Glucose
Affinity for glucose
High
Km= 0.4 Mm
Low
Km = 2 Mm
Capacity for glucose
transport
Low
High
Role
Dietary glucose absorption Renal glucose reabsorption
Renal glucose reabsorption
Lee YJ, at al. Kidney Int Suppl. 2007;72:S27-S35.
Targeting the Kidney
Chao EC, et al. Nat Rev Drug Discovery. 2010;9:551-559.
Renal Glucose Transport
Chao, EC & Henry RR. Nature Reviews Drug Discovery. 2010;9:551-559.
Altered Renal Glucose Control in Diabetes
• Gluconeogenesis is increased in postprandial and
postabsorptive states in patients with Type 2 DM
– Renal contribution to hyperglycemia
– 3-fold increase relative to patients without diabetes
• Glucose reabsorption
– Increased SGLT-2 expression and activity in renal
epithelial cells from patients with diabetes vs.
normoglycemic individuals
Marsenic O. Am J Kidney Dis. 2009;53:875-883.
Bakris GL, et al. Kidney Int. 2009;75(12):1272-1277.
Rahmoune H, et al. Diabetes. 2005;54(12):3427-3434.
Rationale for SGLT2 Inhibitors
• SGLT2 is a low-affinity, high capacity glucose transporter
located in the proximal tubule and is responsible for 90% of
glucose reabsorption
• Mutation in SGLT2 transporter linked to hereditary renal
glycosuria, a relatively benign condition in humans
• Selective SGLT2 inhibitors have a novel & unique mechanism of
action reducing blood glucose levels by increasing renal
excretion of glucose
• Decreased glycemia will decrease glucose toxicity leading to
further improvements in glucose control
• Selective SGLT2 inhibition, would also cause urine loss of the
calories from glucose, potentially leading to weight loss
Brooks AM, Thacker SM. Ann Pharmacother. 2009;42(7):1286-1293.
Effects of SGLT2 Inhibitors
Inhibition of renal tubular Na+- glucose cotransporter
reversal of hyperglycemia
reversal of “glucotoxicity”
Insulin sensitivity in muscle
GLUT4 translocation
Insulin signaling
Insulin sensitivity in liver
Glucose-6-phosphatase
Gluconeogenesis
Decreased Cori Cycle
PEP carboxykinase
Improved beta cell function
DeFronzo RA, et al. Diabetes Obes Metab. 2012;14(1):5-14.
SGLT2 Inhibitors in
Phase 3 Development
• Empagliflozin
• Canagliflozin
• Dapagliflozin
• Ipragliflozin
Empagliflozin: Change in A1C
Randomized, double-blind, 12 week trial comparing
empagliflozin and open-label metformin
*
*
*
*P˂.001 vs. placebo
†500 mg BID for four weeks, then 1000 mg BID or the maximum tolerate dose
Ferrannini E, et al. Abstract 877. EASD 2010.
Empagliflozin: Change in Plasma
Glucose in the Fasting State
Randomized, double-blind, 12 week trial comparing
empagliflozin and open-label metformin
*
*
*
*P˂.001 vs. placebo
†500 mg BID for four weeks, then 1000 mg BID or the maximum tolerate dose
Ferrannini E, et al. Abstract 877. EASD 2010.
Empagliflozin Safety Summary
• In Phase 2b study
- Reported adverse events were comparable among
treatment groups
- Most frequently reported AEs
• Frequent urination, thirst, and nasopharyngitis
- Urinary tract infection frequency was low (1.2%) and
comparable to placebo (1.2%) and metformin (1.2%)
- Incidence of genital infection was low: mycosis (0.8%)
and pruritis (1.2%) with Empagliflozin versus none with
metformin or placebo
- Rates of hypoglycemia were similar between groups
Ferrannini E, et al. Abstract 877. EASD 2010.
Canagliflozin
Metformin + Canagliflozin Dose-Ranging Study
Mean Baseline
A1C (%)
7.71
8.01 7.81 7.57 7.70 7.71 7.62
*
*
*
*
*
Rosenstock J, et al. Abstract 77-OR. ADA 2010.
*
*P˂.001 vs. placebo calculated using LS means
Canagliflozin
SGLT2 Inhibition for Type 2 Diabetes:
Metformin + Canagliflozin Dose-Ranging Study
Mean Baseline
Weight (kg)
85.5 87.5 87.7 87.7 87.8 86.3 87
*
*
*
*
*
*
Rosenstock J, et al. Abstract 77-OR. ADA 2010.
*
*P˂.001 vs. placebo calculated using LS means
Canagliflozin Trials
• Symptomatic genital infections in 3-8% canagliflozin
arms
– 2% placebo
– 2% SITA
• Urinary tract infections in 3-9% canagliflozin arms
– 6% placebo
– 2% SITA
• Hypoglycemia in 0-6% canagliflozin arms
– 2% placebo
– 5% SITA
Rosenstock J, et al. Abstract 77-OR. ADA 2010.
Changes from Baseline in A1C
in Phase 3 Dapagliflozin Studies
Placebo
Dapa 2.5mg
Dapa 5mg
Dapa 10mg
Wilding JPH, et al. Abstract 78-OR. ADA 2010; Strojek K, et al. Abstract 870. EASD 2010;
Ferrannini E, et al. Diabetes Care. 2010;33(10):2217-2224; Bailey CJ, et al. Lancet. 2010;375(9733):2223-2233.
Changes from Baseline in Fasting Plasma
Glucose in Phase 3 Dapagliflozin Studies
5
0
-5 mg/dL
-10
-15
-20
-25
-30
Wilding JPH, et al. Abstract 78-OR. ADA 2010; Strojek K, et al. Abstract 870. EASD 2010;
Ferrannini E, et al. Diabetes Care. 2010;33(10):2217-2224; Bailey CJ, et al. Lancet. 2010;375(9733):2223-2233.
Changes from Baseline in Body Weight
in Phase 3 Dapagliflozin Studies
Placebo
Dapa 2.5mg
Dapa 5mg
Dapa 10mg
Wilding JPH, et al. Abstract 78-OR. ADA 2010; Strojek K, et al. Abstract 870. EASD 2010;
Ferrannini E, et al. Diabetes Care. 2010;33(10):2217-2224; Bailey CJ, et al. Lancet. 2010;375(9733):2223-2233.
Monotherapy Study:
Summary and Conclusion
• In treatment-naïve patient with newly-diagnosed Type 2 DM,
dapagliflozin monotherapy resulted in
- Clinically meaningful decreased in A1C and fasting plasma
glucose with a near absence of hypoglycemia
- Favorable effects on weight and blood pressure
• In the exploratory evening dose cohort, changes from baseline in
A1C, fasting plasma glucose, and body weight at week 24 were
similar to those seen in the main patient cohort
• In the high A1C (QAM) exploratory cohort, dapagliflozin elicited a
considerable improvement in glycemia
Ferrannini E, et al. Diabetes Care. 2010;33(10):2217-2224.
Monotherapy Study: Summary and
Conclusion
• Increased incidence of urinary tract and genital infections with
dapagliflozin treatment:
• Events suggestive of urinary tract infection were 4%, 4.6%, 12.5%, and
5.7% for placebo, DAPA 2.5mg, 5mg, and 10mg groups, respectively
• Events suggestive of genital infections were 1.3%, 7.7%, 7.8%, and
12.9% for placebo, DAPA 2.5mg, 5mg, and 10mg groups, respectively
• Hypoglycemic events occurred in 2.7%, 1.5%, 0%, and 2.9% in patients in
placebo, DAPA 2.5mg, 5mg, and 10mg groups, respectively
Ferrannini E, et al. Diabetes Care. 2010;33(10):2217-2224.
Dapagliflozin as Add-on Therapy:
Summary and Conclusions
Add-on to metformin in patients inadequately controlled
with metformin alone
-
Favorable safety parameters and tolerability
Improved glycemic control
Lowers weight
Not associated with risk for hypoglycemia
Adverse events occurred in similar proportions
- Events suggestive of urinary tract infection were 8%, 4%, 7%, and 8%
for placebo, DAPA 2.5mg, 5mg, and 10mg groups, respectively
- Events suggestive of genital infection were 5%, 8%, 13%, and 9% for
placebo, DAPA 2.5mg, 5mg, and 10 mg groups respectively
- Hypoglycemic events occurred in 3%, 2%, 4%, and 4% of patients in
placebo, DAPA 2.5mg, 5mg, and 10 mg groups respectively
Bailey CJ, et al. Lancet. 2010;375(9733):2223-2233.
Dapagliflozin as Add-on Therapy:
Summary and Conclusions
Add-on to glimepiride in patients poorly controlled sulfonylurea
therapy
-
Significantly improved mean A1C
Reduced weight
Well-tolerated
Adverse events were similar across all treatment groups
- Events suggestive of urinary tract infection were 6.2%, 3.9%, 6.9%,
and 5.3% for placebo, DAPA 2.5mg, 5mg, and 10mg groups,
respectively
- Events suggestive of genital infection were 0.7%, 3.9%, 6.2%, and
6.6% for placebo, DAPA 2.5mg, 5mg, and 10 mg groups respectively
- Hypoglycemic events occurred in 4.8%, 7.1%, 6.9%, and 7.9% in
patients for placebo, DAPA 2.5mg, 5mg, and 10 mg groups
respectively
Strojek K, et al. Abstract 870. EASD 2010
Dapagliflozin as Add-on Therapy:
Summary and Conclusions
Add-on to insulin in patients poorly controlled with insulin
- Sustained effectiveness and stable tolerability
- Less likely to D.C or require insulin up-titration due to poor
glycemic control versus placebo
- Increased frequency of weight loss and reduced frequency of
peripheral edema over time
- Adverse events and discontinuations were balanced across
groups
- Actively solicited signs and symptoms suggestive of urinary
tract (UTI) and genital infections (GI) were higher with
dapagliflozin vs. placebo
-
Events suggestive of urinary tract infection occurred in 8.4%
DAPA vs 4.1% placebo
Events suggestive of genital infection occurred in 7.2% DAPA vs
2.0% placebo
Wilding JPH, et al. Abstract 78-OR. ADA 2010
Dapagliflozin* vs. Glipizide as Add-on
Therapy to Metformin: 2 Years
Treatment
Change in A1c
≥ 1 Hypoglycemic
Episode
Change in Total
Body Weight
Dapagliflozin +
Metformin
(n=315)
-0.32%
(-0.42, -0.21)
4.2%
-3.70 kg
(-4.16, -3.24)
Glipizide +
metformin
(n=309)
-0.14%
(-0.25, -0.03)
45.8%
+ 1.36
(0.88, 1.84)
Urinary tract infection: 13.5% for dapagliflozin; 9.1% for glipizide
Genital infection: 14.8% for dapagliflozin ; 2.9% for glipizide
Nauck MA, et al. Diabetes Care. 2011;34:2015-2022.
*The FDA has not approved this medication for use.
Dapagliflozin as Add-on to
Metformin: 2 Year Extension Study
Δ from BL (SE)
Placebo
DAPA 2.5mg
DAPA 5mg
DAPA 10mg
A1c, %
0.2 (0.11)
-0.48 (-.1)
-0.58 (0.1)
-0.78 (0.09)
FPG, mg/dl
-10.4 (3.6)
-19.3 (3.2)
-26.5 (2.8)
-24.5 (2.7)
Body weight, kg
-0.7 (0.5)
-2.2 (0.5)
-3.4 (0.4)
-2.8 (0.4)
3.6
5.1
5.2
% Pts with ≥ 1
5.8
hypoglycemic event
•
Events suggestive of urinary tract infection
– Dapagliflozin 2.5 mg: 8.0%, 5 mg: 8.8%, 10 mg: 13.3%
– Placebo: 8.0%
• Events suggestive of urinary tract infection
– Dapagliflozin 2.5 mg: 11.7%, 5 mg: 14.6%, 10 mg: 12.6%
– Placebo: 5.1%
•
Events primarily mild or moderate in intensity and responded to standard treatment
Bailey CJ et al. Abstract 988-P. ADA 2011.
Safety: Malignancies
• Bladder cancer incidence rate:
– 0.16% patients (n=5,478) treated with
dapagliflozin vs 0.03% patients (n-3,156) in
placebo group (p = 0.15)
• Breast cancer incidence rate:
– 0.4% patients (n=2,223) treated with dapagliflozin
vs 0.09% patients (n=1,053) in placebo group (p =
0.27)
Jones D. Nat Rev Drug Discov. 2011;10(9):645-646.
Ipragliflozin: Phase 2 Studies
Phase 2, Randomized, Placebo-controlled Study (28 days)
Treatment (n=61)
Change in A1c
FPG(mmol/L)
Ipragliflozin 50mg QD
(n=12)
-0.73% (p<0.003)
-3.35 (p<0.001)
Ipragliflozin 100mg QD
(n=12)
-0.61% (p<0.015)
-2.72 (p<0.004)
Ipragliflozin 200mg QD
(n=12)
-0.84% (p<0.001
-3.92 (p<0.001)
Ipragliflozin 300mg QD
(n=12)
-0.73% (p<0.003)
-3.61 (p<0.001)
Change in Total Body
Weight
Ipragliflozin (n=48)
-3.2 kg to -4.2kg
vs.
Placebo (n=12)
1.8kg
AE’s
Constipation, nausea,
xerosis, and headache
Ipragliflozin as add-on Therapy to Metformin
Phase 2, Double-blind, Placebo-controlled, Dose Finding Study (12 weeks)
Treatment (n=272)
Change in A1c
(95% CI)
FPG (mg/dL)
(95% CI)
Change in Total
Body Weight
Ipragliflozin 12.5mg
(n=69)
-0.53%
(-0.71; -0.36)
-8.5
(-16.1; -0.9)
-0.9 ± 2.3
Ipragliflozin 50mg (n=66)
-0.66%
(-0.84, -0.47)
-14.3
(-22.0; -6.6)
-2.1 ± 2.0
Ipragliflozin 150mg
(n=66)
-0.72%
(-0.90; -0.54)
-24.3
(-32.1; -16.5)
-2.1 ± 2.4
Ipragliflozin 300mg
(n=71)
-0.79%
(-0.97; -0.62)
-27.8
(35.3; -20.3)
-2.3 ± 2.5
AE’s
Urinary tract infections
and genital tract
infections in ipragliflozin
groups were no different
from placebo group.
Hypoglycemia was similar
between placebo and
treatment groups.
Schwartz S, et al. Safety, Pharmacokinetic, And Pharmacodynamic Profiles Of Ipragliflozin (ASP1941), A Novel And Selective Inhibitor Of Sodium-dependent Glucose
Co-transporter 2, In Patients With Type 2 Diabetes Mellitus. Diabetes Technology & Therapeutics. 2011; 13(12): 1219-1227. Wilding J, et al. Efficacy and safety of
ipragliflozin in type 2 diabetes patients inadequately controlled on metformin: a dose-finding study. Abst D-0741. IDF 2011.
BRIGHTEN Trial: Ipragliflozin
Phase 3, Double-blind, Placebo-controlled Study-16 weeks
(n=129)
– Ipragliflozin treatment group 50mg QD (n=62)
• Ipragliflozin achieved a mean decrease of 1.23% in A1c
compared with placebo (p<0.001)
• FPG was reduced by 45.8mg/dL compared with placebo
(p<0.001)
• Total body weight was reduced by 1.47kg compared with
placebo (p<0.001)
• Similar adverse events occurring in about half the patients in
both cohorts.
• 1 case if hypoglycemia and 2 cases of genital infections in
ipragliflozin group
Kashiwagi, A. et al. Ipragliflozin improved glycemic control with additional benefits of reductions of body weight and blood pressure in Japanese patients with
type 2 diabetes mellitus: BRIGHTEN Study. Abst 149. EASD 2011
Case Presentation 1
• 48-year-old African American man with 12 month
history of type 2 diabetes
• Hypertension for past 6 years treated with Lisinopril 10
mg daily;
– most recent blood pressure was 138/84 mm Hg
• Increased LDL-C treated with simvastatin 40 mg qd;
– most recent LDL-C 98 mg/dL
• Diabetes treated with metformin 1000 mg bid and
lifestyle intervention (increased physical activity, medical
nutritional therapy)
– Weight 240 pounds, height 6’ (BMI = 32.5)
• A1C = 7.5 %
Case Presentation 2
• 64-year-old Latina with 8 year history of type 2 diabetes
• Hypertension for past 6 years treated with Olmesartan
10 mg and HCTZ 12 mg daily
– most recent blood pressure was 142/86 mm Hg
• Increased LDL-C treated with simvastatin 40 mg qd;
– most recent LDL-C 98 mg/dL
• Diabetes treated with metformin XR 1500 mg QD;
insulin glargine 30 U QHS and lifestyle intervention
(increased physical activity, medical nutritional therapy)
– Weight 160 pounds, height 5’ 2” (BMI = 29.3)
• A1C = 7.5 %; FPG
Perspectives on SGLT2 Inhibition
• Potential advantages
– Insulin Independence
– Weight loss (75g urine
glucose = 300kcal/day)
– Low risk of hypoglycemia
– Blood pressure
lowering?
• Concerns
– Polyuria
– Electrolyte disturbances
– Bacterial urinary tract
infections
– Fungal genital infections
– Malignancies

similar documents