2011 US Diabetes Statistics Diabetes affects 25.8 million people in the US (8.3% of the U.S....
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Transcript of 2011 US Diabetes Statistics Diabetes affects 25.8 million people in the US (8.3% of the U.S....
2011 US Diabetes Statistics
• Diabetes affects 25.8 million people in the US (8.3% of the U.S. population)– 18.8 million diagnosed, 7.0 million undiagnosed
• 10.9 million (26.9%) of those aged ≥65 have diabetes• 215,000 people <20• 79 million US adults >20 years estimated to have had
prediabetes in 2010• 7th leading cause of death in the U.S.
www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf
Percentage of U.S. Adults With Diagnosed Diabetes
1994 2000
No Data <4.5% 4.5-5.9% 6.0-7.4% 7.5-8.9% >9.0%
2009
www.cdc.gov/diabetes/statistics
Cost of Diabetes
• Total (direct and indirect) estimated diabetes costs in the US in 2007 = $174 billion– Medical expenses for people with diabetes are more than
two times higher than for people without diabetes
• A 50 year old with diabetes dies, on average, 6 years earlier than someone without diabetes
Emerging Risk Factors Collaboration. NEJM. 2011; www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf
Type 2 Diabetes Pathophysiology
1Bergenstal RM, et al. Endocrinology. 2001; 2DeFronzo RA. Diabetes. 1988; 3Poitout V, et al. Endocrinology. 2002.
Gluco-lipotoxicity
Production of glucosein the liver1,2
Acquired/genetic factors (obesity)1,2
FFA1-3
Type 2 DM1
Inherited/acquired factors
Glucose uptake1,2
Insulin deficiency, inappropriate glucagon
secretion1,3
Insulin resistance1
Hyperglycemia1-3
FFA=free fatty acid
Decreased Incretin Effect
Current Therapeutic Targets
Dopamine AnalogsPramlintide
BRAIN PANCREAS
InsulinGLP-1 Agonists
DPP-4 InhibitorsSulfonylureas
Pramlintide (α cells only)Meglitinides
LIVER
MetforminThiazolidinediones (TZD)
GI TRACT
GLP-1 AgonistsAlpha Glucosidase
Inhibitors
MUSCLE/FAT
MetforminThiazolidinediones
(TZD)
?? KIDNEY ??
Updated ADA/EASD Consensus Algorithm
Nathan DM, et al. Diabetes Care. 2009.
At Diagnosis:Lifestyle
+Metformin Lifestyle + Metformin
+Sulfonylurea
Lifestyle + Metformin+
Basal Insulin
Lifestyle + Metformin +
Intensive Insulin
Lifestyle + Metformin+
Pioglitazone
No hypoglycemia, edema/CHF, bone loss
Lifestyle + Metformin+
GLP-1 agonist
No hypoglycemia, weight loss,
nausea/vomiting
Lifestyle + Metformin+
Basal Insulin
Lifestyle + Metformin+
Pioglitazone+
Sulfonylurea
STEP 1 STEP 2 STEP 3
Tier 2: Less well-validated therapies
Tier 1: Well-validated therapies
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.
Risks of Current Therapies: Weight Gain
Met-formin
DPP-4 Inhib-
itorGLP-1
Agonist SU Glinide TZD AGI Insulin Pram-lintide
Weight Gain
Met-formin
DPP-4 Inhib-
itorGLP-1
Agonist SU Glinide TZD AGI Insulin Pram-lintide
Hypoglycemia
NeutralBenefitsCauses
The Kidneys Play an Important Role in the Handling of Glucose
Wright EM, et al. J Intern Med. 2007.
• Total glucose stored in body ~450 g• Glucose utilization ~250 g/day
• Brain ~125 g/day
• Rest of body ~125 g/day
• Glucose in Western diet ~180 g/day• Renal glucose production (gluconeogenesis + ~70 g/day
glycogenolysis)• Renal glucose filtration and reabsorption ~180 g/day• Urinary glucose 0 g
Sodium-Glucose Cotransporters
SGLT1 SGLT2
Site Mostly intestine with some kidney Almost exclusively kidney
Sugar specificity Glucose or galactose Glucose
Affinity for glucose HighKm = 0.4 Mm
LowKm = 2 Mm
Capacity for glucose transport Low High
Role Dietary glucose absorptionRenal glucose reabsorption Renal glucose reabsorption
Lee YJ, et al. Kidney Int Suppl. 2007.
Altered Renal Glucose Control in Diabetes
• Renal gluconeogenesis is increased in patients with Type 2 DM• Renal contribution to hyperglycemia• 3-fold increase relative to patients without
diabetes
• Glucose reabsorption• Increased SGLT2 expression and activity in renal
epithelial cells from patients with diabetes vs. normoglycemic individuals
Marsenic O. Am J Kidney Dis. 2009; Bakris GL, et al. Kidney Int. 2009; Rahmoune H, et al. Diabetes. 2005.
Rationale for SGLT2 Inhibitors
• The SGLT2 is a glucose transporter responsible for 90% of glucose reabsorption
• Selective SGLT2 inhibitors could reduce blood glucose levels due to increased renal excretion of glucose
• Mutations in the SGLT2 transporter linked to hereditary renal glycosuria, a relatively benign condition in humans
• Selective SGLT2 inhibition would cause urine loss of the calories from glucose (200-300 kcal/day), also potentially leading to weight loss
Brooks AM, Thacker SM. Ann Pharmacother. 2009; Nair S, et al. J Clin Endocrinol Metab. 2010.
Effects of SGLT2 InhibitorsInhibition of renal tubular Na+-glucose cotransporter
Reversal of hyperglycemia
Reduction of “glucotoxicity”
Insulin sensitivity in muscle and liverGluconeogenesis
Improved beta cell function
Brooks AM, Thacker SM. Ann Pharmacother. 2009; Nair S, et al. J Clin Endocrinol Metab. 2010.
SGLT2 Inhibitors in Phase 3 Development
• Dapagliflozin
• Canagliflozin
• Empagliflozin
• Ipragliflozin
• Tofogliflozin
Empagliflozin: Change in A1C
N = 408Baseline A1C = 7.9%*P<.001 vs. placebo†500 mg BID for four weeks, then 1000 mg BID or the maximum tolerated dose
-0.8-0.7-0.6-0.5-0.4-0.3-0.2-0.1
00.10.2
*
**
*
5 mg 25 mg10 mg Metformin
Placebo
Chan
ge in
A1C
(%)
Ferrannini E, et al. Abstract 877. EASD 2010.
Randomized, double-blind, 12 week trial comparing empagliflozin and open-label metformin†
Empagliflozin: Change in FPG
N = 408*P<.001 vs. placebo†500 mg BID for four weeks, then 1000 mg BID or the maximum tolerated dose
Ferrannini E, et al. Abstract 877. EASD 2010.
-35
-30
-25
-20
-15
-10
-5
0
5
****
Placebo
5 mg 10 mg 25 mg Metformin
Chan
ge in
FPG
(mg/
dl)
Randomized, double-blind, 12 week trial comparing empagliflozin and open-label metformin†
Empagliflozin: Change in Weight
*
N = 408Baseline BMI = 29 kg/m2
*P<.001 vs. placebo†500 mg BID for four weeks, then 1000 mg BID or the maximum tolerated dose
Ferrannini E, et al. Abstract 877. EASD 2010.
-2.5
-2
-1.5
-1
-0.5
0
**
*
Placebo 5 mg 10 mg 25 mg Metformin
Chan
ge in
wei
ght (
%)
Randomized, double-blind, 12 week trial comparing empagliflozin and open-label metformin†
Empagliflozin: Safety Considerations
Side effects:– Polyuria (3.3% vs. 0% in placebo), thirst (3.3% vs. 0% in
placebo), and nasopharyngitis (2% vs. 1.2% in placebo) were the most frequently reported side effects
– UTI 1.2% vs. 1.2% in placebo and 1.3% in metformin
Ferrannini E, et al. Abstract 877. EASD 2010.
Randomized, double-blind, 12 week trial comparing empagliflozin and open-label metformin†
Canagliflozin: Change in A1C
*P<.001 vs. placebo calculated using LS means Rosenstock J, et al. Abstract 77-OR. ADA 2010. N = 451
-1
-0.8
-0.6
-0.4
-0.2
0
-0.22%
-0.79% -0.760000000
000004%
-0.700000000
000001% -0.92% -0.950000000
000001%
-0.740000000
000003
PBO 50 mg 100 mg 200 mg 300 mg 300 mg BID SITA 100 mg
Chan
ge in
A1C
(%)
***
*
Mean Baseline A1C (%) 7.71 8.01 7.81 7.57 7.70 7.71 7.62
*
*
Canagliflozin add-on to metformin, double-blind, placebo-controlled, dose-ranging study (Phase 2)
Canagliflozin: Change in FPGCh
ange
in F
PG (m
g/dl
)
Rosenstock J, et al. Abstract 77-OR. ADA 2010.
N = 451Baseline FGP 162 mg/dl)*P<.001 vs. placebo calculated using LS means
-35
-30
-25
-20
-15
-10
-5
0
-16.2
-25.2
-32.4 -32.4-30.6
-18
50 mg 100 mg 200 mg 300 mg 300 mg BID SITA 100 mg
*
*
* * *
*
Canagliflozin add-on to metformin, double-blind, placebo-controlled, dose-ranging study (Phase 2)
Canagliflozin: Change in Weight
N = 451Baseline weight 87 kg*P<.01 vs. placebo calculated using LS means Rosenstock J, et al. Abstract 77-OR. ADA 2010.
-4
-3
-2
-1
0
-1.1
-2.3%-2.6% -2.7%
-3.4% -3.4%
-0.600000000
000001%
PBO 50 mg 100 mg 200 mg300 mg 300 mg BID SITA 100 mg
Chan
ge in
wei
ght (
%)
Mean Baseline Weight (kg) 85.5 87.5 87.7 87.7 87.8 86.3 87
** *
* *
Canagliflozin add-on to metformin, double-blind, placebo-controlled, dose-ranging study (Phase 2)
Canagliflozin: Safety Considerations
Side effects:– Mild-to-moderate, transient– Non dose-dependent increase in symptomatic genital
infections: 3-8% in canagliflozin vs. 2% in placebo and 2% in sitagliptin
– UTI: 3-9% in canagliflozin (no dose-dependency) vs. 6% in placebo and 2% in sitagliptin
– Hypoglycemia: 0-6% in canagliflozin (no dose dependency) vs. 2% in placebo and 5% in sitagliptin
Rosenstock J, et al. Abstract 77-OR. ADA 2010.
Canagliflozin add-on to metformin, double-blind, placebo-controlled, dose-ranging study (Phase 2)
Effects of Canagliflozin on Vulvovaginal Candida Colonization (VCC)
– Relative to PBO/SITA, CANA treatment increased conversion to positive vaginal Candida culture and VVC events
– Incidence of VVC in female subjects was 2.9% and 3.7% with PBO and SITA, respectively, and 10.4% with CANA
– None of the VVC events were serious or led to discontinuation; most were treated with topical or oral antifungals, and resolved without study drug interruption
Nyirjesy P, et al. Abstract 0032-LB. ADA 2011.
Bacteria or UTI Incidence with Canagliflozin
– At Week 12, CANA decreased A1C (0.45%-0.73% relative to PBO), lowered weight (1.3%-2.3% relative to PBO), and increased urinary glucose excretion (UGE) (35.4-61.6 mg/mg creatinine)
– Conversion from negative baseline urine bacterial culture to positive culture did not differ in pooled CANA group vs pooled PBO/SITA group (4.8% vs. 3.7%, respectively)
– UTI AEs (both symptomatic and positive post-baseline urine culture reported as a UTI) occurred in 16 (5.0%) in pooled CANA group and 5 (3.8%) in pooled PBO/SITA group
– All UTI AEs considered mild or moderate, and none led to discontinuation
Nicolle L, et al. Abstract 0043-LB. ADA 2011.
Dapagliflozin Phase 3 Studies: Change in A1C
-1
-0.9
-0.8
-0.7
-0.6
-0.5
-0.4
-0.3
-0.2
-0.1
0
Monotherapy
Met add-on
SU add-on
Insulin add-on
Chan
ge in
A1C
(%
)
PlaceboDapa 2.5mg
Dapa 5mg
Dapa 10mg
Wilding JPH, et al. Abstract 871. EASD 2010; Strojek K, et al. Abstract 870. EASD 2010;
Ferrannini E, et al. Diabetes Care. 2010; Bailey CJ, et al. Lancet. 2010.
Baseline-Monotherapy (N=591): 8.6%Met add-on (N=546): 8%SU add-on (N=597): 8.1%Insulin add-on (N=808): 8.5%
Chan
ge in
FPG
(mg/
dl)
Placebo Dapa 2.5mg
Dapa 5mg
Dapa 10mg
Baseline-Monotherapy (N=591): 179 mg/dlMet add-on (N=546): 163.9 mg/dlInsulin add-on (N=808): 178 mg/dl
Wilding JPH, et al. Abstract 871. EASD 2010; Ferrannini E, et al. Diabetes Care. 2010; Bailey CJ, et al. Lancet. 2010.
Dapagliflozin Phase 3 Studies: Change in FPG
Series1
-35
-30
-25
-20
-15
-10
-5
0
5
10
MonotherapyMet add-onInsulin add-on
-3.5
-3
-2.5
-2
-1.5
-1
-0.5
0
0.5
Monotherapy
Met add-on
SU add-on
Insulin add-on
Chan
ge in
wei
ght
(kg)
Placebo Dapa 2.5mg
Dapa 5mg
Dapa 10mg
Baseline-Monotherapy (N=591): 89.7 kgMet add-on (N=546): 85.9 kgSU add-on (N=597): 81.1 kgInsulin add-on (N=808): 94 kg
Wilding JPH, et al. Abstract 871. EASD 2010; Strojek K, et al. Abstract 870. EASD 2010;
Ferrannini E, et al. Diabetes Care. 2010; Bailey CJ, et al. Lancet. 2010.
Dapagliflozin Phase 3 Studies: Change in Weight
Dapagliflozin, Metformin XR, or Both as Initial Therapy
-2.5
-2
-1.5
-1
-0.5
0
-70-60-50-40-30-20-10
0
-3.5-3
-2.5-2
-1.5-1
-0.50
MET
DAPA
5mg
DAPA
+
MET
DAPA +
MET
DAPA
10mg
MET
MET
DAPA
5mg
DAPA
+
MET
DAPA +
MET
DAPA
10mg
MET
MET
DAPA
5mg
DAPA
+
MET
DAPA
+
MET
DAPA
10mg
MET
Change in A1C Change in FPG
Change in Body WeightHenry R, et al. Abstract 307-OR.
ADA 2011.
Dapagliflozin: Effect on BP and Lipids
HDL (% change)– Placebo: +0.4– Dapa 2.5mg: +1.8– Dapa 5mg: +3.3– Dapa 10mg: +4.4
Triglycerides (% change)– Placebo: +2.1– Dapa 2.5mg: -2.4– Dapa 5mg: -6.2– Dapa 10mg: -6.2
Systolic Blood Pressure (mmHg)– Placebo: -0.2– Dapa 2.5mg: -2.1– Dapa 5mg: -4.3– Dapa 10mg: -5.1
Diastolic Blood Pressure (mmHg)– Placebo: -0.1– Dapa 2.5mg: -1.8– Dapa 5mg: -2.5– Dapa 10mg: -1.8
Bailey CJ, et al. Lancet. 2010.
Dapagliflozin: Safety Considerations
Based on all trials (Monotherapy, metformin add-on, sulfonylurea add-on, and insulin add-on)
Side effects:– UTI*: 3.9-13.2% in dapagliflozin vs. 4-6.2% in placebo1-3
– Genital infections*: 3.9-12.9% in dapagliflozin vs. 0.7-5% in placebo1-4
– Hypoglycemia: 0-7.9% in dapagliflozin vs. 2.7-4.8% in placebo2-4
*Most occurred during the first 24 weeks, were generally mild, and responded to routine management 1Wilding JPH, et al. Abstract 871. EASD 2010;
2Strojek K, et al. Abstract 870. EASD 2010; 3Ferrannini E, et al. Diabetes Care. 2010; 4Bailey CJ, et al. Lancet. 2010.
Dapagliflozin:Sulfonylurea Comparator Study
Results• Average A1C: 7.72%• Change in A1C: -0.52% for dapagliflozin vs. -0.52% for glipizide• Weight change: -3.2 kg for dapagliflozin vs. +1.4 kg for glipizide
• Hypoglycemic episodes: 3.5% for dapagliflozin vs. 40.8% with glipizide
• Significant reductions in diastolic and systolic blood pressure and improvement in HDL with dapagliflozin vs. glipizide (P<.0001)
• Side effects:• UTI: 10.8% with dapagliflozin vs. 6.4% with glipizide (actively solicited)
• Genital infection: 12.3% with dapagliflozin vs. 2.7% with glipizide (actively solicited)
• Renal impairment: 5.9% with dapagliflozin vs. 3.4% with glipizide
Nauck MA, et al. Diabetes Care. 2011.
Randomized, double-blind, parallel-group, multicenter trial comparing dapagliflozin to glipizide as add-on to metformin
Dapagliflozin + Insulin for 48 Weeks
Wilding J, et al. Abstract 0021-LB. ADA 2011.
• A1C reductions from baseline for PLA and DAPA 2.5, 5, and 10mg at 24 weeks were maintained at 48 weeks– (−0.43%, −0.74%, −0.94%, −0.93%, respectively)
• 24 week body weight reductions with DAPA were maintained at 48 weeks – −1.5kg with DAPA 10mg vs. +0.9kg with PLA
• AEs, serious AEs, and discontinuations were balanced across all groups
• Actively solicited s/sx suggestive of UTI and genital infections (GI) were more with DAPA vs PLA – UTI 7.9%-10.8% vs. 5.1%; GI 6.4%-10.7% vs. 2.5%– most events were reported during the first 24 weeks, were of
mild/moderate intensity and responded to standard treatmentAE = Adverse eventss/sx = signs and symptoms
Dapagliflozin + Insulin for 48 Weeks:Insulin Dose
Wilding J, et al. Abstract 0021-LB. ADA 2011.
15
10
5
0
-50 4 8 12 16 20 24 28 32 36 40 44 48
Timepoint (weeks)
PLA + INSDAPA 2.5 mg + INSDAPA 5 mg + INSDAPA 10 mg + INS
Insu
lin d
ose
(IU/d
ay)
Adju
sted
mea
n ch
ange
from
bas
elin
e ±
SE
Long-Term Efficacy of Dapagliflozin + Metformin
Week 102 Results
Adj. Mean ∆ From Baseline PBO+MET DAPA 2.5mg +
METDAPA 5mg +
METDAPA 10mg +
MET
A1C, % 0.02 -0.48 -0.58 -0.78
FPG, mg/dL -10.4 -19.3 -26.5 -24.5
Weight, kg -0.7 -2.2 -3.4 -2.8
% with ≥1 hypoglycemic
event5.8 3.6 5.1 5.2
Bailey CJ, et al. Abstract 0988-P. ADA 2011.
Potential SGLT2 Safety Considerations???• Evidence Demonstrates
• Urinary tract/genital infections
• Questions• Hepatic toxicity?• Breast and bladder cancer??• Intravascular volume depletion due to osmotic diuresis??• Nephrotoxicity (AGEs)??• Drug-drug interactions??
• Evidence Does Not Demonstrate• Electrolyte imbalance (Na+, K+, Ca++, PO4)• Increased risk for hypoglycemia• Nocturia
Dapagliflozin PDUFA Date
The FDA issued a Complete Response Letter to the makers of dapagliflozin on January 19, 2012 requesting additional information.
SGLT2 Inhibitors: A New Era in Diabetes Treatment??
• In treatment-naive patients with newly-diagnosed Type 2 DM, SGLT2 inhibitors resulted in:
• Clinically meaningful decreases in A1C and fasting plasma glucose with no increased risk of hypoglycemia
• Also improved glycemic control in combination with a variety of other antihyperglycemic agents
• Metformin, sulfonylureas, insulin
• Side effects generally appear to be mild and transient, while avoiding increased risk of hypoglycemia or weight gain