2011 U.S 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