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

with Type 2 Diabetes

Lawrence Blonde, MDDirector, Ochsner Diabetes Clinical Research Unit,

Department of Endocrinology, Diabetes, and Metabolic DiseasesOchsner 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

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

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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.

Currie CJ, et al. Lancet. 2010;6(375):481-9.

Survival as a Function of A1C in Patients Type 2 Diabetes: A Retrospective Cohort Study*

*28,000 patients 50 years and older

Oral Agents Insulin +/- Oral Agents

*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.

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.

Target Treatment

GoalsAACE/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 (< 70 mg/dL for patients with diabetes and coronary artery disease)

• HDL-C > 40 mg/dL in men;> 50 mg/dL in women

• Triglycerides <150 mg/dL

• LDL-C < 100 mg/dL (< 70 mg/dL for patients with diabetes and coronary artery disease)

• HDL-C > 40 mg/dL in men;> 50 mg/dL in women;

• Triglycerides < 150 mg/dL

ABCs of Type 2 Diabetes: AACE/ACE 2011 and ADA 2011

Handelsman Y, et al. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for Developing a Diabetes Mellitus Comprehensive Care Plan. Endocr Pract. 2011;17(Suppl 2):1-53.

Standards of Medical Care in Diabetes—2011. Diabetes Care. 34(Supplement 1): S11-S61.

*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.

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.

Target Treatment

GoalsAACE/ACE 2011 ADA 2011

A1C ≤ 6.5% < 7.0%

Fasting glucose

Fasting plasma glucose:

< 110 mg/dLPreprandial capillary plasma glucose: 70 – 130 mg/dL

Postprandial glucose

2-hr postprandial glucose:

< 140 mg/dLPeak postprandial capillary plasma glucose: < 180 mg/dL

Glycemic Control Recommendations for Type 2 Diabetes:

AACE/ACE 2011 and ADA 2011

Handelsman Y, et al. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for Developing a Diabetes Mellitus Comprehensive Care Plan. Endocr Pract. 2011;17(Suppl 2):1-53.

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 MedicationsMetformin DPP-4

InhibitorGLP-1

AgonistSulfonylurea Glinide TZD Colesevelam AGI Insulin Pramlintid

e

Benefits

PPG - lowering Mild Moderate Moderate to Marked

Moderate Moderate Mild Mild Moderate Moderate to Marked

Moderate to Marked

FPG - lowering Moderate Mild Mild Moderate Mild Moderate Mild Neutral Moderate to Marked

Mild

Nonalcoholic fatty liver disease (NAFLD)

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

Contra-indicted in CHF

Neutral Neutral Neutral Neutral Mild/ Moderate

Neutral Neutral NeutralUnless

with TZD

Neutral

Contra-indicted in class 1, 4

CHF

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 Interactions

Neutral Neutral Neutral Moderate Moderate Neutral Neutral Neutral Neutral NeutralAmerican 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

Bloomgarden, ZT. Diabtes Care. 2007;30(1):174-180.

Type 2 DM Control is Not Durable

3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48

Time (months)

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

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

The Kidneys Play an Important Role in Glucose Control

Mather, A & Pollock, C. Kidney International. 2011;79:S1-S6.

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

Low Km = 2 Mm

Capacity for glucose transport

Low High

Role Dietary glucose absorptionRenal glucose reabsorption

Renal glucose reabsorption

Lee YJ, at al. Kidney Int Suppl. 2007;72:S27-S35.

Chao EC, et al. Nat Rev Drug Discovery. 2010;9:551-559.

Targeting the Kidney

Chao, EC & Henry RR. Nature Reviews Drug Discovery. 2010;9:551-559.

Renal Glucose Transport

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 muscleGLUT4 translocationInsulin signaling

Insulin sensitivity in liverGlucose-6-phosphatase

GluconeogenesisDecreased Cori CyclePEP 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 A1CRandomized, 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

*P˂.001 vs. placebo calculated using LS meansRosenstock J, et al. Abstract 77-OR. ADA 2010.

Metformin + Canagliflozin Dose-Ranging Study

Mean Baseline A1C (%)

7.71 8.01 7.81 7.57 7.70 7.71 7.62

*

*

*

**

*

CanagliflozinSGLT2 Inhibition for Type 2 Diabetes:

Metformin + Canagliflozin Dose-Ranging Study

*P˂.001 vs. placebo calculated using LS meansRosenstock J, et al. Abstract 77-OR. ADA 2010.

Mean Baseline Weight (kg)

85.5 87.5 87.7 87.7 87.8 86.3 87

* *

*

*

*

*

*

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

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.

Placebo Dapa 2.5mg Dapa 5mg Dapa 10mg

Changes from Baseline in Fasting Plasma Glucose in Phase 3 Dapagliflozin Studies

-5

5

0

-10

-15

-20

-25

-30

mg/dL

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% placeboWilding JPH, et al. Abstract 78-OR. ADA 2010

Dapagliflozin* vs. Glipizide as Add-on Therapy to Metformin: 2 Years

Urinary tract infection: 13.5% for dapagliflozin; 9.1% for glipizideGenital infection: 14.8% for dapagliflozin ; 2.9% for glipizide

Nauck MA, et al. Diabetes Care. 2011;34:2015-2022.

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)

*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)

% Pts with ≥ 1 hypoglycemic event

5.8 3.6 5.1 5.2

Bailey CJ et al. Abstract 988-P. ADA 2011.

• 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

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 StudiesPhase 2, Randomized, Placebo-controlled Study (28 days)

Treatment (n=61) Change in A1c FPG(mmol/L) Change in Total Body Weight

AE’s

Ipragliflozin 50mg QD (n=12)

-0.73% (p<0.003) -3.35 (p<0.001)

Ipragliflozin (n=48)-3.2 kg to -4.2kg

vs.Placebo (n=12)

1.8kg

Constipation, nausea, xerosis, and headache

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)

Ipragliflozin as add-on Therapy to MetforminPhase 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 AE’s

Ipragliflozin 12.5mg (n=69)

-0.53% (-0.71; -0.36)

-8.5(-16.1; -0.9)

-0.9 ± 2.3Urinary tract infections

and genital tract infections in ipragliflozin groups were no different

from placebo group. Hypoglycemia was similar

between placebo and treatment groups.

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

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: IpragliflozinPhase 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

• Concerns– Polyuria– Electrolyte disturbances– Bacterial urinary tract

infections– Fungal genital infections– Malignancies

• Potential advantages– Insulin Independence– Weight loss (75g urine

glucose = 300kcal/day)– Low risk of hypoglycemia– Blood pressure

lowering?