Improving Outcomes with SGLT2 Cotransporter Inhibitors in Challenging T2DM Patients Part 3 of 4

LX4211, a Dual Inhibitor, SGLT1 and SGLT2, Reduces Blood Pressure in Patients with T2DM Lapuerta P, et al. Presented at the 49th EASD Annual Meeting; Sept 2013; Barcelona, Spain. Abstract 948. LX4211, a dual inhibitor, SGLT1 and SGLT2 (N=299) SBP reductions were 0, 4, 4, 6, and 0 mm Hg with LX mg qd, 200 mg qd, 200 mg bid, 400 mg qd, and placebo, respectively (P<0.05 vs. placebo for LX mg bid and 400 mg qd). DBP reductions were 1, 3, 2, 2, and 0 mm Hg (P=NS vs. placebo for all dose arms). In those with baseline SBP ≥130 mm Hg, placebo-subtracted SBP reductions for LX mg were 14 mm Hg (P=0.002) as compared with 1 mm Hg (P=0.6) for those with baseline SBP <130 mm Hg. Placebo-subtracted DBP reductions for LX mg were 3 mm Hg (P=0.2) and 0 mm Hg (P=0.9) in those with baseline DBP ≥80 mm Hg and DBP <80 mm Hg, respectively.

Empagliflozin Cardiovascular Outcome Event Trial Abbreviations: CAD=coronary artery disease, revasc.=revascularization. *CAD defined as ≥50% luminal narrowing detected on invasive coronary angioplasty or multisliced computed tomography angiography. Inzucchi S, et al. Presented at the 49th EASD Annual Meeting; Sept 2013; Barcelona, Spain. Abstract 944. Ongoing multicenter, randomized, double-blind, placebo-controlled trial designed to assess the impact of the empagliflozin 10 or 25 mg, compared with placebo (1:1:1), on cardiovascular events; 7,000 patients Glycemic entry criterion (A1C): Drug-naive patients: 7.0% – 9.0% Stable pharmacologic therapy: 7.0% – 10.0% CV entry criteria – any of the following: History of myocardial infarction (>2 months prior to enrollment) Evidence of CAD* in ≥2 major vessels or left main coronary artery Evidence of single-vessel CAD* with no scheduled revasc./previously unsuccessful revasc. and a)positive noninvasive, functional stress test for ischemia (ECG, echo or nuclear) or b)hospital discharge due to unstable angina pectoris ≤12 months before enrollment Hospital discharge due to unstable angina pectoris > 2 months before enrollment with evidence of CAD* according to any of the following: a)left main coronary artery b)≥2 major vessels c)single vessel with positive noninvasive, functional stress test for ischemia (ECG, echo or nuclear) and no scheduled revasc. /previously unsuccessful revasc. History of stroke (>2 months prior to enrollment) Peripheral occlusive arterial disease according to any of the following: a)Previous limb angioplasty, stenting or bypass surgery b)Previous limb or foot amputation due to circulatory insufficiency c)Significant peripheral artery stenosis (>50%) in at least 1 limb (angiography or noninvasive) d)ankle brachial index <0.9 in at least 1 limb

Summary: Investigational SGLT2 Inhibitors Multiple new SGLT2 inhibitors are in development with apparent comparable efficacy Safety issues with each new agent need to be monitored Combining SGLT2 inhibition with a tolerable degree of SGLT1 inhibition may lead to more efficacious therapy

Safety of SGLT2 Inhibitors in Patients with T2DM: Updates from EASD Vivian Fonseca, MD Professor of Medicine and Pharmacology Tullis Tulane Alumni Chair in Diabetes Chief, Section of Endocrinology Tulane University Health Sciences Center New Orleans, LA

Genital Mycotic Infections

Genital Mycotic Infections with Canagliflozin Pooled analyses of data from 4 randomized, double-blind, 26-week, placebo-controlled studies in subjects with type 2 diabetes mellitus (N=2,313) † Including genital fungal infection, vaginal infection, vulvitis, vulvovaginal candidiasis, vulvovaginal mycotic infection and vulvovaginitis ‡ Possibly, probably, or very likely related to study drug, as assessed by investigators § Including balanitis, balanitis candida, balanoposthitis, and genital fungal infection Ways K, et al. Presented at the 49th EASD Annual Meeting. Barcelona, Spain. September 23 – 27, Abstract 950. Female genital mycotic infection adverse events, n=1,167 † Subjects, n (%)Placebo (n=312) Canagliflozin 100 mg (n=425) Canagliflozin 300 mg (n=430) Canagliflozin All (n=855) Any adverse event10 (3.2)44 (10.4)49 (11.4)93 (10.9) Adverse events leading to discontinuation04 (0.9)2 (0.5)6 (0.7) Adverse events relating to study drug ‡ 8 (2.6)33 (7.8)43 (10.5)78 (9.1) Serious Adverse events0000 Male genital mycotic infection adverse events. n=1,146 § Subjects, n (%)Placebo (n=334) Canagliflozin 100 mg (n=408) Canagliflozin 300 mg (n=404) Canagliflozin All (n=812) Any adverse event2 (0.6)17 (4.2)15 (3.7)32 (3.9) Adverse events leading to discontinuation02 (0.5) 4 (0.5) Adverse events related to study drug ‡ 2 (0.6)12 (2.9)12 (3.0)24 (3.0) Serious Adverse events0000

Osmotic Diuresis and Reduced Intravascular Volume

Adverse Events Related to Osmotic Diuresis and Reduced Intravascular Volume with Canagliflozin Pooled analyses of data from 4 randomized, double-blind, 26-week, placebo-controlled studies in subjects with type 2 diabetes mellitus at week 26 (N=2,313) Weir M, et al. Presented at the 49th EASD Annual Meeting. Barcelona, Spain. September 23 – 27, Abstract 945. Adverse events were generally mild or moderate in severity and led to few discontinuations. SubjectsCanagliflozin 100 mg Canagliflozin 300 mg Placebo Adverse events related to osmotic diuresis6.7%5.6%0.8% Pollakiuria (abnormally frequent urination)4.2%3.1%0.6% Thirst1.3%1.9%0.2% Polyuria0.7%1.4%0% Reduced intravascular volume1.2%1.3%1.1% Hypotension0.7%0.2%0.6% Postural dizziness0.4%0.5%0.3% Orthostatic hypotension0%0.5%0.2%

Safety of SGLT2 Inhibitors in Older Patients

SafetyofCanagliflozin in Older Adults with T2DM Sinclair A, et al. Presented at the 49th EASD Annual Meeting. Barcelona, Spain. September 23 – 27, Abstract 955. Pooled from 4 randomized, placebo- controlled, 26-week studies (N=2,313) Patients ages <65 yearsPatients ages ≥ 65 years Selected adverse events, n (%)Placebo (n=509) Canagliflozin 100 mg (n=674) Canagliflozin 300 mg (n=685) Placebo (n=137) Canagliflozin 100 mg (n=159) Canagliflozin 300 mg (n=149) Genital mycotic infection2 (0.8)14 (4.3)11 (3.4)03 (3.7)4 (5.2) Male Female10 (4.1)37 (10.7)44 (12.3)07 (9.0)5 (6.9) Urinary tract infection20 (3.9)41 (6.1)29 (4.2)6 (4.4)8 (5.0)7 (4.7) Osmotic diuresis-related adverse events 4 (0.8)44 (6.5)39 (5.7)1 (0.7)12 (7.5)8 (5.4) Volume-related adverse events5 (1.0)6 (0.9)8 (1.2)2 (1.5)4 (2.5)3 (2.0) Renal-related adverse events2 (0.4)2 (0.3)12 (1.8)2 (1.5)3 (1.9)2 (1.3)

SafetyofDapagliflozin inOlder Patients with T2DM Fioretto P, et al. Presented at the 49th EASD Annual Meeting. Barcelona, Spain. September 23 – 27, Abstract 954. Safety variables were analyzed using pooled data from 12 phase 2b/3 studies of dapagliflozin (N=4,684; placebo=1,393; dapagliflozin=3,291), including studies as monotherapy or in combination with metformin, pioglitazone, sulfonylurea or insulin. Patients ages <65 yearsPatients ages ≥ 65 years n (%)Placebo (n=1,117)Dapagliflozin 10 mg (n=989) Placebo (n=276)Dapagliflozin 10 mg (n=204) All adverse events638 (57.1)611 (61.8)154 (55.8)123 (60.3) Hypoglycemia72 (6.4)95 (9.6)26 (9.4)27 (13.2) Urinary tract infection45 (4.0)41 (4.1)7 (2.5)10 (4.9) Genital infection10 (0.9)50 (5.1)2 (0.7)7 (3.4) Hypotension/hypovolemia/dehydration (volume depletion) 4 (0.4)6 (0.6)1 (0.4)2 (1.0) Renal impairment or failure9 (0.8)6 (0.6)3 (1.1)5 (2.5)

Long-term Safety

52 Week Data: Canagliflozin in Patients with T2DM Inadequately Controlled with Metformin Plus Sulfonylurea Randomized, double-blind, placebo- controlled, 52-week, phase 3 study Subjects, n (%) Vercruysse F, et al. Presented at the 49th EASD Annual Meeting. Barcelona, Spain. September 23 – 27, Abstract 934. Placebo (n=156) Canagliflozin 100 mg (n=157) Canagliflozin 300 mg (n=156) Any adverse event111 (71.2)106 (67.5)114 (73.1) Serious adverse events13 (8.3)7 (4.5)8 (5.1) Adverse events leading to discontinuation 7 (4.5)11 (7.0)12 (7.7)

52-week Data: Canagliflozin in Patients with T2DM Inadequately Controlled with Metformin Plus Sulfonylurea Subjects, n (%) Vercruysse F, et al. Presented at the 49th EASD Annual Meeting. Barcelona, Spain. September 23 – 27, Abstract 934. Placebo (n=156) Canagliflozin 100 mg (n=157) Canagliflozin 300 mg (n=156) Genital mycotic infection Male ‡,§ Female ı,¶ 1 (1.3) 4 (5.0) 6 (7.9) 15 (18.5) 5 (5.7) 13 (18.8) Osmotic diuresis-related adverse events # 3 (1.9)9 (5.7)11 (7.1) Urinary tract infection12 (7.7)13 (8.3) Volume-related adverse events** Documented hypoglycemia episodes †† Severe episodes 3 (1.9) 28 (17.9) 1 (0.6) 53 (33.8) 1 (0.6) 6 (3.8) 57 (36.5) 1 (0.6) *All adverse events are reported regardless of rescue medication; hypoglycemia episodes are reported for prior to rescue medication. †Possibly, probably or very likely related to study drug, as assessed by investigators. ‡Placebo, n=76; canagliflozin 100 mg, n=76; canagliflozin 300 mg, n=87. §Including balanitis, balanitis candida, and balanoposthisis. ı Placebo, n=80; canagliflozin 100 mg, n=81; canagliflozin 300 mg, n=69. ¶Including vaginal infection, vulvitis, vulvovaginal candidiasis, vulvovaginal mycotic infection, and vulvovsginitis. #Including dry mouth, nocturia, pollakiuria, polyuria, thirst, and urine output increased. **Including dizziness postural, hypotension, orthostatic hypotension, and syncope. ††Including biochemically documented episodes (≤3.9 mmol/L) with or without symptoms and several episodes (ie, requiring the assistance of another individual or resulting in seizure or loss of consciousness).

4-year Data: Dapagliflozin vs Glipizide as Add-on Therapies in T2DM Inadequately Controlled on Metformin Double-blind extension of this study, patients continued to receive dapagliflozin (n=204) and glipizide (n=188) added to metformin Overall frequencies of adverse events and serious adverse events were similar between groups Langkilde A, et al. Presented at the 49th EASD Annual Meeting. Barcelona, Spain. September 23 – 27, Abstract 936. n (%)Dapagliflozin + metformin (n=406) Glipizide + metformin (n=408) ≥ 1 adverse event356 (87.7)355 (87.0) ≥ 1 serious adverse event75 (18.5)81 (19.9) Adverse event leading to discontinuation 54 (13.3)46 (11.3)

4-year Data: Dapagliflozin vs Glipizide as Add-on Therapies in T2DM Inadequately Langkilde A, et al. Presented at the 49th EASD Annual Meeting. Barcelona, Spain. September 23 – 27, Abstract 936. Controlled on Metformin Genital infections: – The majority of patients with genital infections and urinary tract infections first presented during year 1. – The majority of events were of mild/moderate intensity and resolved with standard treatment. There were no signs of deteriorating renal function as measured by eGFR over 4 years. n (%)Dapagliflozin + metformin (n=406) Glipizide + metformin (n=408) Events of urinary tract infection55 (13.5)38 (9.3) Events of genital infection58 (14.3)12 (2.9)