Faculty Affiliation. Faculty Disclosures. Learning Objectives. Macrovascular and Microvascular Complications

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1 Faculty Affiliation Combined Targeted Approaches for the Treatment of Type 2 Diabetes: The Role of the Kidney Mark Stolar, MD Associate Professor of Clinical Medicine Division of General Internal Medicine and Geriatrics Northwestern University Feinberg School of Medicine Chicago, Illinois Sponsored by Integrity Continuing Education, Inc. Supported by an educational grant from AstraZeneca. 1 2 Faculty Disclosures Consultant: AstraZeneca, Takeda Speakers bureau: AstraZeneca, Takeda Learning Objectives Implement current evidence-based guidelines for the detection and diagnosis of prediabetes and diabetes Describe the role of the kidney and sodiumglucose co-transporter 2 (SGLT2) inhibitionbased therapeutic strategies Apply evidence-based and individualized management strategies to ensure appropriate and effective management of type 2 diabetes mellitus (T2DM) 3 4 Prevalence and Burden of Diabetes in the United States Macrovascular and Microvascular Complications Affects ~26 million individuals Estimated that ~3% of adults will have diabetes by 25 7th leading cause of death in 212 Disease sequelae include: Kidney failure, lower-limb amputations, blindness, neuropathy, cardiovascular disease (CVD), and stroke Diabetes diagnosis continues to increase because of obesity epidemic Macrovascular Coronary artery disease 5% of people with T2DM die of coronary artery disease Peripheral arterial disease 2-fold increase in lowerlimb amputations Cerebrovascular disease 15%-4% increased risk of stroke Microvascular Neuropathy Affects up to 5% of patients with diabetes Retinopathy After 15 years, ~1% of patients with diabetes develop severe visual impairment Nephropathy 1%-2% of people with T2DM die of kidney failure Centers for Disease Control and Prevention. Diabetes Report Card 212. American Diabetes Association. Diabetes Care. 213;36: American Diabetes Association. Diabetes Care. 214;37(suppl 1):S14-S8. 5 Fowler MJ. Clin Diabetes. 28;26(2):

2 CVD in T2DM The Natural History of T2DM Major cause of morbidity and mortality for individuals with diabetes Largest contributor to diabetes-associated direct and indirect costs Common T2DM comorbidities (eg, hypertension and dyslipidemia) are clear risk factors for CVD Diabetes confers independent risk for CVD Years from diagnosis Incretin effect -Cell function Insulin resistance Insulin secretion Postprandial glucose Fasting glucose Prediabetes Onset Diagnosis Microvascular complications Macrovascular complications Type 2 diabetes ADA 215 Guidelines. Diabetes Care. 215;38(suppl 1):S49 S57. 7 Defronzo RA. Diabetes. 29;58: ; Holman RR. Diabetes Res Clin Pract. 1998;4(suppl):S21-S25; U.K. Prospective Diabetes Study Group. Diabetes. 1995;44: ; Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26: ; Nathan DM. N Engl J Med. 22;347: Progressive β-cell Dysfunction Is a Key Driver of Progressive Dysglycemia in T2DM ADA Guideline Recommendations for Prevention or Delay of Diabetes Onset Deteriorating β-cell function is partially driven by the incretin defect By the time of diabetes onset, up to 8% of β-cell function may be lost 1,2 PPG FPG β-cell Function Normal Impaired Glucose Glucose Tolerance Tolerance Insulin Resistance Insulin Secretion Diagnosis Severity of Glucose Intolerance Time in Years PPG, postprandial plasma glucose; FPG, fasting plasma glucose. 1. Defronzo RA. Diabetes. 29;58: ; 2. Fehse F, et al. J Clin Endocrinol Metab. 25;9: ; Figure adapted from Kendall DM, et al. Am J Med.29;122(6, suppl):s37-s5. 9 Recommendations Patients with impaired glucose tolerance (IGT) A, impaired fasting glucose (IFG) E, or an A1c 5.7% 6.4% E should be referred to an intensive diet and physical activity behavioral counseling program targeting loss of 7% of body weight and increasing moderate-intensity physical activity (such as brisk walking) to at least 15 min/week. Follow-up counseling may be important for success. B Based on the cost-effectiveness of diabetes prevention, such programs should be covered by third-party payers. B Metformin therapy for prevention of type 2 diabetes may be considered in those with IGT A, IFG E, or an A1c 5.7% 6.4% E, especially for those with BMI >35 kg/m 2, aged <6 years, and women with prior gestational diabetes mellitus. A At least annual monitoring for the development of diabetes in those with prediabetes is suggested. E Screening for and treatment of modifiable risk factors for CVD is suggested. B Diabetes self-management education and support programs are appropriate venues for people with prediabetes to receive education and support to develop and maintain behaviors that can prevent or delay the onset of diabetes. C ADA, American Diabetes Association; BMI, body mass index. ADA 215 Guidelines. Diabetes Care 215;38(suppl 1):S a 1 Risk Prevention Trials: Lifestyle Modification Risk Prevention Trials: Medication Study Da Qing Finnish Diabetes Prevention Study Groups Control, diet, exercise, diet & exercise Control, lifestyle Average Follow-up (Years) Incidence of Diabetes* Relative Risk Reduction (%) P Value 31% (control vs diet); 46% (control vs exercise); all <.5 42% (control vs diet and exercise) % <.1 US DPP PBO, lifestyle % <.1 Indian DPP Control, lifestyle *Per 1 person-years. DPP, Diabetes Prevention Program; PBO, placebo. Reviewed in Kahn SE, et al. Lancet. 214;383(9922): % Study Groups Average Follow-up (Years) Incidence of Diabetes* Relative Risk Reduction (%) P Value US DPP PBO, metformin % <.1 Indian DPP Control, metformin %.29 Nepi Antidiabetes Study PBO, glimepiride %.72 STOP-NIDDM PBO, acarbose %.15 XENDOS PBO, orlistat %.24 NAVIGATOR PBO, nateglinide % NS ORIGIN Control, insulin glargine %.6 TRIPOD PBO, troglitazone % <.1 US DPP PBO, troglitazone % <.1 DREAM PBO, rosiglitazone % <.1 ACT NOW PBO, pioglitazone % <.1 *Per 1 person-years. NS, not significant. Reviewed in Kahn SE, et al. Lancet. 214;383(9922):

3 Hazard Ratio Hazard Ratio Hazard Ratio Hazard Ratio 1-year Follow-up of Intensive Glucose Control in T2DM: Myocardial Infarction United Kingdom Prospective Diabetes Study Survivor Cohort 1-year Follow-up of Intensive Glucose Control in T2DM: Death From Any Cause United Kingdom Prospective Diabetes Study Survivor Cohort SU-INS SU-INS P=.52 P= P=.1 P= P=.44 P= P=.1 P= Risk of myocardial infarction was reduced in patients treated with SU-INS (15%) or (33%) vs conventional therapy.* Risk of death from any cause was reduced in patients treated with SU-INS (13%) or (27%) vs conventional therapy.* *Conventional therapy was dietary restriction alone. SU, sulfonylurea; INS, insulin;, metformin. Holman RR, et al. N Engl J Med. 28;359(15): *Conventional therapy was dietary restriction alone. Holman RR, et al. N Engl J Med. 28;359(15): ADA Guidelines for Diabetes Screening Guideline Recommendations for Screening and Diagnosis Adults BMI >25 kg/m 2 * with additional risk factors >45 years of age without risk factors Children and adolescents Overweight with 2 risk factors Individuals with normal test results should follow up every 3 years *BMI >23 kg/m 2 for Asian Americans. ADA 215 Guidelines. Diabetes Care. 215;38(suppl 1):S8-S General Risk Factors for Diabetes Metabolic Risk Factors for Diabetes Physical inactivity Increased caloric intake (obesity) First-degree relative with diabetes Race/ethnicity Delivery of a baby weighing >9 lb or diagnosed with gestational diabetes mellitus Clinical conditions associated with insulin resistance (eg, severe obesity, metabolic syndrome, acanthosis nigricans) Polycystic ovarian syndrome A1c >5.7%, IGT, or IFG on previous testing Hypertension (>14/9 mm Hg or on therapy for hypertension) HDL-C level 35 mg/dl (.9 mmol/l) and/or a triglyceride level 25 mg/dl (2.82 mmol/l) History of CVD American Diabetes Association. Diabetes Care. 214;37(suppl 1):S14-S8. 18 HDL-C, high-density lipoprotein cholesterol. American Diabetes Association. Diabetes Care. 214;37(suppl 1):S14-S

4 Individualization of Care: ADA/EASD Position Statement Approach to management of hyperglycemia: More stringent Less stringent Patient attitude and expected treatment efforts Highly motivated, adherent, excellent self-care capacities Less motivated, nonadherent, poor self-care capacities Guideline Recommendations for Management of T2DM Risks potentially associated with hypoglycemia, other adverse events Disease duration Low Newly diagnosed High Long-standing Life expectancy Long Short Important comorbidities Absent Few/mild Severe Established vascular complications Absent Few/mild Severe Resources, support system Readily available Limited Management of hyperglycemia in type 2 diabetes: a patient-centered approach. Position statement of the ADA and the European Association for the Study of Diabetes (EASD). Diabetologia. February Goals of Therapy in T2DM Management Recommendations for Dietary Modifications Glycemic Control Decreases onset and progression of T2DM-related microvascular complications Impact on cardiovascular complications remains uncertain Modest long-term benefit to achievement of good glycemic control early in disease course Aggressive control in older patients with advanced disease may present some risk without significant benefit Comprehensive Cardiovascular Risk Reduction Reduces CVD risk in T2DM Significant benefits of globally addressing multiple risk factors Strategies Smoking cessation Blood pressure (BP) control Lipid management (statins) Antiplatelet therapy in some circumstances Reduce total daily calorie intake Reduce sodium intake: <23 mg/day; lower for patients with hypertension Reduce simple carbohydrates, sugars, and high-fat foods (eliminate trans fats) Limit saturated fat: <7% of calories, <2-3 g/day Limit cholesterol: <2 mg/day Increase water-soluble fiber: 1-25 g/day Increase unsaturated fat and marine-based omega-3s Limit alcohol consumption: <1 drink day for adult women and 2 drinks per day for adult men Inzucchi SE, et al. Diabetes Care. 215;38(1): ADA 215 Guidelines. Diabetes Care. 215;38(suppl 1):S2-S3. 23 ADA 215 Guidelines. Diabetes Care. 215;38(suppl 1):S2-S3. Evert AB, et al. Diabetes Care. 214;37(suppl 1):S12 S Recommendations for Physical Activity Psychosocial Assessment and Care Children 6 minutes of physical activity each day (Grade B) Adults 15 minutes/week of moderate-intensity aerobic physical activity (5%-7% of maximum heart rate), spread over at least 3 days/week with no more than 2 consecutive days without exercise (Grade A) Reduce sedentary time, particularly by breaking up extended amounts of time (>9 min) spent sitting (Grade B) In the absence of contraindications, resistance training at least twice per week (Grade A) Assessment of patient s psychological and social situation Psychosocial screening and follow-up: Attitudes about illness Expectations for medical management and outcomes Affect/mood Quality of life Financial, social, and emotional resources Psychiatric history Routinely screen for psychosocial problems: depression, diabetes-related distress, anxiety, eating disorders, and cognitive impairment Patients 65 years of age should be screened and treated for depression Patients with comorbid depression should receive a stepwise collaborative care approach for depression management ADA 215 Guidelines. Diabetes Care. 215;38(suppl 1):S2-S3. 27 ADA 215 Guidelines. Diabetes Care. 215;38(suppl 1):S2-S

5 Negative Reactions to Initial Diagnosis of Diabetes Are Common Guilty Type 1 Type 2 Angry Depressed Pharmacologic Treatment of T2DM Anxious Agreeing (%) Base: all patients Peyrot M, et al. Diabetes Care. 25;28(11): Pharmacologic Targeting of Pathophysiological Disturbances in T2DM Pharmacologic Targeting of Pathophysiological Disturbances in T2DM (cont d) Decreased INS secretion Decreased incretin effect Increased lipolysis GLP-1 RAs DPP-4 inhibitors TZDs SUs Meglitinides GLP-1 RAs DPP-4 inhibitors Bile acid sequestrants α-glucosidase inhibitors TZDs Increased glucagon secretion HYPERGLYCEMIA Increased glucose reabsorption GLP-1 RAs DPP-4 inhibitors Amylin analogs SGLT2 inhibitors Increased HGP Neurotransmitter dysfunction Decreased glucose uptake GLP-1 RAs TZDs HGP, hepatic glucose production. DeFronzo RA. Diabetes. 29;58: GLP-1, glucagon-like peptide 1; RA, receptor agonist; DPP-4, dipeptidyl peptidase-4; TZDs, thiazolidinediones. DeFronzo RA. Diabetes. 29;58: The Role of the Kidney in Glucose Homeostasis Targeting the Kidney for the Treatment of T2DM: SGLT2 Inhibition Under normal conditions, the kidney is involved in maintaining glucose homeostasis via 3 different mechanisms: Release of glucose into circulation via gluconeogenesis Uptake of glucose to meet its own energy needs Reabsorption of glucose from the glomerular filtrate Abdul-Ghani MA, et al. Endocr Rev. 211;32(4): Gerich JE. Diabet Med. 21;27: Stumvoll M, et al. J Clin Invest. 1995;96:

6 Altered Renal Glucose Control in Diabetes Glucose Reabsorption in the Kidney by SGLT2 Gluconeogenesis is increased in postprandial and postabsorptive states in patients with T2DM Renal contribution to hyperglycemia postprandially is significant 3-fold increase in glucose output relative to patients without diabetes In renal insufficiency renal glucose output is decreased increasing risk of hypoglycemia Glucose reabsorption Increased SGLT2 expression and activity in renal epithelial cells from patients with diabetes vs normoglycemic individuals GLUT, glucose transporter; ATP, adenosine triphosphate; ATPase, adenosine triphosphatase; S1, segment 1; S2, segment 2; S3, segment 3. Marsenic O. Am J Kidney Dis. 29;53: Bakris GL, et al. Kidney Int. 29;75(12): Rahmoune H, et al. Diabetes. 25;54(12): Gerich JE. Diabet Med. 21;27: Whaley JM, et al. Diabetes Metab Syndr Obes. 212;5: Rosenwasser RF, et al. Diabetes Metab Syndr Obes. 213;6: Rationale for SGLT2 Inhibitors Therapeutic Benefits Associated with SGLT2 Inhibition SGLT2 is a low-affinity, high-capacity glucose transporter located in the proximal tubule and is responsible for 9% of glucose reabsorption Mutation in SGLT2 transporter is linked to hereditary renal glycosuria, a relatively benign condition in humans Selective SGLT2 inhibitors have a novel and unique mechanism of action reducing blood glucose levels by increasing renal excretion of glucose Insulin-independent glucose lowering poses little risk of hypoglycemia Selective SGLT2 inhibition would also cause urine loss of the calories from glucose, potentially leading to weight loss Reduces A1c, FPG, and PPG by an INS-independent mechanism Weight loss due to renal glucosuria/negative caloric balance Reduces BP Improves INS sensitivity and INS secretion (ie, correction of glucotoxicity) Gerich JE. Diabet Med. 21;27: Plosker GL. Drugs. 212;72: Whaley JM, et al. Diabetes Metab Syndr Obes. 212;5: Mudaliar S, et al. Diabetes Technol Ther. 214;16: Brooks AM, Thacker SM. Ann Pharmacother. 29;42(7): Merovci A, et al. J Clin Invest. 214;124(2): Case Study: A 65-year-old Female Current Exam Case Study: 65-year-old Female Physical exam (BP higher vs last visit): Height: 5 5 Weight: 195 lb BMI: 31 kg/m 2 BP: 15/81 Current medications: extended release 15 mg/day with evening meal Dietary review: Consumes mostly high-fat and high-carbohydrate diet Activity review: Limited physical activity due to arthritis of the knees 41 6

7 LS Mean Change (±SE) in HbA1c From Baseline (%) C-Pep (-12) / G (-12) 1/TGD Change in Baseline A1c (%) Case Study: A 65-year-old Female Current Laboratory Results Diabetes Panel Today 3 Months Ago 6 Months Ago A1c 8.2% 7.8% 7.6% FPG 155 mg/dl 142 mg/dl 138 mg/dl Lipid Panel Today 3 Months Ago 6 Months Ago Total Cholesterol 24 mg/dl 245 mg/dl 25 mg/dl LDL-C 13 mg/dl 144 mg/dl 15 mg/dl HDL-C 39 mg/dl 37 mg/dl 36 mg/dl Triglycerides 25 mg/dl 28 mg/dl 21 mg/dl Case Study: Discussion What are your primary goals for treatment of this patient? What is more important in this patient: glycemic control or disease progression? What adjustments would you make to the patient s treatment plan? Increase dose to maximum daily dose? Add a second medication? If so, what medication would you recommend? What is the most important determinant of your choice in this patient? How can you ensure that needed lifestyle modifications are successful? (Success brings success) Currently Approved SGLT2 Inhibitors Overview of SGLT2 Inhibitor Glycemic Efficacy: Changes in Baseline A1c Level SGLT2 Inhibitor Initial Dose Max Dose* Renal Dose Adjustment Canagliflozin (CANA) Dapagliflozin (DAPA) Empagliflozin (EMPA) 1 mg qd 3 mg qd 5 mg qd 1 mg qd 1 mg qd 25 mg qd egfr 45 <6 ml/min/1.73 m 2 : 1 mg CANA qd egfr <45 ml/min/1.73 m 2 : Not recommended egfr <3 ml/min/1.73 m 2 : egfr <6 ml/min/1.73 m 2 : Not recommended egfr <3 ml/min/1.73 m 2 : egfr <45 ml/min/1.73 m 2 : Not recommended egfr <3 ml/min/1.73 m 2 : CANA DAPA EMPA PBO SGLT2 inhibitor (low dose)* SGLT2 inhibitor (high dose)* *May be prescribed for patients requiring better glycemic control if agent is well tolerated. qd, once per day; egfr, estimated glomerular filtration rate. Med Lett Drugs Ther. 214;56(1457): *Doses evaluated in studies cited: CANA=1 or 3 mg, DAPA=5 or 1 mg, EMPA=1 or 25 mg. MONO, monotherapy; PIO, pioglitazone; GLIM, glimepiride; SITA, sitagliptin. 45 CANA Treatment Improves Glycemic Levels Independent of Disease Duration Effects of DAPA Treatment on β-cell Function N Baseline (%) T2DM Duration <5 Years % (95% CI: -.84, -.56) -.96% (95% CI: -1.1, -.82) T2DM Duration 5-<1 Years % (95% CI: -.9, -.59) -.91% (95% CI: -1.6, -.75) T2DM Duration 1 Years % (95% CI: -.89, -.58) -.85% (95% CI: -1., -.7) C-Pep (-12) / G (-12) DAPA PBO Baseline * DAPA PBO Treatment DAPA PBO Baseline Two weeks of DAPA treatment was associated with increased C-Pep ( 12) /G ( 12) IR, suggesting an improvement in β-cell function. * DAPA PBO Treatment LS, least squares; SE, standard error; CI, confidence interval. Wilding JP, et al. J Diabetes Complications. 215;29(3): Placebo CANA 1 mg CANA 3 mg 46 *P <.5 vs baseline and vs placebo. ΔC-Pep (-12), incremental area under the plasma C-peptide concentration curve; ΔG (-12), incremental area under the plasma glucose concentration curve; TGD, total body glucose disposal; IR, insulin resistance Merovci A, et al. J Clin Endocrinol Metab. 215;1(5):

8 Mean (SE) HbA1c, % Change in Total Body Weight From BL (kg) Change in HbA1c From BL (%) Change in Baseline Body Weight (kg) Change in Adipose Tissue Volume (cm 3 ) Overview of Changes in Body Weight Associated with SGLT2 Inhibition Effects of Dapagliflozin on Regional Adipose Tissue Distribution CANA DAPA EMPA Mean change from baseline in VAT and SAT volume with treatment at 24 weeks 2 PBO + n=42; n=37 DAPA 1 mg + n=37; n= * *Doses evaluated in studies cited: CANA=1 or 3 mg, DAPA=5 or 1 mg, EMPA=1 or 25 mg. PBO SGLT2 inhibitor (low dose)* SGLT2 inhibitor (high dose)* VAT SAT -8 Dapagliflozin reduces total body weight predominantly by reducing fat mass, visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT) volume. *VAT, cm 3 (95 CI = to -68.6; nominal P =.84). SAT, cm 3 (95% CI = -359 to -1.1; nominal P =.385). Bolinder J, et al. J Clin Endocrinol Metab (3): DAPA Added on to Metformin Durably Reduces A1c Levels & Body Weight at 4 Years Combination Therapy with SGLT2 Inhibitors.6.4.2% (95% CI:.5.36) Diff..3% (95% CI:.51 to.9).1% (95% CI:.25 to.5) SGLT2 Inhibitor Previously Studied Therapeutic Combinations Dual Therapy Triple Therapy Study Week Sample size per time point (excluding data after rescue), n DAPA GLIP DAPA + GLIP + CANA Sulfonylurea and sulfonylurea and PIO INS ± other AHAs N 4 41 BL (%) kg (95% CI:.6 1.4) Diff kg (95% CI: 5.31 to 3.46) 3.65 kg (95% CI: 4.3 to 3.1) DAPA EMPA Sulfonylurea PIO Sulfonylurea and sulfonylurea and DPP-4 inhibitor INS ± other AHAs and sulfonylurea PIO ± Study Week Sample size (including data after rescue), n DAPA GLIP DAPA + GLIP + N 4 41 BL, baseline; GLIP, glipizide. BL (kg) Del Prato S, et al. Diabetes Obes Metab. 215; AHAs, antihyperglycemic agents. Peene B, et al. Ther Adv Endocrinol Metab. 214;5(5): Wilding JP. Metabolism. 214;63(1): Add-on Therapy with DAPA and SAXA for Patients Inadequately Controlled With Currently Approved Fixed-dose SGLT2 Inhibitor Combination Therapies SAXA+DAPA+ SAXA+ DAPA+ Combination CANA/ Initial Dose 5/5-15/5 mg bid with meals Maximum Daily Dose 3/2 mg Renal Dose Adjustment egfr 45-<6 ml/min/1.73 m 2 : Adjust to 5 mg CANA bid egfr <45 ml/min/1.73 m 2 : 8. DAPA/ 5/5-1/1 mg qd in the morning 1/2 mg egfr <6 ml/min/1.73 m 2 : Weeks EMPA/ linagliptin 1/5 mg qd in the morning, with or without food 25/5 mg egfr <45 ml/min/1.73 m 2 : Not recommended egfr <3 ml/min/1.73 m 2 : SAXA, saxagliptin. Rosenstock J, et al. Diabetes Care. 215;38(3): bid, twice a day. Med Lett Drugs Ther. 214;56(1457):

9 LS Mean % Change (±SE) in Systolic BP From Baseline (mm Hg) LS Mean % Change (±SE) in Body Weight From Baseline HbA1c (%) Adjusted Mean Change From Baseline HbA1c (%) INS Dose (U/day) Change From Baseline HbA1c (%) Fixed-dose Combination Therapy: EMPA and Linagliptin Mean baseline 7.99% 8.4% 7.99% 8.5% 8.5% (64 mmol/mol) (64 mmol/mol) (64 mmol/mol) (64 mmol/mol) (64 mmol/mol).. EMPA 25 mg/linagliptin 5 mg (n=134) EMPA 1 mg/linagliptin 5 mg (n=135) EMPA 25 mg (n=133) EMPA 1 mg (n=132) Linagliptin 5 mg (n=133) -.51% % % % -1.22% (95% CI: -.39,.7) P= (95% CI: -.9,.43) P< (95% CI: -.94,.48) P< (95% CI: -.94,.48) P<.1 Change From Baseline HbA1c (mmol/mol) Long-term Treatment with SGLT2 Inhibitors Special Populations: Obesity, Hypertension, CVD Reductions from baseline HbA1c with EMPA/linagliptin were greater vs linagliptin and EMPA 1 mg, but not vs EMPA 25 mg. Lewin A, et al. Diabetes Care. 215;38(3): EMPA in Obese Patients Inadequately Controlled with INS at 1 Year Effects of SGLT2 Inhibitors on BP INS Dose HbA1c Week 11.2 ± 2.1 MDI INS + placebo 92.9 ± ± % ±.7% (6 ±.8 mmol/mol) 7.24% ±.7% (58 ±.8 mmol/mol) 7.8% ±.7% (54 ±.8 mmol/mol) MDI INS + EMPA 1 mg MDI INS + EMPA 25 mg 52 weeks of EMPA treatment was associated with reduced A1c levels, INS requirements, and body weight in obese patients with T2DM. SGLT2 inhibition is associated with reductions in BP presumably due to chronic natriuresis although changes in insulin sensitivity cannot be excluded Decreases in systolic BP have consistently been observed with CANA, DAPA, and EMPA treatment (up to 5 mm Hg with DAPA) Reports of changes in diastolic BP have been smaller and inconsistent May afford vascular protection, particularly against the risks of stroke and heart failure. These benefits not yet demonstrated in clinical trials MDI, multiple daily injection. Rosenstock J, et al. Diabetes Care. 214;37(7): Foote C, et al. Diab Vasc Dis Res. 212;9(2): Haring HU, et al. Diabetes Care. 214;37(6): CANA Improves Weight and Systolic BP in Older* Patients with T2DM at 2 Years Add-on DAPA Improves Glycemic Control in Older Patients with Advanced T2DM and Preexisting CVD Baseline (kg) Weight LS mean % change -.6% (-.6 kg) -3.% (-2.7 kg) -3.8% (-3.5 kg) -2.3% (95% CI: -3.1, -1.6) (-2.1 kg) -3.2% (95% CI: -4., -2.4) (-2.9 kg) Placebo CANA 1 mg CANA 3 mg Efficacy endpoint evaluation period Placebo; HbA1c baseline 8.% DAPA; HbA1c baseline 8.% Time Point (Weeks) -.4 Baseline (mm Hg) LS mean % change -.6 Systolic BP Time Point (Weeks) *55-8 years of age. Bode B, et al. Diabetes Obes Metab. 215;17(3): mm Hg -1.2 mm Hg -3. mm Hg -5.8 mm Hg (95% CI: -8., -3.5) -7.5 mm Hg (95% CI: -9.8, -5.2) DAPA added on to background therapy improved A1c levels without increasing hypoglycemic risk, promoted weight loss, and was well tolerated in patients >65 years old. Leiter LA, et al. J Am Geriatr Soc. 214;62(7): Time (Weeks) 59 9

10 CANA Monotherapy Improves Cardiovascular Risk Factors Safety and Tolerability Outcome Measure CANA 1 mg CANA 3 mg Difference versus placebo Systolic BP -3.7* -5.4* Diastolic BP Triglycerides (mg/dl) LDL-C (mg/dl) HDL-C (mg/dl) 6.8* 6.1 LDL-C/HDL-C Non HDL-C (mg/dl) *P<.1; P<.1. Stenlof K, et al. Diabetes Obes Metab. 213;15: Adverse Events Associated with SGLT2 Inhibitor Treatment Patients for Whom SGLT2 Inhibitors Are Not Recommended Most common adverse events (AEs): Genital mycotic infections (GMIs) Lower urinary tract infections (UTIs) Usually mild in intensity and respond to standard over-the-counter treatment More often observed in women than in men Risk higher for women prone to fungal infection and uncircumcised men Meta-analysis of 8 studies found GMIs and UTIs to be more common with SGLT2 inhibitor treatment* vs other antidiabetics AE Odds Ratio 95% CI UTI , 1.9 GMI , 7.45 Patients with chronic kidney disease Increased risk of SGLT2 inhibitor-associated hypoglycemia when combined with other background therapies Decreased or lack of efficacy Particularly susceptible to nephrotoxic effects of SGLT2 inhibitors Patients with history of bladder cancer Possible increased risk of bladder cancer was observed in DAPA trials DAPA should not be used in patients with history of bladder cancer *CANA or DAPA. Nauck MA. Drug Des Devel Ther. 214;8: Vasilakou D, et al. Ann Intern Med. 213;159(4): Yale JF, et al. Diabetes Obes Metab. 213;15(5): Mikhail N. World J Diabetes. 214;5(6): Peene B, et al. Ther Adv Endocrinol Metab. 214;5(5): Summary Prompt diagnosis of diabetes and achievement of glycemic control is necessary to reduce the risk of microvascular and possibly cardiovascular complications T2DM management requires individualized treatment, patient education, and support to empower patients to manage their disease SGLT2 inhibitors: Target hyperglycemia through prevention of renal glucose reabsorption Are effective alone and with oral therapies or INS Are associated with a low risk for hypoglycemia and other side effects Thank You! 64 1