Faculty Affiliation. Faculty Disclosures. Learning Objectives. Prevalence and Burden of Diabetes in the United States

Transcription

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 SGLT2 inhibition-based therapeutic strategies Apply evidence-based and individualized management strategies to ensure appropriate and effective management of T2DM 3 SGLT2, sodium/glucose cotransporter 2; T2DM, type 2 diabetes mellitus. 4 Prevalence and Burden of Diabetes in the United States Macrovascular and Microvascular Complications Affects ~26 million individuals Estimated that ~30% of adults will have diabetes by th leading cause of death in 2012 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 50% of people with T2DM die of coronary artery disease Peripheral arterial disease 20-fold increase in lower-limb amputations Cerebrovascular disease 150%-400% increased risk of stroke Microvascular Neuropathy Affects up to 50% of patients with diabetes Retinopathy After 15 years, ~10% of patients with diabetes develop severe visual impairment Nephropathy 10%-20% of people with T2DM die of kidney failure Centers for Disease Control and Prevention. Diabetes Report Card American Diabetes Association. Diabetes Care. 2013;36: American Diabetes Association. Diabetes Care. 2014;37(suppl 1):S14-S80. 5 Fowler MJ. Clin Diabetes. 2008;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 ADA 2015 Guidelines. Diabetes Care. 2015;38(suppl 1):S49 S57. 7 Defronzo RA. Diabetes. 2009;58: ; Holman RR. Diabetes Res Clin Pract. 1998;40(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. 2002;347: Progressive β-cell Dysfunction Is a Key Driver of Progressive Dysglycemia in T2D 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 80% 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 indicates postprandial plasma glucose; FPG, fasting plasma glucose; T2D, type 2 diabetes; 1. Defronzo RA. Diabetes 2009;58: ; 2. Fehse F, et al. J Clin Endocrinol Metab 2005;90: ; Figure adapted from Kendall DM, et al. Am J Med 2009;122(6 Supp):S37-S50 9 ADA 2015 Guidelines. Diabetes Care 2015;38(S1):S 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 <.05 42% (control vs diet and exercise) % <.001 US DPP PBO, lifestyle % <.001 US DPP PBO, troglitazone % <.001 Control, Indian DPP lifestyle %.018 DREAM PBO, rosiglitazone % <.001 ACT NOW PBO, pioglitazone % <.001 *per 100 person-years PBO, placebo. Reviewed in Kahn SE et al. Lancet. 2014;383(9922): Reviewed in Kahn SE et al. Lancet. 2014;383(9922): Study Groups Average Follow-up (Years) Incidence of Diabetes Relative Risk Reduction (%) P Value US DPP PBO, metformin % <.001 Indian DPP Control, metformin %.029 Nepi Antidiabetes Study PBO, glimepiride %.072 STOP-NIDDM PBO, acarbose %.0015 XENDOS PBO, orlistat %.0024 NAVIGATOR PBO, nateglinide % NS ORIGIN Control, insulin glargine %.006 TRIPOD PBO, troglitazone % <.01 2

3 Hazard Ratio Hazard Ratio Hazard Ratio Hazard Ratio 10-year Follow-up of Intensive Glucose Control in T2DM: Myocardial Infarction United Kingdom Prospective Diabetes Study Survivor Cohort 10-year Follow-up of Intensive Glucose Control in T2DM: Death From Any Cause United Kingdom Prospective Diabetes Study Survivor Cohort SU-INS SU-INS 1.4 P=.52 P= P=.01 P= P=.44 P= P=.01 P= Risk of myocardial infarction was reduced in patients treated with SU-INS (15%) or (33%) ve 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. *Conventional therapy was dietary restriction alone. Holman RR, et al. N Engl J Med. 2008;359(15): Holman RR, et al. N Engl J Med. 2008;359(15): ADA Guidelines for Diabetes Screening Adults BMI >25 kg/m 2 * with additional risk factors >45 years of age without risk factors Guideline Recommendations for Screening and Diagnosis 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, American Diabetes Association; BMI, body mass index. ADA 2015 Guidelines. Diabetes Care. 2015;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 A1c >5.7%, IGT, or IFG on previous testing Hypertension (>140/90 mm Hg or on therapy for hypertension) HDL cholesterol level 35 mg/dl (0.90 mmol/l) and/or a triglyceride level 250 mg/dl (2.82 mmol/l) Delivery of a baby weighing >9 lb or diagnosed with gestational diabetes mellitus History of cardiovascular disease Clinical conditions associated with insulin resistance (eg, severe obesity, metabolic syndrome, acanthosis nigricans) Polycystic ovarian syndrome American Diabetes Association. Diabetes Care. 2014;37(suppl 1):S14-S American Diabetes Association. Diabetes Care. 2014;37(suppl 1):S14-S

4 Diagnostic Criteria Prediabetes Test FPG 2-hour plasma glucose (75-g OGTT) Overt Diabetes Test Prediabetic Range mg/dl (IFG) mg/dl (IGT) A1c 5.7%-6.4% Note: For all 3 tests, risk is continuous, extending below the lower limit of the range and becoming disproportionately greater at higher ends of the range. FPG 2-hour plasma glucose (75-g OGTT) A1c FPG, fasting plasma glucose; OGTT, oral glucose tolerance test; IFG, impaired fasting glucose; IGT, impaired glucose tolerance. ADA 2015 Guidelines. Diabetes Care. 2015;38(suppl 1):S8-S16. Threshold for Diabetes 126 mg/dl 200 mg/dl 6.5% Note: In the absence of unequivocal hyperglycemia, results should be confirmed by repeat testing. 20 Guideline Recommendations for Management of T2DM Individualization of Care: ADA/EASD Position Statement Goals of Therapy in T2DM Management Approach to management of hyperglycemia: Patient attitude and expected treatment efforts Risks potentially associated with hypoglycemia, other adverse events Disease duration Life expectancy Important comorbidities Established vascular complications More Less stringent stringent Highly motivated, adherent, Less motivated, nonadherent, excellent self-care capacities poor self-care capacities Low High Newly diagnosed Long-standing Long Short Absent Few/mild Severe Absent Few/mild Severe 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 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 Inzucchi SE, et al. Diabetes Care. 2015;38(1): ADA 2015 Guidelines. Diabetes Care. 2015;38(suppl 1):S20-S Guideline-recommended Targets for Patients with T2DM ADA Foundations of Patient Care A1c (%) BP (mm Hg) LDL-C (mg/dl) ADA AACE <7.0 < / /80 <100 <100 More or less stringent glycemic goals may be appropriate depending upon duration of diabetes, age/life expectancy, comorbid conditions, known CVD or advanced microvascular complications, hypoglycemia unawareness, and individual patient considerations. Patients with T2DM should be provided with education and support that empowers them to self-manage their disease Information should emphasize the importance of the following aspects of disease management: Nutrition Physical activity Smoking cessation Psychosocial care Immunization AACE, American Association of Clinical Endocrinologists; LDL-C, low-density lipoprotein cholesterol. Garber AJ, et al. Endocr Pract. 2013;19: ADA 2015 Guidelines. Diabetes Care. 2015;38(suppl 1):S33-S ADA 2015 Guidelines. Diabetes Care. 2015;38(suppl 1):S20-S

5 Recommendations for Dietary Modifications Recommendations for Physical Activity Reduce total daily calorie intake Reduce sodium intake: <2300 mg/day; lower for patients with hypertension Reduce simple carbohydrates, sugars, and high-fat foods (eliminate trans fats) Limit saturated fat: <7% of calories, <20-30 g/day Limit cholesterol: <200 mg/day Increase water-soluble fiber: 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 Children 60 minutes of physical activity each day (Grade B) Adults 150 minutes/week of moderate-intensity aerobic physical activity (50%-70% 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 (>90 min) spent sitting (Grade B) In the absence of contraindications, resistance training at least twice per week (Grade A) ADA 2015 Guidelines. Diabetes Care. 2015;38(suppl 1):S20-S30. Evert AB, et al. Diabetes Care. 2014;37(suppl 1):S120 S ADA 2015 Guidelines. Diabetes Care. 2015;38(suppl 1):S20-S Psychosocial Assessment and Care 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 2015 Guidelines. Diabetes Care. 2015;38(suppl 1):S20-S Negative Reactions to Initial Diagnosis of Diabetes Are Common Base: all patients G u i l t y A n g r y D e p r e s s e d A n x i o u s Peyrot M, et al. Diabetes Care. 2005;28(11): T y p e 1 T y p e % Agreeing Pharmacologic Targeting of Pathophysiological Disturbances in T2DM Decreased incretin effect Decreased INS secretion Increased lipolysis Pharmacologic Treatment of T2DM Increased glucagon secretion HYPERGLYCEMIA Increased glucose reabsorption Increased HGP Neurotransmitter dysfunction Decreased glucose uptake HGP, hepatic glucose production. DeFronzo RA. Diabetes. 2009;58:

6 Pharmacologic Targeting of Pathophysiological Disturbances in T2DM (cont d) Recommendations for Pharmacologic Treatment Approach GLP-1 RAs DPP-4 inhibitors TZDs SUs Meglitinides GLP-1 RAs DPP-4 inhibitors Amylin analogs GLP-1 RAs DPP-4 inhibitors Bile acid sequestrants α-glucosidase inhibitors GLP-1 RAs TZDs SGLT2 inhibitors TZDs GLP-1, glucagon-like peptide 1; RA, receptor agonist; DPP-4, dipeptidyl peptidase-4; TZDs, thiazolidinediones. DeFronzo RA. Diabetes. 2009;58: as first-line treatment for diagnosed patients If glycemic goals are unmet, add-on therapy is recommended TZD Pioglitazone (PIO) Sulfonylurea DPP-4 inhibitor SGLT2 inhibitor GLP-1 RA INS Medication should be based upon individual patient characteristics: Effect on glycemic control Body weight Risk of hypoglycemia With the wide spectrum of antihyperglycemic agents available, the ideal choice of therapeutic combination is not always clear Inzucchi SE, et al. Diabetes Care. 2012;35(6): ADA 2015 Guidelines. Diabetes Care. 2015;38(suppl 1):S41-S The Role of the Kidney in Glucose Homeostasis Under normal conditions, the kidney is involved in maintaining glucose homeostasis via 3 different mechanisms: Targeting the Kidney for the Treatment of T2DM: SGLT2 Inhibition 1. Release of glucose into circulation via gluconeogenesis 2. Uptake of glucose to meet its own energy needs 3. Reabsorption of glucose from the glomerular filtrate Abdul-Ghani MA, et al. Endocr Rev. 2011;32(4): Gerich JE. Diabet Med. 2010;27: Stumvoll M, et al. J Clin Invest. 1995;96: Altered Renal Glucose Control in Diabetes Glucose Reabsorption in the Kidney by SGLT2 Gluconeogenesis is increased in postprandial and postabsorptive states in patients with Type 2 DM 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 GLUT, glucose transporter; ATP, adenosine triphosphate; ATPase, adenosine triphosphatase; S1, segment 1; S2, segment 2; S3, segment 3. Marsenic O. Am J Kidney Dis. 2009;53: Bakris GL, et al. Kidney Int. 2009;75(12): Rahmoune H, et al. Diabetes. 2005;54(12): Increased SGLT-2 expression and activity in renal epithelial cells from patients with diabetes vs. Gerich JE. Diabet Med. 2010;27: Whaley JM, et al. Diabetes Metab Syndr Obes. 2012;5: Rosenwasser RF, et al. Diabetes Metab Syndr Obes. 2013;6:

7 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 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 Therapeutic Benefits Associated with SGLT2 Inhibition 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) PPG, postprandial glucose. Gerich JE. Diabet Med. 2010;27: Plosker GL. Drugs. 2012;72: Whaley JM, et al. Diabetes Metab Syndr Obes. 2012;5: Mudaliar S, et al. Diabetes Technol Ther. 2014;16: Brooks AM, Thacker SM. Ann Pharmacother. 2009;42(7): Merovci A, et al. J Clin Invest. 2014;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 BP: 150/81 Current medications: extended release 1500 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 Case Study : A 65-year-old Female Current Laboratory Results Case Study #2: Discussion 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 Total Cholesterol Lipid Panel Today 3 Months Ago 6 Months Ago 240 mg/dl 245 mg/dl 250 mg/dl LDL-C 130 mg/dl 144 mg/dl 150 mg/dl HDL-C 39 mg/dl 37 mg/dl 36 mg/dl Triglycerides 205 mg/dl 208 mg/dl 210 mg/dl HDL-C, high-density lipoprotein cholesterol. 42 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) 43 7

8 Change in Baseline Body Weight (kg) Change in adipose tissue volume (cm 3 ) LS Mean Change (±SE) in HbA 1c From Baseline (%) Change in Baseline A1c (%) Currently Approved SGLT2 Inhibitors Overview of SGLT2 Inhibitor Glycemic Efficacy: Changes in Baseline A1c Level SGLT2 Inhibitor Initial Dose Max Dose* Renal Dose Adjustment CANA DAPA EMPA Canagliflozin (CANA) Dapagliflozin (DAPA) Empagliflozin (EMPA) 100 mg qd 300 mg qd 5 mg qd 10 mg qd 10 mg qd 25 mg qd *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. 2014;56(1457): egfr 45 <60 ml/min/1.73 m 2 : 100 mg CANA qd egfr <45 ml/min/1.73 m 2 : Not recommended egfr <30 ml/min/1.73 m 2 : egfr <60 ml/min/1.73 m 2 : Not recommended egfr <30 ml/min/1.73 m 2 : egfr <45 ml/min/1.73 m 2 : Not recommended egfr <30 ml/min/1.73 m 2 : *Doses evaluated in studies cited: CANA=100 or 300 mg, DAPA=5 or 10 mg, EMPA=10 or 25 mg. MONO, monotherapy; GLIM, glimepiride; SITA, sitagliptin; PBO, placebo. PBO SGLT2 inhibitor (low dose)* SGLT2 inhibitor (high dose)* 45 CANA Treatment Improves Glycemic Levels Independent of Disease Duration Effects of DAPA Treatment on β-cell Function N Baseline (%) T2DM Duration <5 Years T2DM Duration 5-<10 Years T2DM Duration 10 Years % (95% CI: -0.84, -0.56) -0.96% (95% CI: -1.10, -0.82) -0.74% (95% CI: -0.90, -0.59) -0.91% (95% CI: -1.06, -0.75) -0.74% (95% CI: -0.89, -0.58) -0.85% (95% CI: -1.00, -0.70) Two weeks of DAPA treatment was associated with increased C-Pep0 120/G0 120 IR, suggesting an improvement in β-cell function Wilding JP, et al. J Diabetes Complications. 2015;29(3): *P <.05 vs baseline and vs placebo. Merovci A et al. J Clin Endocrinol Metab. 2015:jc 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 wk 200 Placebo + Metformin n=42; n=37 Dapagliflozin 10 mg + Metformin n=37; n= PBO SGLT2 inhibitor (low dose)* *Doses evaluated in studies cited: CANA=100 or 300 mg, DAPA=5 or 10 mg, EMPA=10 or 25 mg. SGLT2 inhibitor (high dose)* Visceral AT Subcutaneous AT Dapagliflozin reduces total body weight predominantly by reducing fat mass, visceral adipose tissue and SC adipose tissue volume., VAT, cm 3 (95 CI = to -68.6; nominal P = ); Bolinder J, et al. J Clin Endocrinol Metab (3): , SAT, cm 3 (95% CI = -359 to -10.1; nominal P = ). 49 8

9 Change From Baseline HbA 1c (%) Mean (SE) HbA 1c, % DAPA Added on to Metformin Durably Reduces A1c Levels & Body Weight at 4 Years Combination Therapy with SGLT2 Inhibitors SGLT2 Inhibitor Previously Studied Therapeutic Combinations Dual Therapy Triple Therapy CANA DAPA EMPA Sulfonylurea Sulfonylurea PIO Sulfonylurea and sulfonylurea and PIO INS ± other AHAs and sulfonylurea and DPP-4 inhibitor INS ± other AHAs and sulfonylurea PIO ± Del Prato S et al. Diabetes Obes Metab AHAs, antihyperglycemic agents. Peene B, et al. Ther Adv Endocrinol Metab. 2014;5(5): Wilding JP. Metabolism. 2014;63(10): Add-on Therapy with DAPA and SAXA for Patients Inadequately Controlled With Currently Approved Fixed-dose SGLT2 Inhibitor Combination Therapies 9.5 SAXA+DAPA+ Combination Initial Dose Maximum Daily Dose Renal Dose Adjustment SAXA+ DAPA+ CANA/ 50/ /500 mg bid with meals 300/2000 mg egfr 45 <60 ml/min/1.73 m 2 : Adjust to 50 mg CANA bid egfr <45 ml/min/1.73 m 2 : DAPA/ 5/500 10/1000 mg qd in the morning 10/2000 mg egfr <60 ml/min/1.73 m 2 : Weeks EMPA/ linagliptin 10/5 mg qd in the morning, with or without food 25/5 mg egfr <45 ml/min/1.73 m 2 : Not recommended egfr <30 ml/min/1.73 m 2 : SAXA, saxagliptin. bid, twice a day. Rosenstock J, et al. Diabetes Care. 2015;38(3): Med Lett Drugs Ther. 2014;56(1457): Fixed-dose Combination Therapy: EMPA and Linagliptin Mean baseline 7.99% 8.04% 7.99% 8.05% 8.05% (64 mmol/mol) (64 mmol/mol) (64 mmol/mol) (64 mmol/mol) (64 mmol/mol) (95% CI: -0.39, 0.07) P= (95% CI: -0.90, 0.43) P< (95% CI: -0.94, 0.48) P< (95% CI: -0.94, 0.48) P<.001 Reductions from baseline HbA 1c with EMPA/linagliptin were greater vs linagliptin and EMPA 10 mg, but not vs EMPA 25 mg. Change From Baseline HbA 1c (mmol/mol) Long-term Treatment with SGLT2 Inhibitors Special Populations:Obesity,Hypertension,CVD Lewin A, et al. Diabetes Care. 2015;38(3):

10 LS Mean % Change (±SE) in Systolic BP From Baseline (mm Hg) LS Mean % Change (±SE) In Body Weight From Baseline HbA 1c (%) Adjusted Mean Change From Baseline HbA 1c (%) INS Dose (u/day) EMPA in Obese Patients Inadequately Controlled with INS at 1 Year Effects of SGLT2 Inhibitors on BP INS Dose HbA1c Week ± 2.1 MDI INS + placebo 92.9 ± ± % ± 0.07% (60 ± 0.8 mmol/mol) 7.24% ± 0.07% (58 ± 0.8 mmol/mol) 7.08% ± 0.07% (54 ± 0.8 mmol/mol) MDI INS + EMPA 10 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 sensitivty 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. 2014;37(7): Foote C, et al. Diab Vasc Dis Res. 2012;9(2): Haring HU, et al. Diabetes Care. 2014;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 -0.6% (-0.6 kg) -3.0% (-2.7 kg) -3.8% (-3.5 kg) -2.3% (95% CI: -3.1, -1.6) (-2.1 kg) -3.2% (95% CI: -4.0, -2.4) (-2.9 kg) Placebo CANA 100 mg CANA 300 mg Efficacy endpoint evaluation period Placebo; HbA 1c baseline 8.0% DAPA; HbA 1c baseline 8.0% Time Point (Weeks) -0.4 Baseline (mm Hg) LS mean % change -0.6 Systolic BP Time Point (Weeks) *55-80 years of age. Bode B, et al. Diabetes Obes Metab. 2015;17(3): mm Hg -1.2 mm Hg -3.0 mm Hg -5.8 mm Hg (95% CI: -8.0, -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. 2014;62(7): Time (Weeks) 59 CANA Monotherapy Improves Cardiovascular Risk Factors Safety and Tolerability Outcome Measure CANA 100 mg CANA 300 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<.001; P<.01. Stenlof K, et al. Diabetes Obes Metab. 2013;15:

11 Patients for Whom SGLT2 Inhibitors Are Not Recommended 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 Yale JF, et al. Diabetes Obes Metab. 2013;15(5): Mikhail N. World J Diabetes. 2014;5(6): Peene B, et al. Ther Adv Endocrinol Metab. 2014;5(5): Adverse Events Associated with SGLT2 Inhibitor Treatment Most common adverse events (AE): Genital mycotic infection (GMIs) Lower urinary tract infection (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 , 1.90 GMI , 7.45 *CANA or DAPA. Nauck MA. Drug Des Devel Ther. 2014;8: Vasilakou D, et al. Ann Intern Med. 2013;159(4): Patients for Whom SGLT2 Inhibitors Are Not Recommended Summary 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 Yale JF, et al. Diabetes Obes Metab. 2013;15(5): Mikhail N. World J Diabetes. 2014;5(6): Peene B, et al. Ther Adv Endocrinol Metab. 2014;5(5): 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 65 Thank You! 11