Diabetes Update What s the fuss about CV Death?

Transcription

1 Diabetes Update What s the fuss about CV Death? Peter J. Lin, MD, CCFP Director Primary Care Initiatives Canadian Heart Research Centre Associate Editor, Elsevier WebPortal

2 Copyright 2017 by Sea Courses Inc. All rights reserved. No part of this document may be reproduced, copied, stored, or transmitted in any form or by any means graphic, electronic, or mechanical, including photocopying, recording, or information storage and retrieval systems without prior written permission of Sea Courses Inc. except where permitted by law. Sea Courses is not responsible for any speaker or participant s statements, materials, acts or omissions.

3 Faculty/Presenter Disclosure Faculty: Dr. Peter Lin Relationships with commercial interests: Grants/Research Support: Speakers Bureau/Honoraria: Astrazeneca, Takeda, Boeringher Ingelheim, Eli Lilly, Sanofi, Janssen, Merck, Pfizer, Servier, Abbott, Forest Laboratories, Novartis, Purdue Consulting Fees: Other:

4 HbA1C 120 Days new one 8% Image used only as an educational purpose. Astra Zeneca is not responsible for the copyright

5 Damage Is Done Prevent Damage Image used only as an educational purpose. Astra Zeneca is not responsible for the copyright

6 Type 2 Diabetes Chronic Complications Microvascular Complications Diabetic Retinopathy Most common cause of blindness in active adult population 1 Diabetic Nephropathy Most common cause of Chronic Renal Failure and Dialysis 2 Diabetic Neuropathy Most common cause of nontraumatic amputation of lower limbs 6 1. Fong DS et al. Diabetes Care 2003; 26 (Suppl 1):S99-S Molitch ME et al. Diabetes Care 2003; 26(Suppl 1):S94-S Kannel WB et al. Am J Heart 1990; 120: Duckworth W et al. N Engl J Med 2009;360: Smith NL et al. Diabetes Care 2006;29: Mayfield JA et al. Diabetes Care 2003; 26 (Suppl 1):S78-S79. 6

7 Microvascular Events and Glucose Control TYPE 1 DIABETES TYPE 2 DIABETES DCCT/EDIC 1 (DCCT n=1441) (EDIC n=1375) UKPDS 2 (n = 3,867) ADVANCE 3 (n = 11,140) VADT 4 (n = 1,791) ACCORD 5 (n = 10,251) In-trial 6.5 years Extensio n 17 years In-trial 10 years Extension 20 years In-trial 4.5 years Extension 10 years In-trial 5.6 years Extension 9.8 years In-trial 4-5 years Extension 8 years A1C achieved (%)* 7.2 vs vs vs vs vs. 7.6 All microvascular (HR) NS Nephropathy (HR) 0.46 NS 0.91 NS** 0.71 Neuropathy (HR) 0.40 NS NS NS 0.92 Retinopathy (HR) NS NS 0.67 *Average A1C achieved, intensive vs. standard ** No significant effect, intensive vs. standard, with the exception of worsening of albumin excretion (P=0.01) and progression to macroalbuminuria (P=0.04). NS = non significant; HR = hazard ratio 1. DCCT Research Group N Engl J Med 1993;329:977-86; DCCT/EDIC Study Research Group. N Engl J Med 2005;353: UKPDS Group. Lancet 1998;352: ; Holman R et al. NEJM 2008; ADVANCE Collaborative Group. N Engl J Med 2008;358: ; ADVANCE-ON Collaborative Group. N Engl J Med 2014;371: ; 4.Duckworth W et al. N Engl J Med 2009;360: ; VADT Investigators. N Engl J Med 2015;372: ; 5.ACCORD Study Group. NEJM 2018;358: Ismail-Beigi F et al. Lancet 2010; 376: ACCORD Study Group. NEJM IDF 2015; Abstracts 277 &

8 Microvascular Events and Glucose Control TYPE 1 DIABETES TYPE 2 DIABETES DCCT/EDIC 1 (DCCT n=1441) (EDIC n=1375) UKPDS 2 (n = 3,867) ADVANCE 3 (n = 11,140) VADT 4 (n = 1,791) ACCORD 5 (n = 10,251) In-trial 6.5 years Extensio n 17 years In-trial 10 years Extension 20 years In-trial 4.5 years Extension 10 years In-trial 5.6 years Extension 9.8 years In-trial 4-5 years Extension 8 years A1C achieved (%)* 7.2 vs vs vs vs vs. 7.6 All microvascular (HR) NS NS Nephropathy (HR) NS (ESRD) NS** 0.71 Neuropathy (HR) NS NS NS 0.92 Retinopathy (HR) NS NS NS *Average A1C achieved, intensive vs. standard ** No significant effect, intensive vs. standard, with the exception of worsening of albumin excretion (P=0.01) and progression to macroalbuminuria (P=0.04). NS = non significant; HR = hazard ratio 1. DCCT Research Group N Engl J Med 1993;329:977-86; DCCT/EDIC Study Research Group. N Engl J Med 2005;353: UKPDS Group. Lancet 1998;352: ; Holman R et al. NEJM 2008; ADVANCE Collaborative Group. N Engl J Med 2008;358: ; ADVANCE-ON Collaborative Group. N Engl J Med 2014;371: ; 4.Duckworth W et al. N Engl J Med 2009;360: ; VADT Investigators. N Engl J Med 2015;372: ; 5.ACCORD Study Group. NEJM 2018;358: Ismail-Beigi F et al. Lancet 2010; 376: ACCORD Study Group. NEJM 2010; IDF 2015; Abstracts 277 &

9 Type 2 Diabetes Chronic Complications Macrovascular Complications CVA 2 to 4 fold in CV mortality and strokes 3 Myocardial Infarction, Heart failure Peripheral arterial disease 40-60% die of a CV event 4,5 Patients with Diabetes Die of Heart Disease 1. Fong DS et al. Diabetes Care 2003; 26 (Suppl 1):S99-S Molitch ME et al. Diabetes Care 2003; 26(Suppl 1):S94-S Kannel WB et al. Am J Heart 1990; 120: Duckworth W et al. N Engl J Med 2009;360: Smith NL et al. Diabetes Care 2006;29: Mayfield JA et al. Diabetes Care 2003; 26 (Suppl 1):S78-S79. 9

10 Macrovascular Events and Glucose Control DCCT/EDIC 1 (DCCT n=1441) (EDIC n=1375) UKPDS 2 (n = 3,867) ADVANCE 3 (n = 11,140) VADT 4 (n = 1,791) ACCORD 5 (n = 10,251) In-trial 6.5 years Extension 17 years In-trial 10 years Extension 20 years In-trial 4.5 years Extension 10 years In-trial 5.6 years Extension 9.8 years In-trial 3.7 years Extension 8.8 years A1C achieved (%)* 7.2 vs vs vs vs vs. 7.5 All macrovascular (HR) NS NS NS NS NS CV Mortality (HR) NS NS NS 1.35 Myocardial Infarction (HR) NS NS 0.76 *Average A1C achieved, intensive vs. standard NS = non significant; HR = hazard ratio 1. DCCT Research Group N Engl J Med 1993;329:977-86; DCCT/EDIC Study Research Group. N Engl J Med 2005;353: UKPDS Group. Lancet 1998;352: ; Holman R et al. NEJM 2008; ADVANCE Collaborative Group. N Engl J Med 2008;358: ; ADVANCE-ON Collaborative Group. N Engl J Med 2014;371: ; 4.Duckworth W et al. N Engl J Med 2009;360: ; VADT Investigators. N Engl J Med 2015;372: ; 5.ACCORD Study Group. NEJM 2018;358: Ismail-Beigi F et al. Lancet 2010; 376: ACCORD Study Group. NEJM 2010; IDF 2015; Abstracts 277 &

11 Macrovascular Events and Glucose Control DCCT/EDIC 1 (DCCT n=1441) (EDIC n=1375) UKPDS 2 (n = 3,867) ADVANCE 3 (n = 11,140) VADT 4 (n = 1,791) ACCORD 5 (n = 10,251) In-trial 6.5 years Extension 17 years In-trial 10 years Extension 20 years In-trial 4.5 years Extensio n 10 years In-trial 5.6 years Extension 9.8 years In-trial 3.7 years Extension 8.8 years A1C achieved (%)* 7.2 vs vs vs vs vs. 7.5 All macrovascular (HR) CV Mortality (HR) Myocardial Infarction (HR) NS 0.43 NS NS NS NS 0.83 NS NS 0.87 NS NS NS NS NS (total mortality) NS 0.85 NS NS 0.76 NS *Average A1C achieved, intensive vs. standard NS = non significant; HR = hazard ratio 1. DCCT Research Group N Engl J Med 1993;329:977-86; DCCT/EDIC Study Research Group. N Engl J Med 2005;353: UKPDS Group. Lancet 1998;352: ; Holman R et al. NEJM 2008; ADVANCE Collaborative Group. N Engl J Med 2008;358: ; ADVANCE-ON Collaborative Group. N Engl J Med 2014;371: ; 4.Duckworth W et al. N Engl J Med 2009;360: ; VADT Investigators. N Engl J Med 2015;372: ; 5.ACCORD Study Group. NEJM 2018;358: Ismail-Beigi F et al. Lancet 2010; 376: ACCORD Study Group. NEJM 2010; IDF 2015; Abstracts 277 &

12 Severe Hypoglycemia Requiring Medical Assistance ACCORD Study Group, NEJM : Intensive Group Annual Incidence Rate = 3.3% Standard Group Annual Incidence Rate = 1.0%

13 Rate/100 Patient Years DCCT RESULTS Severe Hypoglycemia 100 Persistent three-fold increase in INT Intensive Increased risk of multiple episodes within same patient (INT = 22%, CON = 4%) Number of prior episodes was strongest predictor of future risk 20 Current A1C not solely predictive of risk 0 Conventional HbA 1c (%) During Study DCCT Research Group, Diabetes 1997;46:

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15 CV Consequences of Hypoglycemia Prolonged QT- intervals- Diabetologia 52:42,2009 Can be of pronged duration IJCP Sup 129, 7/02 Greater with higher catecholamine levels Europace 10,860 Associated with Angina Diabetes Care 26, 1485, 2003 / Ischemic EKG changes Porcellati, ADA2010 Associated with Arrhythmias Associated with Sudden Death Endocrine Practice 16,¾ 2010 Increased Glycemic Variabilty- Adverse ICU outcomes/increased vascular inflammation Hirsch ADA2010

16 Cumulative Incidence of Primary End-Point Events (%) EXAMINE: Alogliptin was non-inferior but not superior to placebo with respect to the primary end point Composite of death from CV causes, nonfatal MI, or nonfatal stroke Alogliptin or placebo was added to usual antihyperglycemic therapies Alogliptin Placebo HR (95% CI) = 0.96 (upper boundary of the one-sided repeated CI 1.16) P < for noninferiority P = 0.32 for superiority No. at Risk Months Placebo Alogliptin CI, confidence interval; CV, cardiovascular; EXAMINE, Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome; MI, myocardial infarction. White WB et al. N Engl J Med. 2013;369:

17 Patients with End Point (%) SAVOR-TIMI 53: Saxagliptin was non-inferior but not superior to placebo with respect to the primary endpoint Composite of CV death, MI, or ischemic stroke Saxagliptin or placebo was added to usual antihyperglycemic therapies No. at Risk Saxagliptin Placebo HR (95% CI) = 1.00 ( ) P < for noninferiority P = 0.99 for superiority Days Placebo Saxagliptin CI, confidence interval; CV, cardiovascular; MI, myocardial infarction; HR, hazard ratio; SAVOR-TIMI 53, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus Thrombolysis in Myocardial Infarction 53. Scirica BM et al. N Engl J Med. 2013;369:

18 Percent of patients with an event TECOS: Sitagliptin was non-inferior but not superior to placebo with respect to the primary end point Time from randomization to the first confirmed CV-related death, nonfatal MI, nonfatal stroke, or UA requiring hospitalization Sitagliptin or placebo was added to usual antihyperglycemic therapies Sitagliptin Placebo HR (95% CI): 0.98 (0.89, 1.08) P = for superiority P <0.001 for non-inferiority Patients at risk: Months in the trial Sitagliptin 7,332 7,131 6,937 6,777 6,579 6,386 4,525 3,346 2,058 1,248 Placebo 7,339 7,146 6,902 6,751 6,512 6,292 4,411 3,272 2,034 1,234 CV, cardiovascular; MI, myocardial infarction; TECOS, Trial Evaluating Cardiovascular Outcomes with Sitagliptin; UA, unstable angina. Green JB et al. N Engl J Med 2015;373:

19 Hospitalization for Heart Failure: EXAMINE, SAVOR-TIMI 53, and TECOS Study Drug n/n (%) Placebo n/n (%) Hazard Ratio 95% CI P Value SAVOR-TIMI 53 (saxagliptin vs. placebo) 289/8280 (3.5%) 228/8212 (2.8%) , EXAMINE (alogliptin vs. placebo) 106/2701 (3.9%) 89/2679 (3.3%) , TECOS (sitagliptin vs. placebo) 228/7332 (3.1%) 229/7339 (3.1%) , SAVOR + EXAMINE + TECOS 623/18313 (3.4%) 546/18230 (3.0%) , Favours Treatment Favours Placebo

20 Renal handling of glucose (180 L/day) (1000 mg/l) =180 g/day Glomerulus S1 Proximal tubule Distal tubule Collecting duct Glucose filtration ~90% ~10% S3 Glucose reabsorption Loop of Henle No/minimal glucose excretion S1 segment of proximal tubule - ~90% glucose reabsorbed - Facilitated by SGLT2 S3 segment of proximal tubule - ~10% glucose reabsorbed - Facilitated by SGLT1 SGLT = Sodium-dependent glucose transporter Adapted from: 1. Bailey CJ. Trends in Pharmacol Sci 2011;32: Chao EC. Core Evidence 2012;7:21-28.

21 Renal handling of glucose IN DIABETES PATIENTS (180 L/day) (1000 mg/l) =180 g/day Glomerulus S1 Proximal tubule Distal tubule Collecting duct Glucose filtration ~90% S3 Glucose reabsorption Loop of Henle SGLT = Sodium-dependent SGLT2 Inhibitor glucose transporter S1 segment of proximal tubule - ~90% glucose reabsorbed - Facilitated by SGLT2 Adapted from: 1. Bailey CJ. Trends in Pharmacol Sci 2011;32: Chao EC. Core Evidence 2012;7:21-28.

22 11/2016 Add another agent best suited to the individual by prioritizing patient characteristics: PATIENT CHARACTERISTIC PRIORITY: Clinical Clinical Cardiovascular cardiovascular Disease disease Degree of hyperglycemia Risk of hypoglycemia Overweight or obesity CV disease or multiple risk factors Comorbidities (renal, CHF, hepatic) Preferences & access to treatment CHOICE OF AGENT Antihyperglycemic agent with demonstrated CV outcome benefit (empagliflozin, liraglutide) Consider relative A1C lowering Rare hypoglycemia Weight loss or weight neutral Effect on cardiovascular outcome See therapeutic considerations; consider egfr See cost column; consider access guidelines.diabetes.ca BANTING ( ) diabetes.ca Copyright 2016 Canadian Diabetes Association

23 Patient with an event (%) LEADER: CV death Patients at risk Time from randomization (months) Placebo HR: % CI ( ) p=0.007 Liraglutide Liraglutide Placebo The cumulative incidences were estimated with the use of the Kaplan Meier method, and the hazard ratios with the use of the Cox proportional-hazard regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months. CI: confidence interval; CV: cardiovascular; HR: hazard ratio. Marso S et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes N Engl J Med June 2016 doi: /NEJMoa Presented at the American Diabetes Association 76 th Scientific Sessions, Session 3-CT-SY24. June , New Orleans, LA, USA.

24 AACE s most recent guideline update has moved SGLT2 inhibitors ahead of DPP4i of DPP4 inhibitors as the first suggested oral addon1 *. Order of medications represents a suggested hierarchy of usage. AACE, American Association of Clinical Endocrinologists; AG, -glucosidase; DPP4, dipeptidyl peptidase-4; GLP1, glucagon-like peptide-1; QR, quick release; SGLT2, sodium-glucose co-transporter-2; SU, sulphonylurea; TZD, thiazolidinedione. 1. Garber AJ, et al. Endocr Pract 2016;22;84 113

25 AACE s most recent guideline update has moved SGLT2 inhibitors ahead of DPP4i of DPP4 inhibitors as the first suggested oral addon1 *. Order of medications represents a suggested hierarchy of usage. AACE, American Association of Clinical Endocrinologists; AG, -glucosidase; DPP4, dipeptidyl peptidase-4; GLP1, glucagon-like peptide-1; QR, quick release; SGLT2, sodium-glucose co-transporter-2; SU, sulphonylurea; TZD, thiazolidinedione. 1. Garber AJ, et al. Endocr Pract 2016;22;84 113

26 Oral Pharmacologic Treatment of Type 2 Diabetes Mellitus: A Clinical Practice Guideline Update From the American College of Physicians Comparative Efficacy & Adverse Effects for Add On Oral Therapies to Metformin Comparative Efficacy vs. Other Combinations with Metformin (Quality of Evidence) Sulfonylurea Comparative Harms vs. Other combinations with Metformin/Class Adverse Effects and FDA Warnings Adverse Effects SU + metformin favored for weight vs. TZD + Metformin (moderate) Thiazolidinediones Higher risk for hypoglycemia than with Metformin combinations with TZD, DPP4 inhibitor, or SGLT 2 inhibitor Diarrhea, gas, jitteriness, dizziness, nausea, upper abdominal fullness, uncontrollable shaking, red or itchy skin, rash, hives and blisters TZD + Metformin favored for short term CVD Mortality (rosiglitazone only) increase risk congestive heart failure. May also be Headache, muscle, arm or leg pain, runny nose other (low) and HbA1c vs. DPP4 + metformin (moderate) associated with increased risk for fracture bladder cancer cold symptoms, sore throat, back pain gas SGLT 2 inhibitor + Metformin favored for weight and DPP4 inhibitors systolic blood pressure (moderate) vs. DPP4 inhibitor + FDA warns that sitagliptin, saxagliptin, linagliptin, and alogliptin, maybe associated with potentially severe and disabling joint pain Metformin DPP4 inhibitor + metformin favored for long term all-cause mortality, long term CVD mortality, and CVD morbidity vs. SU + metformin (low) DPP4 inhibitor + Metformin favored for short term CVD morbidity vs. pioglitazone + metformin (low) DPP4 inhibitor + Metformin favored for weight vs. SU + Metformin (high) or TZD + Metformin (moderate) Headache, stuffy or runny nose, diarrhea, sore throat, and joint pain SGLT-2 Inhibitors SGLT 2 inhibitor + 2Metformin inhibitor favored for CVD mortality + (low), Metformin favored for CVD mortality higher risk for genital mycotic infection than HbA1c (moderate), weight (high), systolic blood pressure (high), and heart rate (moderate) vs. SU + Metformin metformin alone or metformin combinations with SU excessive urination, including at night; increased or DPP4 inhibitor (low), HbA1c (moderate), weight (high), systolic blood pressure FDA warns that canagliflozin may be associated with thirst; constipation; and dry mouth SGLT 2 inhibitor + Metformin favored for weight and systolic blood increased risk for bone fracture and risk for decreased pressure (moderate) bone mineral density vs. DPP4 inhibitor + Metformin (high), and heart rate (moderate) vs. SU + Metformin Adapted from Quaseem et.al. Oral Pharmacologic Treatment of Type 2 Diabetes Mellitus: A Clinical Practice Guideline Update From the American College of Physicians. Ann Intern Med. 2017;166: doi: /m January 2017

27 CV death HR 0.62 (95% CI 0.49, 0.77) p< % Cumulative incidence function. HR, hazard ratio 27

28 Hospitalisation for heart failure HR 0.65 (95% CI 0.50, 0.85) p= % Cumulative incidence function. HR, hazard ratio 28

29 Categories of CV Death Patients with CV death Placebo (n=2333) Empagliflozin 10 mg (n=2345) Empagliflozin 25 mg (n=2342) Pooled Empagliflozin (n=4687) 137 (5.9) 90 (3.8) 82 (3.5) 172 (3.7) Sudden death 38 (1.6) 30 (1.3) 23 (1.0) 53 (1.1) Worsening of heart failure 19 (0.8) 7 (0.3) 4 (0.2) 11 (0.2) Acute MI 11 (0.5) 6 (0.3) 9 (0.4) 15 (0.3) Stroke 11 (0.5) 9 (0.4) 7 (0.3) 16 (0.3) Cardiogenic shock 3 (0.1) 1 (<0.1) 2 (0.1) 3 (0.1) Other CV death 55 (2.4) 37 (1.6) 37 (1.6) 74 (1.6) Data are n (%) Zinman B et al. N Engl J Med. 2015;373:

30 Hypothetical Situation H H H L L L L H 7-10 mmol/l

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33 SGLT2 Inhibitor Outcomes Trials EMPA-REG Outcome CANVAS CANVAS-R CREDENCE DECLARE Ertugliflozin CVOT n Interventions (randomization) EMPA/PBO (2:1) CANA/PBO (2:1) CANA/PBO (1:1) CANA/PBO (1:1) DAPA/PBO (1:1) ERTU/PBO (2:1) Key inclusion criteria Established vascular complications HbA1c % Age 18 yearsa Established vascular complications (age >30) or 2 CV risk factors (age >50 years) HbA1c % Established vascular complications or 2 CV risk factors HbA1c % Age >30 years Stage 2 or 3 CKD and microalbuminuria and on ACEi/ARB HbA1c % Age >30 years High risk for CV events (Established and at risk) HbA1c TBD Age 40 years Established vascular complications HbA1c % Age 40 years Primary endpoint CV death, non-fatal MI, non-fatal stroke CV death, non-fatal MI, non-fatal stroke Progression of albuminuria ESKD, serum creatinine doubling, renal/cv death CV death, non-fatal MI, non-fatal ischemic stroke CV death, non-fatal MI, non-fatal stroke Target no. events TBD TBD 1390 TBD a 20 yrs in Japan and also 65 years in India ACEi, angiotensin converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CANA, canagliflozin; CKD, chronic kidney disease; DAPA, dapagliflozin; EMPA, empagliflozin; ERTU, ertugliflozin; ESKD, end stage kidney disease; HbA 1c, glycated hemoglobin; MI, myocardial infarction; PBO, placebo; TBD, to be determined Inzucchi SE, et al. Diab Vasc Dis Res 2015;12: Dapagliflozin does not have indication for Cardiovascular Disease Reduction

34 Primary MACE Outcome CV Death, Nonfatal Myocardial Infarction or Nonfatal Stroke No. of patients Placebo 434 Canagliflozin Intent-to-treat analysis Years since randomization

35 Hospitalization for Heart Failure No. of patients Placebo 434 Canagliflozin Intent-to-treat analysis Years since randomization

36 CV Death Component of Primary Outcome Empa Type Patients = 6656 No. of patients Placebo 434 Canagliflozin Intent-to-treat analysis Years since randomization

37 Follow-up CANVAS-R weeks CANVAS weeks CANVAS Program mean follow-up 188 weeks Patients remaining on randomized treatment: Canagliflozin 71% Placebo 70%

38 Lower-extremity Amputations No. at risk Placebo Canagliflozin Years since randomization Increased risk communicated to health authorities, investigators, and providers in 2016 based on IDMC letter.

39 Amputation Risk Factors - Multivariate Analysis Risk Factor at Baseline Hazard Ratio 95% CI Amputation 20.9 ( ) Peripheral vascular disease* 3.1 ( ) Male 2.4 ( ) Neuropathy 2.1 ( ) HbA1c >8% 1.9 ( ) Canagliflozin treatment 1.8 ( ) Presence of CV disease 1.5 ( ) Predictors of amputation risk are similar in both arms Canagliflozin treatment, independent of the risk factors, increased amputation risk Predictive on univariate analysis: nephropathy, insulin use, retinopathy, loop diuretic, egfr, diabetes duration Factors assessed but not significantly predictive: non-loop diuretic, smoking, SBP, hemoglobin, age * Excludes amputations

40 Any Amputation SGTL2 inhibitors and amputations in the US FDA Adverse Event Reporting System Published Online July 18, S (17)

41 Toe Amputations SGTL2 inhibitors and amputations in the US FDA Adverse Event Reporting System Published Online July 18, S (17)

42 Diabetic Foot SGTL2 inhibitors and amputations in the US FDA Adverse Event Reporting System Diabetes Diabetes No Insulin Published Online July 18, S (17)

43 SGLT2 Inhibitor Outcomes Trials 7000 Secondary Primary EMPA-REG Outcome CANVAS CANVAS-R CREDENCE DECLARE Ertugliflozin CVOT n Interventions (randomization) EMPA/PBO (2:1) CANA/PBO (2:1) CANA/PBO (1:1) CANA/PBO (1:1) DAPA/PBO (1:1) ERTU/PBO (2:1) Key inclusion criteria Established vascular complications HbA1c % Age 18 yearsa Established vascular complications (age >30) or 2 CV risk factors (age >50 years) HbA1c % Established vascular complications or 2 CV risk factors HbA1c % Age >30 years Stage 2 or 3 CKD and microalbuminuria and on ACEi/ARB HbA1c % Age >30 years High risk for CV events (Established and at risk) HbA1c TBD Age 40 years Established vascular complications HbA1c % Age 40 years Primary endpoint CV death, non-fatal MI, non-fatal stroke CV death, non-fatal MI, non-fatal stroke Progression of albuminuria ESKD, serum creatinine doubling, renal/cv death CV death, non-fatal MI, non-fatal ischemic stroke CV death, non-fatal MI, non-fatal stroke Target no. events TBD TBD 1390 TBD a 20 yrs in Japan and also 65 years in India ACEi, angiotensin converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CANA, canagliflozin; CKD, chronic kidney disease; DAPA, dapagliflozin; EMPA, empagliflozin; ERTU, ertugliflozin; ESKD, end stage kidney disease; HbA 1c, glycated hemoglobin; MI, myocardial infarction; PBO, placebo; TBD, to be determined Inzucchi SE, et al. Diab Vasc Dis Res 2015;12: Dapagliflozin does not have indication for Cardiovascular Disease Reduction

44 CVD REAL Study (US, UK, Norway, Denmark, Sweden, Germany) 1,299,915 new users of SGLT2 inhibitor or other glucose-lowering drug fulfilling the eligibility criteria 160,010 SGLT2 inhibitor 1,139,905 other glucose-lowering drug 5487 (3%) excluded during 1:1 match process 1:1 propensity match 985,382 (86%) excluded during 1:1 match process 154,523 SGLT2 inhibitor 154,523 other glucoselowering drug Kosiborod et al. ACC 2017; Washington DC [Presentation ]

45 USA What is propensity matching? Less Difference /CIRCULATIONAHA

46 USA /CIRCULATIONAHA

47 CVD REAL Study (US, UK, Norway, Denmark, Sweden, Germany) 1,299,915 new users of SGLT2 inhibitor or other glucose-lowering drug fulfilling the eligibility criteria 160,010 SGLT2 inhibitor 1,139,905 other glucose-lowering drug 5487 (3%) excluded during 1:1 match process 1:1 propensity match 985,382 (86%) excluded during 1:1 match process 154,523 SGLT2 inhibitor DAPA & CANA Kosiborod et al. ACC 2017; Washington DC [Presentation ] 154,523 other glucoselowering drug 309,000 patient Data

48 Baseline characteristics for the full propensity matched cohort (Cohort 1) SGLT2 inhibitor* N=154,523 Other glucose-lowering drug* N=154,523 Age (years), mean (SD) 57.0 (9.9) 57.0 (10.1) Women 68,419 (44.3) 68,770 (44.5) Established cardiovascular disease 20,043 (13.0) 20,302 (13.1) Acute myocardial infarction 3792 (2.5) 3882 (2.5) Primary Prevention 87% Unstable angina 2529 (1.6) 2568 (1.7) Heart failure 4714 (3.1) 4759 (3.1) Insulin Users 29% (45,000) Atrial fibrillation 5632 (3.6) 5698 (3.7) Stroke 6347 (4.1) 6394 (4.1) Peripheral arterial disease 5239 (3.4) 5229 (3.4) Microvascular disease 42,214 (27.3) 42,221 (27.3) Chronic kidney disease 3920 (2.5) 4170 (2.7) *Data are n (%) unless otherwise stated; Myocardial infarction, unstable angina, stroke, heart failure, transient ischemic attack, coronary revascularization or occlusive peripheral Kosiborod et al. ACC 2017; Washington DC [Presentation ] artery disease

49 CVD REAL - Hospitalization for heart failure primary analysis HHF 39% P-value for SGLT2 inhibitor vs other glucose-lowering drug: p-value <0.001 Data are on treatment, unadjusted. Kosiborod et al. ACC 2017; Washington DC [Presentation ] Heterogeneity p-value: 0.17

50 CVD REAL - All-cause death primary analysis DEATH 51% SGLT2i vs other glucose-lowering drug: P <0.001 Data are on treatment, unadjusted. Kosiborod et al. ACC 2017; Washington DC [Presentation ] Heterogeneity p-value: 0.09

51 Worry List Reality DKA

52 Other adverse events (1) Placebo (n=2333) Empagliflozin 10 mg (n=2345) Empagliflozin 25 mg (n=2342) n (%) Rate n (%) Rate n (%) Rate Diabetic ketoacidosis* 1 (<0.1%) Acute kidney injury 155 (6.6%) Events consistent with 115 volume depletion (4.9%) Serious events 24 (1.0%) Events leading to discontinuation 7 (0.3%) Venous thrombotic events** 20 (0.9%) Rate = per100 patient-years Patients treated with 1 dose of study drug *Based on 4 MedDRA preferred terms. Based on 1 standardised MedDRA query Based on 8 MedDRA preferred terms. **Based on 1 standardised MedDRA query (0.1%) (5.2%) (4.9%) (0.8%) (<0.1%) (0.4%) (<0.1%) (5.3%) (5.3%) (1.1%) (0.2%) (0.9%) % on Insulin

53 1. Don t Stop Insulin 2. If patient is missing Insulin give insulin (Type 1, LADA, Losing weight high sugars) Image used for academic purpose only. AstraZeneca is not responsible for the copyrights

54 Counsel all Patients About Sick Day Medication List 2015 DM: SU, Metformin, SGLT2 BP: Diuretic, ACEi, ARB NSAIDS

55 Worry List Reality DKA < 0.1% Tell Patients not to stop insulin If patients are missing insulin then give them insulin If Sick stop SGLT2i

56 Worry List Reality Genital Infections 7 per time Simple to Treat UTIs 3 per time Simple to Treat Frequency of urination 1 Extra pee Per Day

57 Renal handling of glucose IN DIABETES PATIENTS Glomerulus Proximal tubule Distal tubule Collecting duct Glucose Sticks No Stick Loop of Henle Adapted from: 1. Bailey CJ. Trends in Pharmacol Sci 2011;32: Chao EC. Core Evidence 2012;7:

58 IN Pipe OUT Pipe Image used only as an educational purpose. Astra Zeneca is not responsible for the copyright

59 RAAS AND SGLT2 AND KIDNEY FLOW Diabetic Kidney In Too Big Out Too Small SGLT2i ACEi Pressure Hyperfiltration Proteinuria Renal Cell Damage Normal Pressure Normal Filtration less Proteinuria Less Renal Cell Damage Skrtic M, Cherney DZ, et al. Diabetologia 2014;57:

60 Adjusted mean (SE) egfr (ml/min/1.73m 2 ) egfr (CKD-EPI formula) over 192 weeks 78 Placebo Empagliflozin 10 mg Empagliflozin 25 mg No. analyzed Placebo Week % on ACE or ARB Empagliflozin 10 mg Empagliflozin 25 mg No. in follow-up for adverse/outcome events Total Mixed model repeated measures analysis. CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration. 60

61 Dapagliflozin in Patients With Type 2 Diabetes and Moderate Renal Impairment UACR: Urine Albumin Creatinine Ratio CI=confidence interval; DAPA=dapagliflozin; PBO=placebo. Sjöström CD et al. World Congress of Nephrology. March 13-17, 2015; Cape Town, South Africa. Poster SAT-461. T2D=type 2 diabetes; CKD=chronic kidney disease; SGLT=sodium-glucose cotransporter; egfr=estimated glomerular filtration rate; GFR=glomerular filtration rate; UACR=urine albumin:creatinine ratio. Kohan DE et al. Kidney Int. 2014;85: Yale JF et al. Diabetes Obes Metab. 2013;15: Barnett AH et al. Lancet Diabetes Endocrinol. 2014;doi: /S (13) Gilbert RE. Kidney Int. 2013; doi: /ki

62 ARB + Dapagliflozin Reduces Albuminuria ARB/ACE +DAPA 5mg +DAPA 10mg 62 HJ Lambers Heerspink, 1 Eva Johnsson, 2 Ingrid Gause-Nilsson, 2 Irina Baldycheva, 3 C David Sjöstrom 2 Presented at the 75th Scientific Sessions of the American Diabetes Association, Boston, MA, June 5 9th, 2015 Accessed on 18 th June 2015 ACEi, angiotensin-converting enzyme inhibitor; ACR, albumin: creatinine ratio; ARB, angiotensin receptor blocker; DAPA, dapagliflozin; PBO, placebo. Image is used for academic purposes only. Astra Zeneca is not responsible for copyright

63 Ongoing SGLT2i Renal Outcome Trials Trial Study Arms N Population 1 o endpoint End Date CANVAS-R Canagliflozin Placebo 5,813 CVD or high risk for CVD 1 : Progression of albuminuria 2 : CV death, non-fatal MI or non-fatal stroke Feb 2017 CREDENCE Canagliflozin Placebo 4,200 egfr 30 and <90 ml/min/1.73m 2, and ACR mg/mmol on ACEi or ARB 1 : ESKD, doubling of serum creatinine, renal or CV death 2 : CV death, non-fatal MI or non-fatal stroke June 2019 Dapa-CKD Dapagliflozin Placebo 4,000 egfr 25 and 75 ml/min/1.73m 2, and ACR mg/mmol on ACEi or ARB 1 : ESKD, 50% decline in egfr, renal or CV death 2 : CV death or hospitalization for. HF Nov 2020 ACE, angiotensin-converting enzyme; ACR, albumin-creatinine ratio; ARB, angiotensin receptor blocker; CV, cardiovascular; egfr, estimated glomerular filtration rate; ESKD, end-stage kidney disease; HF, heart failure; MI, myocardial infarction. clinicaltrials.org, accessed February 2, 2017.