T2DM Management is More than HbA1c Control.pptx

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1. 1 FOR TOMORROW FOR TODAY Type 2 Diabetes Management Is More Than Just HbA1c Control Firas Annabi.FACE

2. Diabetes… Large and growing epidemic globally with HF and CKD complications Vicious circle of HF and CKD : one causes/worsens the other 4 463M 1 (2019) 700M 1 (2045) T 2D CKD 1. . International Diabetes Federation. IDF Diabetes Atlas, 9th edn. Brussels, Belgium: International Diabetes Federation, 2019; 2. American Diabetes Association. Diabetes Care. 2019;42(Suppl 1):S103–S123. 3. Alicic R, Rooney M, Tuttle K. Diabetic Kidney Disease. Clinical Journal of the American Society of Nephrology. 2017; 12(12):2032-2045. 4 . Ronco C, Haapio M, House A et al. American College of Cardiology. 2008;52(19):1527-1539 Projected increase Up to 40% of patients with T2D will develop CKD 3 Up to 50% of patients with T2D will develop HF 2 HF

3. Birkeland, K. I., Bodegard, J., Eriksson, J. W. et al.. Heart failure and chronic kidney disease manifestation and mortality risk associations in type 2 diabetes: A large multinational cohort study. Diabetes, Obesity and Metabolism. 2020. 22(9), 1607–1618. Cardiorenal disease (CKD and/or HF) is an under-recognized, early, common, and serious complication of T2D CKD = chronic kidney disease; HF = heart failure; MI = myocardial infarction; PAD = peripheral artery disease; T2D = type 2 diabetes. 1. Stevens LA et al. J Am Soc Nephrol . 2005;16:2439-2448; 2. Boonman-de Winter LJM et al. Diabetologia . 2012;55:2154-2162; 3. Birkeland KI et al. Poster presented at: ADA 79 th Scientific Sessions; June 7-11, 2019; San Francisco, CA. Poster 206-LB. CV = cardiovascular; HF = heart failure; PAD = peripheral artery disease; T2D = type 2 diabetes. Birkeland KI et al. Poster presented at: ADA 79 th Scientific Sessions; June 7-11, 2019; San Francisco, CA. Poster 206-LB. Time in study, years Germany Japan Norway Sweden Patients with an event (%) 48% cardiorenal disease 52% cardiorenal disease 70% cardiorenal disease 66% cardiorenal disease Multinational observational cohort study including 645,180 comorbidity-free T2D patients (mean follow-up of 4.3 years) FXG-230-SK-0921-0923-JOR

4. Heart failure and CKD are the most common and early CV complications Birkeland, K. I., Bodegard, J., Eriksson, J. W. et al.. Heart failure and chronic kidney disease manifestation and mortality risk associations in type 2 diabetes: A large multinational cohort study. Diabetes, Obesity and Metabolism. 2020. 22(9), 1607–1618. 60% Cardiorenal diseases (HF or CKD) INITIAL CV DISEASE MANIFESTATION IN T2D PATIENTS 1

5. Cardiorenal disease (HF and CKD) significantly increases the risk of mortality in Type 2 diabetes Decreased risk Increased risk a Adjusted for age and sex; b CV death was not obtainable in Germany, Japan and the Netherlands Adapted from: Birkeland KI, et al. Diabetes Obes Metab 2020;22:1607–1618

6. Oxidative stress Inflammation Hyperfiltration 1. Muralidaran, Y. and Viswanathan, P., 2015. Diabetic Cardiomyopathy: A New Perspective of Mechanistic Approach.  Journal of Diabetes & Metabolism , 6(10). 2. Sattar, N. and McGuire, D., 2018. Pathways to Cardiorenal Complications in Type 2 Diabetes Mellitus.  Circulation , 138(1), pp.7-9. 3. Strain, W. and Paldánius, P., 2021. Correction to: Diabetes, cardiovascular disease and the microcirculation.  Cardiovascular Diabetology , 20(1). The pathophysiology behind the interconnectivity of diabetes on HF and CKD ↑Cardiac preload/afterload ↑Cardiac wall stress ↓Cardiac efficiency/output TYPE 2 DIABETES ↑Glucose/sodium reabsorption ↑Intraglomerular pressure ↑RAAS activity KIDNEY 2 HEART 1 ↑Volume expansion 2 ↑Vasoconstriction 3 ↑Systolic blood pressure 3 CIRCULATION

7. Type 2 diabetes, cardiovascular and renal disease are closely interconnected T2D/Hyperglycemia Acute or chronic disorder of one can induce dysfunction in the other 1. Maqbool, Cooper, Karin et al. Cardiovascular Disease and Diabetic Kidney Disease. Semin Nephrol 2018;38:217-232 2. Ronco C, Haapio M, House A et al. American College of Cardiology. 2008;52(19):1527-1539

8. Diabetes and the Heart

9. Events per 1000 Patient-years 20 40 60 80 100 CHF MI (previous MI) PAD Stroke (previous MI) MI (no previous MI) Death Stroke (no previous MI) Pancreatitis Chronic Kidney Disease Blindness Heart Failure predominates the risk of complications in patients with diabetes Richard M. Bergenstal, Clifford J. Bailey and David M. Kendall. Type 2 Diabetes: Assessing the Relative Risks and Benefits of Glucose-lowering Medications. The American Journal of Medicine. 2010; 123 ,374.e9-374.e18 People with diabetes may be more likely to experience a CV complication, with heart failure occurring more commonly than ischemic events . 1

10. Patients with T2D are at higher risk of developing HF compared with the general population Rørth, R., Jhund, P., Mogensen, U. et al.,2018. Risk of Incident Heart Failure in Patients With Diabetes and Asymptomatic Left Ventricular Systolic Dysfunction.  Diabetes Care , 41(6), pp.1285-1291. The presence of diabetes increases the risk of developing HF 50 45 40 35 30 25 20 15 10 5 Cumulative incidence (%) 4 1 2 3 Time from randomization (years) Diabetes No diabetes P <0 .000 1

11. Heart failure is an early complication of type 2 diabetes Based on a prospective study of 386 people with T2DM without overt cardiac disease Systolic LVD N=106 Systolic and diastolic LVD N=95 Normal LV function N=124 Diastolic LVD N=61 Faden, G., Faganello, G., De Feo, S., et al. The increasing detection of asymptomatic left ventricular dysfunction in patients with type 2 diabetes mellitus without overt cardiac disease: Data from the SHORTWAVE study.  Diabetes Research and Clinical Practice , 2013 101(3), pp.309-316. 68% had evidence of LV dysfunction 5 years post T2D diagnosis

12. The presence of HF in patients with diabetes is associated with an increased risk of death 115,803 adults 65 years and older in fee-for-service Medicare without a prior HF claim were followed for 5 years Bertoni AG, Hundley WG, Massing MW, et al. Heart failure prevalence, incidence, and mortality in the elderly with diabetes. Diabetes Care . 2004;27:699-703. Mortality in people with diabetes ± HF

13. Heart Failure in Diabetes Early Heart failure is one of the earliest CV complications in T2D 1 Fatal The presence of HF in patients with diabetes is associated with an increased risk of death 3 Frequent Heart Failure predominates the risk of complications in patients with diabetes 2 Faden, G., Faganello, G., De Feo, S., et al. The increasing detection of asymptomatic left ventricular dysfunction in patients with type 2 diabetes mellitus without overt cardiac disease: Data from the SHORTWAVE study.  Diabetes Research and Clinical Practice , 2013 101(3), pp.309-316. Richard M. Bergenstal, Clifford J. Bailey and David M. Kendall. Type 2 Diabetes: Assessing the Relative Risks and Benefits of Glucose-lowering Medications. The American Journal of Medicine. 2010; 123 ,374.e9-374.e18 Bertoni AG, Hundley WG, Massing MW, et al. Heart failure prevalence, incidence, and mortality in the elderly with diabetes. Diabetes Care . 2004;27:699-703.

14. Type 2 diabetes, cardiovascular and renal disease are closely interconnected T2D/Hyperglycemia Acute or chronic disorder of one can induce dysfunction in the other 1. Maqbool, Cooper, Karin et al. Cardiovascular Disease and Diabetic Kidney Disease. Semin Nephrol 2018;38:217-232 2. Ronco C, Haapio M, House A et al. American College of Cardiology. 2008;52(19):1527-1539

15. Diabetes and the Kidneys

16. Patients with T2D are at higher risk of developing CKD compared with the general population ACR, albumin:creatinine ratio; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; HF, heart failure; T2D, Type 2 diabetes Zelnick L., Weiss N., Kestenbaum B et al. Diabetes and CKD in the United States Population, 2009–2014.  Clinical Journal of the American Society of Nephrology. 2017 . 12(12), pp.1984-1990. The presence and duration of diabetes increases the risk of developing CKD No diabetes Undiagnosed diabetes <10 years 10–19 years ≥20 years Any CKD ACR ≥30 mg/g ACR ≥300 mg/g eGFR eGFR <60 mL/min/ <30 mL/min/ 1.73 m 2 1.73 m 2 10 20 30 40 50 Prevalence (%)

17. Prevalence and manifestations of kidney disease GFR, glomerular filtration rate. Adapted from Afkarian M et al. J Am Soc Nephrol. 2013;24(2):302-8. Manifestations Prevalence

18. Mortality is More Frequent Present in Diabetes and Kidney Disease than Those Without The dashed line indicates mortality in persons without diabetes or kidney disease (the reference group). Percentages indicate absolute excess mortality above the reference group (individuals with no diabetes or kidney disease) Afkarian, M., Sachs, M., Kestenbaum et al. Kidney Disease and Increased Mortality Risk in Type 2 Diabetes. Journal of the American Society of Nephrology. 2013 24(2), pp.302-308. Standardized 10-year cumulative incidence of mortality (%) Excess mortality

19. T2D T2D management : Addressing Cardio-Renal Risks (HF & CKD) early on is Key

20. There is a high burden of undiagnosed HF and CKD in patients with T2D a This multicenter study calculated the proportion of detected and undiagnosed CKD in 9307 patients with T2D in the primary care setting using the following: a clinician survey; a patient physical exam and medical history; a single blood draw for eGFR and HbA1c; urine dipstick for protein; UACR; two patient quality of life questionnaires; and a 15-month medical record review Boonman-de Winter LJM et al. High prevalence of previously unknown heart failure and left ventricular dysfunction in patients with type 2 diabetes Diabetologia . 2012; 55(8): 2154–2162. doi: 10.1007/s00125-012-2579-0 | Szczech LA, et al. PLoS One 2014;9:e110535 Undiagnosed HF was detected in 28% of patients (age ≥60 years) with diabetes (N=581) during cardiac screening 1 72% H ea rt fa il ure ( H Fr E F) Hea rt f a il ure ( H Fp E F) No heart failure 23% 5% 20 40 60 80 1 1 2 CKD stage 1–2 CKD stage 3 Adapted from Szczech et al. 2 CKD stage 4–5 Undiagnosed CKD (%) There is a large proportion of undiagnosed CKD across all CKD stages 2,a

21. A call to action… Improvements in HF-related survival have been modest over years Clare J Taylor,1 José M Ordóñez-Mena,1 Andrea K Roalfe et al . Trends in survival after a diagnosis of heart failure in the United Kingdom 2000-2017: population based cohort study. . BMJ , 2019 p.l5840. Trends in survival from HF 20 40 60 80 100 Survival (%) 5-year survival ( P trend <0.001) 10-year survival ( P trend =0.002) 1-year survival ( P trend <0.001) 2000 2005 2010 2015 2020 Year of diagnosis

22. A call to action… Worsening in CKD mortality is seen over the years CKD, chronic kidney disease; HF, heart failure United States Renal Data System. Annual Data Report 2018;3:45–78 All-cause mortality rates in patients with and without CKD 2 CKD NO CKD Deaths per 1000 patient-years at risk 250 200 150 100 50 2004 2006 2008 2010 2012 2014 2016 Year

23. Today… You can have a different path for your T2D patient Early & Sustained HbA1c reductions 1 From guidelines to real life DECLARE… Go Beyond A1c reduction 2 3

24. Today… You can have a different path for your T2D patient Early & Sustained HbA1c reductions 1 From guidelines to real life DECLARE… Go Beyond A1c reduction 2 3

25. 2020 AACE/ACE Algorithm for Glycemic Management AACE = American Association of Clinical Endocrinologists; ACE = American College of Endocrinology.

26. AACE Considerations for Individualized Glycemic Target Selection A1C = glycated hemoglobin; AACE = American Association of Clinical Endocrinologists. Garber AJ et al. Endocr Pract. 2020;26(1):107-139. A1C ≤6.5% For patients without concurrent serious illness and at low hypoglycemia risk For patients with concurrent serious illness and at risk for hypoglycemia Glycemic Targets Adjustments Based On: Age Duration of diabetes Comorbid conditions Hypoglycemia risk Patient motivation Life expectancy Adherence A1C >6.5%

27. 2020 AACE/ACE Algorithm for Glycemic Management Choice of therapy reflects patients’ ASCVD, HF and renal status. - If established ASCVD or high risk, CKD 3 or HFrEF is present, LA GLP-1 RA or SGLT-2i with proven efficacy is recommended, independent of glycemic control. Pharmacotherapy should prioritize minimizing weight gain and the risk of hypoglycemia. When selecting add-on treatment, consider therapies with complementary mechanisms of action for optimum glycemic control. A1C = glycated hemoglobin; AACE = American Association of Clinical Endocrinologists; ACE = American College of Endocrinology; ASCVD = atherosclerotic cardiovascular disease; CKD = chronic kidney disease; DPP-4i = dipeptidyl peptidase-4 inhibitor; LA GLP-1 RA = long-acting glucagon-like peptide 1 receptor agonist; HF = heart failure; HFrEF = heart failure with reduced ejection fraction; SGLT-2i = sodium-glucose cotransporter 2 inhibitor. Garber AJ et al. Endocr Pract . 2020;26(1):107-139. A1C ≥7.5% Dual Therapy should be considered

28. AACE/ACE 2020 Algorithm for Glycemic Management : SGLT2i preferred oral option after metformin a. If not at goal in 3 months, proceed to next level of therapy. bOrder of medications listed are a suggested hierarchy of usage. cCKD 3: canagliflozin; HFrEF: dapagliflozin Garber AJ et al. Endocr Pract. 2020;26(1):107-139. Progression of Disease Monotherapy Entry A1C < 7.5% Entry A1C > 9.0% Entry A1C ≥ 7.5%-9.0% No Symptoms Triple Therapy Insulin ± Other Agents Symptoms Add or Intensify Insulin Dual Therapy Monotherapy b Dual Therapy b Triple Therapy b MET or other agent MET or other agent + Metformin GLP-1RA SGLT-2i DPP-4i TZD AG-i SU/GLN ✓ ✓ ✓ ✓ ✓ ! ! + GLP-1RA SGLT-2i DPP-4i TZD SU/GLN Basal Insulin Colesevelam Bromocriptine QR AG-i ✓ ✓ ✓ ! ✓ ✓ ✓ ! ! GLP-1RA SGLT-2i TZD SU/GLN Basal Insulin DPP-4i Colesevelam Bromocriptine QR AG-i ✓ ✓ ! ✓ ✓ ✓ ! ! ✓ Lifestyle Modifications and Ongoing Glucose Monitoring (CGM preferred) Independent of Glycemic Control, If Established or High ASCVD Risk and/or CKD, Recommend SGLT-2i and/or LA GLP-1 RA 3 months a 3 months a 3 months a Independent of glycemic control, if established ASCVD or high risk, CKD 3 or HFrEF, start LA GLP-1 RA or SGLT-2i with proven efficacy c

29. 2021 ADA Standards of Care: Management of Hyperglycemia in Type 2 Diabetes

30. 2021 ADA Standards of Care: Decision Cycle for Patient-Centered Glycemic Management A1C = glycated hemoglobin; ADA = American Diabetes Association; ASCVD = atherosclerotic cardiovascular disease; BP = blood pressure; CKD = chronic kidney disease; DSMES = diabetes self-management education and support; HF = heart failure; SMBG = self-monitored blood glucose. American Diabetes Association. Diabetes Care. 2021;44(suppl 1):S1-S232. Review management plan Mutual agreement on changes Ensure agreed modification of therapy is implemented in a timely fashion to avoid clinical inertia Decision cycle undertaken regularly (at least once/twice a year) Assess Key Patient Characteristics Consider Specific Factors Which Impact Choice of Treatment Shared Decision-Making Agree on Management Plan Implement Management Plan Ongoing Monitoring and Support Including: Review and Agree on Management Plan Goals of Care Prevent Complications Optimize Quality of Life Current lifestyle Comorbidities ie, ASCVD, CKD, HF Clinical characteristics i.e. age, A1C, weight Issues such as motivation and depression Cultural and socio-economic context Individualized A1C target Impact on weight and hypoglycemia Side effect profile of medication Complexity of regimen i.e. frequency, mode of administration Choose regimen to optimize adherence and persistence Access, cost and availability of medication Involves an educated and informed patient (and their family/caregiver) Seeks patient preferences Effective consultation includes motivational interviewing, goal setting and shared decision making Empowers the patient Ensure access to DSMES Specify SMART Goals: S pecific M easurable A chievable R ealistic T ime limited Patients not meeting goals generally should be seen at least every 3 months as long as progress is being made; more frequent contact initially is often desirable for DSMES Emotional well-being Check tolerability of medication Monitor glycemic status Biofeedback including SMBG, weight, step count, A1C, BP and lipids

31. If A1C above target GLP-1 RA with proven CVD benefit c SGLT2i with proven CVD benefit c EITHER/ OR ADA 2021 Standards of Care Antihyperglycemic Medication in T2D: Overall Approach To avoid therapeutic inertia reassess and modify treatment regularly (3-6 months). aActioned whenever these become new clinical considerations regardless of background glucose-lowering medications; bMost patients enrolled in the relevant trials were on metformin at baseline as glucose-lowering therapy; cProven CVD benefit means it has label indication of reducing CVD events; dLow dose may be better tolerated though less well studied for CVD effects; eDegludec or U100 glargine have demonstrated CVD safety; fChoose later generation SU to lower risk of hypoglycemia; glimepiride has shown similar CV safety to DPP-4i; gBe aware that the SGLT2 inhibitor labeling varies by region and individual agent with regard to indicated level of eGFR for initiation and continued use; hDapagliflozin, empagliflozin, and canagliflozin have shown reduction in HF and reduction in CKD progression in CVOTs. Dapagliflozin and canagliflozin have primary renal outcome data. Dapagliflozin and empagliflozin have primary HF outcome data; iProven benefit means it has label indication of reducing HF in this population; jRefer to Section 11: Microvascular Complications and Foot Care; kDegludec/glargine U300 < glargine U100/detemir < NPH insulin lSemaglutide > liraglutide > dulaglutide > exenatide > lixisenatide; mIf no specific comorbidities (ie, no established CVD, low risk of hypoglycemia, and lower priority to avoid weight gain or no weight-related comorbidities); nConsider country- and region-specific cost of drugs. In some countries TZDs are relatively more expensive and DPP-4i are relatively cheaper. American Diabetes Association. Diabetes Care. 2021;44(suppl 1):S1-S232. COMPELLING NEED TO MINIMIZE HYPOGLYCEMIA If A1C Above Individualized Target, Proceed as Below DPP-4i GLP-1 RA SGLT2i TZD Consider addition of SU f or basal insulin: Choose later generation SU with lower risk of hypoglycemia Consider basal insulin with lower risk of hypoglycemia k OR SGLT2i TZD OR SGLT2i TZD OR OR TZD DPP-4i OR GLP-1 RA GLP-1 RA SGLT2i NO If A1C above target If A1C above target If A1C above target If A1C above target Insulin therapy basal insulin with lowest acquisition cost OR Consider other therapies based on cost SU f TZD n If A1C above target If A1C above target If A1C above target If A1C above target SU f TZD n DPP-4i If quadruple therapy required or SGLT2i and/or GLP-1 RA not tolerated or contraindicated, use regimen with lowest risk of weight gain. Preferably : DPP-4i (if not on GLP-1 RA) based on weight neutrality GLP-1 RA with good efficacy for weight loss l SGLT2i If A1C above target If A1C above target If A1C above target If A1C above target If DPP-4i not tolerated or contraindicated or patient already on GLP-1 RA, cautious addition of: -SU f -TZD d - Basal Insulin OR Continue with addition of other agents listed above If A1C above target If A1C above target EITHER/ OR GLP-1 RA with good efficacy for weight loss l SGLT2i Consider Independently of Baseline A1C, Individualized A1C Target, or Metformin Use b Indicators of High-Risk or Established ASCVD, CKD or HF a First-Line Therapy is Metformin and Comprehensive Lifestyle (including weight management and physical activity) +ASCVD/INDICATORS of High Risk +HF +CKD DKD and Albuminuria j GLP-1 RA with proven CVD benefit c SGLT2i with proven CVD benefit c,i SGLT2i with primary evidence of reducing CKD progression SGLT2i with evidence of reducing CKD progression in CVOTs g,h,j GLP-1 RA with proven CVD benefit c if SGLT2i not tolerated or contraindicated OR OR NO EITHER/ OR Particularly HFrEF (LVEF <45%) SGLT2i with proven benefit in this population g,h,i Established ASCVD Indicators of high ASCVD risk (age≥55 years with coronary, carotid, or lower extremity artery stenosis >50%, or LVH) If further intensification is required or patient is unable to tolerate GLP-1 RA and/or SGLT2i, choose agents demonstrating CV benefit and/or safety: For patients on a GLP-1 RA, con-sider adding SGLT2i with proven CVD benefit and vice versa c TZD d DPP-4i if not on GLP-1 RA Basal insulin e SU f PREFERABLY For patients with T2D and CKD j (e.g., eGFR <60 mL/min/1.73 m 2 ) and thus at increased risk of cardiovascular events COMPELLING NEED TO MINIMIZE WEIGHT GAIN OR PROMOTE WEIGHT LOSS COST IS A MAJOR ISSUE

32. “ In appropriate high-risk individuals with established T2D , the decision to treat with a GLP-1 RA or SGLT2 inhibitor to reduce MACE, HHF, CV death or CKD progression should be considered independently of baseline HbA1c or individualised HbA1c target ” 1 ASCVD, atherosclerotic cardiovascular disease; HHF, hospitalisation for heart failure 1. Buse JB et al. Diabetes Care 2020;43:487; 2. American Diabetes Association. Diabetes Care 2020;43:S1 ; 3. Davies MJ et al. Diabetes Care 2018;41:2669 ADA–EASD 2019 Consensus Report update ADA–EASD consensus statements recommend that choice of second-line therapy should be initially based upon assessment of established ASCVD, CKD or HF 32 These recommendations have been also incorporated into the ADA Standards of Medical Care in Diabetes 2020 2 and should be considered in conjunction with the ADA–EASD 2018 consensus report 3

33. Patients Without Indicators of High-Risk or Established ASCVD, HF, or CKD: Need to Minimize Hypoglycemia aUnless contraindicated or intolerable; bIf renal function is adequate; cSelect a later generation SU with lower risk of hypoglycemia; dDegludec/glargine U300 < glargine U100/detemir < NPH insulin. A1C = glycated hemoglobin; ASCVD = atherosclerotic cardiovascular disease; CKD = chronic kidney disease; DPP-4 = dipeptidyl peptidase-4; GLP-1 = glucagon-like peptide-1; HF = heart failure; NPH = neutral protamine Hagedorn; SGLT2 = sodium-glucose cotransporter 2; SU = sulfonylurea; TZD = thiazolidinedione. American Diabetes Association. Diabetes Care. 2021;44(suppl 1):S1-S232. OR OR OR OR OR OR A1C above goal SGLT2 inhibitor b GLP-1 receptor agonist DPP-4 inhibitor TZD GLP-1 receptor agonist SGLT2 inhibitor b SGLT2 inhibitor b SGLT2 inhibitor b DPP-4 inhibitor DPP-4 inhibitor TZD TZD Continue with addition of classes in the algorithm above A1C above goa l A1C above goa l A1C above goa l A1C above goa l TZD GLP-1 receptor agonist Consider SU c or basal insulin with lower risk of hypoglycemia d A1C above goal A1C above goal A1C above goal A1C above goal If not at A1C goal with metformin, continue metformin a and consider the drug classes below.

34. Patients Without Indicators of High-Risk or Established ASCVD, HF, or CKD: Need to Promote Weight Loss or Minimize Weight Gain aIf renal function is adequate; bSemaglutide > liraglutide > dulaglutide > exenatide > lixisenatide; cSelect a later generation SU with lower risk of hypoglycemia; dLow dose less studied for CVD effects but may be better tolerated. A1C = glycated hemoglobin; ASCVD = atherosclerotic cardiovascular disease; CKD = chronic kidney disease; CVD = cardiovascular disease; DPP-4 = dipeptidyl peptidase-4; GLP-1 = glucagon-like peptide-1; HF = heart failure; SGLT2 = sodium-glucose cotransporter 2; SU = sulfonylurea; TZD = thiazolidinedione. American Diabetes Association. Diabetes Care. 2021;44(suppl 1):S1-S232. Consider agents with lowest risk of weight gain, preferably DPP-4 inhibitors if not on GLP-1 receptor agonist. Cautious addition of SU c , Basal Insulin, TZD d Metformin is first-line therapy SGLT2 inhibitor a GLP-1 receptor agonist with good weight loss efficacy b GLP-1 receptor agonist with good weight loss efficacy b SGLT2 inhibitor a A1C above goa l A1C above goa l A1C above goa l A1C above goa l A1C above goa l Either/Or

35. Today… You can have a different path for your T2D patient Early & Sustained HbA1c reductions 1 From guidelines to real life DECLARE… Go Beyond A1c reduction 2 3

36. Phase III, 24-week, randomised, double-blind, active-controlled, parallel-group study to compare the efficacy and safety of the dual add-on of saxagliptin and FORXIGA with either saxagliptin 5 mg or dapagliflozin 10 mg added alone in adults with Type 2 diabetes who had inadequate glycaemic control (HbA1c ≥8% to ≤12%) on metformin. The primary efficacy endpoint was adjusted mean change from baseline in HbA 1c at 24 weeks. The study met its primary endpoint. This is a retrospective post-hoc analysis. 2 **Metformin XR. † Number of randomised patients with non-missing baseline values and Week 24 values last observation carried forward. *DPP4- inhibitor = saxaglitpin 5mg CI, confidence interval; DPP4, dipeptidyl peptidase-4; XR, extended release. FORXIGA® demonstrated more effective reductions in HbA 1c at 24 weeks versus DPP4i* 1 FORXIGA® 10 mg added on to metformin XR -1.20% DPP4i* added on to metformin XR 1. Rosenstock J, et al. Diabetes Care 2015; 38 :376–83; 2. Data on file 801453. AstraZeneca. September 2016.

37. FORXIGA® demonstrated HbA 1c reductions of around 1.4% in uncontrolled patients on metformin with high baseline HbA 1c *Clinical trial data from patients with high baseline HbA 1c who had Forxiga added to metformin or metformin XR. † Adjusted mean change from baseline HbA 1c (%). ‡ Phase III, multicentre, randomised, double-blind, placebo-controlled, parallel-group, 24-weeks clinical study to evaluate the efficacy and safety of Forxiga 10 mg + metformin (≥1500 mg/day) versus glycaemic control (HbA 1c ≥7% and ≤10%) on metformin alone. 1 § Phase III, 24-week, multicentre, randomised, double-blind, active controlled, parallel-group study to compare the efficacy and safety of the dual add-on of saxagliptin 5 mg and Forxiga 10 mg with either saxagliptin 5 mg or Forxiga 10 mg added on alone in adult patients with Type 2 diabetes who had inadequate glycaemic control (HbA 1c ≥8% to ≤12%) on metformin alone. The study met its primary endpoint. This is a retrospective post hoc analysis of the data. ¶ Phase III, 28-week, multicentre double-blind, randomised, active-controlled trial to compare the efficacy and safety of exenatide (2 mg/day) plus Forxiga (10 mg/day) with exenatide or Forxiga alone in patients with Type 2 diabetes inadequately controlled by metformin (HbA 1c ≥8% to ≤12%). The primary endpoint was change in HbA 1c from baseline to week 28. 3 XR, extended release. This combination is not indicated in the current licence of exenatide. Recent 2016 data have shown 1.4% HbA 1c reduction Mean change from baseline in patients with HbA1c baseline ≥ 8.5% 1. Rosenstock J, et al. Diabetes Care 2015; 38 :376–83; 2. Bailey CJ, et al. Lancet 2010; 375 :2223–33; 3. Fr ὶ as JP, et al. Lancet Diabetes Endocrinol 2016. Epub ahead of print.

38. FORXIGA® demonstrated significantly great reductions in HbA1c at 24 weeks Henry RR, et al. Int J Clin Pract 2012;66: 446-56

39. More sustained HbA1c efficacy when adding FORXIGA® compared to adding SU to metformin over 4 years*¹ Data are adjusted mean change from baseline derived from a longitudinal repeated-measures mixed model. A Phase III, multicentre, randomised, double-blind, parallel-group, 52-week, glipizide-controlled, non-inferiority study with a double-blind extension to evaluate the efficacy and safety profile of Forxiga 10 mg + metformin (1500–2500 mg/day) versus glipizide + metformin (1500–2500 mg/day) in patients with inadequate glycaemic control (HbA 1c >6.5% and ≤10%) on metformin alone. 1 CI, confidence interval. 1. Del Prato S, et al. Diabetes Obes Metab 2015; 17 :581–90. FORXIGA ® 10mg + metformin

40. FORXIGA® demonstrated significant and sustained weight loss over 4 years At 52 weeks, XIGDUO was associated with weight loss of –3.2 kg versus weight gain of +1.4 kg with glipizide (p<0.0001). 2 Weight loss was maintained over 4 years 1 XIGDUO XR is not indicated for the management of weight loss. Weight change was a secondary endpoint in clinical trials. Data are adjusted mean change from baseline derived from a longitudinal repeated measures mixed model. A Phase III, multicentre, randomised, double-blind, parallel-group, 52-week, glipizide-controlled, non-inferiority study with a double-blind extension to evaluate the efficacy and safety profile of dapagliflozin 10 mg + metformin (1500–2500 mg/day) versus glipizide + metformin (1500–2500 mg/day) in patients with inadequate glycaemic control (HbA1c >6.5% and ≤10%) on metformin alone. CI, confidence interval; SU, sulphonylurea. Del Prato S, et al. Diabetes Obes Metab 2015;17:581–90; 2. Nauck MA, et al. Diabetes Care 2011;34:2015–22.

41. FORXIGA® demonstrated significant and sustained blood pressure reductions over 4 years At 52 weeks, FORXIGA ® delivered significant reductions in SBP (–4.3 mmHg) versus glipizide (+0.8 mmHg). 2 SBP reductions were sustained over 4 years 1 XIGDUO XR is not indicated for the management of high blood pressure. Blood pressure change was primarily assessed as a safety or exploratory efficacy endpoint in clinical trials. A Phase III, multicentre, randomised, double-blind, parallel-group, 52-week, glipizide-controlled, non-inferiority study with a double-blind extension to evaluate the efficacy and safety profile of dapagliflozin 10 mg + metformin (1500–2500 mg/day) versus glipizide + metformin (1500–2500 mg/day) in patients with inadequate glycaemic control (HbA1c >6.5% and ≤10%) on metformin alone.1 CI, confidence interval, SBP, systolic blood pressure. Del Prato S , et al. Diabetes Obes Metab 2015;17:581–90; Nauk MA, at al. Diabetes Care 2011;34:2015-22 (supplementary data).

42. Add FORXIGA to a broad range of dual treatments at the earliest opportunity Consistent reduction in HbA1c at 24 weeks 1-3 Add-on to metformin + DPP-4i 1 Add-on to metformin + SU 2 Add-on to insulin 3 1.Mathieu C, Ranetti AE, Li D, et al. Randomized, double-blind, phase 3 trial of triple therapy with dapagliflozin add-on to saxagliptin plus metformin in type 2 diabetes. Diabetes Care. 2015;38(11):2009-2017. 2. Matthaei S, Bowering K, Rohwedder K, Grohl A, Parikh S; for the Study 05 Group. Dapagliflozin improves glycemic control and reduces body weight as add-on therapy to metformin plus sulfonylurea: a 24-week randomized, double-blind clinical trial. Diabetes Care . 2015;38(3):365-372. 3. Wilding JP, Woo V, Soler NG, Pahor A, Sugg J, Rohwedder K, et al.; for the Dapagliflozin 006 Study Group. Long-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin: a randomized trial. Ann Intern Med . 2012;156(6):405-415

43. Forxiga Adverse Reactions Vulvovaginitis, balanitis and related genital infections were reported in 5.5% and 0.6% of subjects who received dapagliflozin 10 mg and placebo, respectively. Most infections were mild to moderate, and subjects responded to an initial course of standard treatment and rarely resulted in discontinuation from dapagliflozin treatment. These infections were more frequent in females (8.4% and 1.2% for dapagliflozin and placebo, respectively), and subjects with a prior history were more likely to have a recurrent infection. Urinary tract infections Urinary tract infections were more frequently reported for dapagliflozin 10 mg compared to placebo (4.7% versus 3.5%, respectively; Most infections were mild to moderate, and subjects responded to an initial course of standard treatment and rarely resulted in discontinuation from dapagliflozin treatment. These infections were more frequent in females, and subjects with a prior history were more likely to have a recurrent infection. Hypoglycemia The frequency of hypoglycaemia depended on the type of background therapy used in the clinical studies in diabetes mellitus. Across all studies, major events of hypoglycaemia were uncommon and comparable between the groups treated with dapagliflozin or placebo. Studies with add-on sulphonylurea and add-on insulin therapies had higher rates of hypoglycemia. Volume depletion Reactions suggestive of volume depletion (including, reports of dehydration, hypovolaemia or hypotension) were reported in 1.1% and 0.7% of subjects who received dapagliflozin 10 mg and placebo, respectively; serious reactions occurred in < 0.2% of subjects balanced between dapagliflozin 10 mg and placebo. 43 Source: Forxiga Local Label; Refer to local label for complete information about Forxiga Adverse Reactions

44. Forxiga Adverse Reactions Necrotizing fasciitis of the perineum (Fournier’s gangrene) Cases of Fournier’s gangrene have been reported post marketing in patients taking SGLT2 inhibitors, including dapagliflozin. In the DECLARE study with 17,160 type 2 diabetes mellitus patients and a median exposure time of 48 months, a total of 6 cases of Fournier’s gangrene were reported, one in the dapagliflozin-treated group and 5 in the placebo group. Diabetic ketoacidosis in type 2 diabetes mellitus In the DECLARE study, with a median exposure time of 48 months, events of DKA were reported in 27 patients in the dapagliflozin 10 mg group and 12 patients in the placebo group. Of the 27 patients with DKA events in the dapagliflozin group, 22 had concomitant insulin treatment at the time of the event. Precipitating factors for DKA were as expected in a type 2 diabetes mellitus population. In the DAPA-HF study, events of DKA were reported in 3 patients with type 2 diabetes mellitus in the dapagliflozin group and none in the placebo group. Increased Creatinine Increased Creatinine was reported in 3.2% and 1.8% of patients who received dapagliflozin 10 mg and placebo, respectively. These reactions were more common in patients with baseline eGFR ≥ 30 and < 60 mL/min/1.73m2 (18.5% dapagliflozin 10 mg vs 9.3% placebo). Further evaluation of patients who had renal-related adverse events showed that most had serum creatinine changes of ≤ 0.5 mg/dL from baseline. The increases in creatinine were generally transient during continuous treatment or reversible after discontinuation of treatment. 44 Source: Forxiga Local Label; Refer to local label for complete information about Forxiga Adverse Reactions

45. Forxiga Adverse Reactions Lactic Acidosis: There have been post-marketing cases of metformin-associated lactic acidosis, including fatal cases Hypotension. Dapagliflozin causes intravascular volume contraction. Symptomatic hypotension can occur after initiating dapagliflozin, particularly in patients with impaired renal function (eGFR less than 60 mL/min/1.73 m2), elderly patients, or patients on loop diuretics. Ketoacidosis. Reports of ketoacidosis, a serious life-threatening condition requiring urgent hospitalization have been identified in patients with type 1 and type 2 diabetes mellitus taking sodium-glucose co transporter 2 (SGLT2) inhibitors, including dapagliflozin. Urosepsis and Pyelonephritis: There have been post marketing reports of serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalisation in patients receiving SGLT2 inhibitors, including dapagliflozin. Treatment with SGLT2 inhibitors increases the risk for urinary tract infections. Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues Genital Mycotic Infections Dapagliflozin increases the risk of genital mycotic infections. Patients with a history of genital mycotic infections were more likely to develop genital mycotic infections. Monitor and treat appropriately. 45 Source: Forxiga Local Label; Refer to local label for complete information about Forxiga Adverse Reactions