DISCLOSURES. Learning objectives NAVIGATING THE TREATMENT OF TYPE 2 DIABETES: WHAT S NEW? Investigator Initiated Trial Support:

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1 NAVIGATING THE TREATMENT OF TYPE 2 DIABETES: WHAT S NEW? Jane E-B Reusch MD Professor of Medicine, Biochemistry and Bioengineering Associate Director Center for Women s Health Research University of Colorado SOM AMC Denver VA Medical Center American Diabetes Association, President for Medicine and Science DISCLOSURES Investigator Initiated Trial Support: Amylin/BMS: Exenatide impact on exercise function in humans and rodents BMS: Saxagliptin impact on exercise capacity (rats) Merck: Saxagliptin impact on exercise capacity (T2D) Recent and current funding: ADA (President), NIH, VA Consultant: GSK: International Incretin Advisory Board Employee /Speaker s Bureau/Stock/Shareholder: none Learning objectives 1. Understand the importance of lifestyle in the management of diabetes across the lifespan 2. Develope strategies to facilitate sustainable changes in diet and physical activity for people with type 2 DM 3. Become familiar with the latest evidence from CV outcomes trials with glucose lowering agents 4. Be able to employ evidence based type 2 diabetes treatment considering the presence or absence of CVD.

2 Outline and Goals: To present up to date, practical strategies for the treatment of persons with type 2 DM by discussing 2 cases. Focus on principles and pearls rather than an in-depth presentation of published data. Format: - Case 1: Newly diagnosed T2D focusing on lifestyle and behavior modification. - Case 2: Not at goal on metformin-next steps - Case 2: Type 2 DM and existing CVD focusing on recent cardiovascular CV outcomes studies and evidence based consideration of CVD and renal protection. Interactive discussion with the audience regarding clinical and logistic barriers to effective diabetes care. Case 1: 27 y/o SA female FBS-135 mg/dl PMH: G2P2 9# 2oz, 10# 1oz no mention of GDM or glucose during pregnancy FH: HTN, DM with ESRD, CHF 126/77, 88, 18 (99%RA), BMI 32 A1c 7.2%, no evidence of microvascular or macrovascular complications What factors will guide your recommendations? a. Patient preference b. Cost c. Comorbid conditions d. Motivation e. All of the above Answer: Approach to the management Patient Centered Decision Tree: of hyperglycemia PATIENT / DISEASE FEATURES Risks potentially associated with hypoglycemia and other drug adverse effects more stringent low HbA1c& 7%!& less stringent high Disease duration newly diagnosed long-standing Life expectancy long short Usually no modifiable Important comorbidities absent few / mild severe Established vascular complications absent few / mild severe Patient attitude and expected treatment efforts highly motivated, adherent, excellent self-care capacities less motivated, non-adherent, poor self-care capacities Potentially modifiable Courtesy of S Inzucchi Resources and support system Readily available limited Diabetes Care 2015;38: ; Diabetologia 2015; /s

3 Physiology centered: Lifestyle targets pathophysiology Genes Normal Insulin Resistance Decreased Insulin Secretion Environment: Diet Physical Activity Type 2 Diabetes Adapted form CR Kahn Diabetes 43: , 1994 Lifestyle as medicine Diabetes Prevention Program: Impressive evidence of the power of lifestyle N Engl J Med Volume 346;6:

4 Relationship of walking to mortality among US adults with diabetes: Impressive evidence of the power of physical activity DESIGN: Prospective cohort study SUBJECTS: 2896 adults 1990 and 1991 National Health Interview Survey RESULTS: Mortality Inactive 2 hours/wk 3-4 hours/wk All Cause Ref % 54% CV Ref % 53% CONCLUSIONS: Walking was associated with lower mortality across a diverse spectrum of adults with diabetes. One death per year may be preventable for every 61 people who could be persuaded to walk at least 2 h/wk. Arch Intern Med Jun 23;163(12): First two years: Began walking with a neighborhood group 3x/wk 45 minutes (reinforced by a pedometer) Took a cooking class at the ADA Became an community wellness volunteer Switched from 12 to 8 dinner plate (no refills) BMI 29; FBS 88mg/dl; A1c 6.2% CASE Point: 1 When baseline behavior is diabetogenic doable minor behavioral changes work very well Background on Behavioral Theory Human Behavior is influenced by motivation and ability Models vary, but generally identify factors related to motivation and ability: Motivation: Cognitive factors Environmental/Social factors Ability: Behavioral factors Bandura, Social Cognitive Theory, 1986

5 How can YOU support lifestyle change? Ø Providers need to reinforce the use lifestyle as medicine Ø Messaging needs to be non-judgmental and realistic Ø People with diabetes need a toolkit Ø Use of Diabetes Self Management Education (DSME) and Certified Diabetes Educators (CDE) enhances success Human behavior is influenced by motivation and ability Provide a reminder Provide Training Courtesy of A Huebschmann Fogg Behavior Model, 5A s Adapted to be DM Specific Ask Ask for permission to discuss dietary habits and activity Explore readiness for change. Assess Assess lifestyle habits and history. Success and failures of prior attempts to alter behavior and perceived barriers for making changes. Advise Advise the patient about the health risks of poor lifestyle habits, the benefits of changes, the need for long-term strategy, and treatment options. Agree Agree on realistic expectations, targets, behavioral changes, and specific details of the treatment plan. Arrange/Assist Assist in identifying and addressing barriers; provide resources; assist in finding and consulting with appropriate providers; arrange regular follow up. Adapted From Obesity Algorithm Obesity Medicine Association courtesy of T Halliday.

6 If patients hear from a physician or other healthcare professional that they are overweight, they are ~6x more likely to perceive themselves as overweight ~2.5x more likely to attempt weight loss In this study 45.2% of individuals with BMI 25 had been told they were overweight 66.4% of individuals with BMI 30 had been told they were overweight Post RE, et al. Arch Intern Med Courtesy T Halliday Tools: Use trustworthy sources People eat food (not carbohydrate, protein and fat): and CVD CHF Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes Diabetes Care 2018; 41 (Suppl. 1): S73-S85

7 Diabetes is VERY Demanding Lifestyle take home points: Diet and Exercise are the cornerstones of successful diabetes management (on or off medication) People with diabetes and the providers need skills to implement sustainable lifestyle intervention Provider silence on lifestyle in unacceptable Patient support in the form of diabetes self management education is crucial (early and often) If at first you donʼt succeed-try something else Lifestyle can add or subtract medications Still..Diabetes is progressive

8 CASE 2: Metformin what s next 62 y/o F with 10 year H/O T2D controlled with metformin 2 gm/d and lifestyle FBS-198; A1c7.8; TC 210 HDL 30 TG 250 LDL 130; miroal/cr Diabetes ratio 41, BMI is 27. a progressive disease which usually requires medication over time PMH: HTN hctz avg BP 130/80; DJD-NSAIDS; SHmarried 4 children, occas etoh no tob; Lifestyle: works out 5x week and diet excellent (husband had CABG 3 years ago) UKPDS: Progressive hyperglycemia secondary to beta-cell failure 9 8 HbA 1c (%) 7 6 Conventional NOT your fault! Intensive Monotherapy Conventional Sulfonylurea Metformin Years from Randomization Beta-Cell Function (%) Lancet 1998;352: UKPDS 16. Diabetes 1995;44: What is the next drug? Sulfonylurea (SU) Glucagon like peptide 1 agonist (GLP1) Basal Insulin Dipeptidyl peptidase 4 inhibitor (DPP4) Thiazolidinedione (TZD) Prandial insulin Sodium Glucose Transporter 2 inhibitor (SGLT2) None of the above Any of the above

9 Back to the Pathophysiological Abnormalities in T2DM incretin effect gut carbohydrate delivery & absorption - HYPERGLYCEMIA pancreatic insulin secretion pancreatic glucagon secretion? + - hepatic glucose production Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011 peripheral glucose uptake Pathophysiologically-Based Therapies for T2DM GLP-1R agonists incretin effect DPP-4 inhibitors A G I s gut carbohydrate delivery & absorption Metformin - HYPERGLYCEMIA Bile acid sequestrants Insulin Glinides S U s Amylin mimetics pancreatic insulin secretion pancreatic glucagon secretion - DA agonists T Z D s? hepatic glucose production Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine SGLT-2 inhibitors peripheral glucose uptake CASE 2-Channel 9 Health Fair Pt has done extensive research and wants you to decipher the guidelines

10 Case 2 Answer: Any agent Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes Diabetes Care 2018; 41 (Suppl. 1): S73-S85 How do you decide: It s personal PATIENT / DISEASE FEATURES Risks potentially associated with hypoglycemia and other drug adverse effects more stringent low Approach to the management of hyperglycemia HbA1c& 7%!& less stringent high Disease duration newly diagnosed long-standing Life expectancy long short Usually no modifiable Important comorbidities absent few / mild severe Established vascular complications absent few / mild severe Patient attitude and expected treatment efforts highly motivated, adherent, excellent self-care capacities less motivated, non-adherent, poor self-care capacities Potentiall modifiabl Resources and support system Readily available limited Courtesy of S Inzucchi Diabetes Care 2015;38: ; Diabetologia 2015; /s Case 3: T2D and Cardiovascular Disease 54 y.o. black female. Type 2 DM for 14 years on metformin 2000 mg daily. Recently hospitalized for ACS/stent required. Also mild diastolic dysfunction by echo (EF 45%). A1c at that admission was 8.4%. She is referred by Cardiology for counsel about improving her metabolic/glycemic control. She is well controlled in terms of blood pressure, lipids, antiplatelet, and ACE inhibitor therapy. GFR is 76 ml/min and urine microalbumin ratio of 220 mg/dl. Do what now?

11 What is the next drug? a) Glucagon like peptide 1 agonist (GLP1) b) Basal Insulin c) Thiazolidinedione (TZD) d) Sodium Glucose Transporter 2 inhibitor (SGLT2) e) a or c f) a or d g) Any of the above Major Cardiovascular Outcomes in Type 2 DM and Controls in Sweden Rawshani A et al. N Engl J Med 2017;376: Premature mortality persists in people with DM Framingham Intensive multifactorial treatment (STENO-2) Preis, et al. Circulation (2011);119(13): Gaede P, et al. Diabetologia 2016; 59:

12 Copyright 2017 American Medical Diabetes Shortens Life Expectancy From: Association of Cardiometabolic Multimorbidity With Mortality JAMA. 2015;314(1): doi: /jama Association. All rights reserved. Age of onset Age of onset Modeling of Years of Life Lost by Disease Status Case 3 Answer: a. Liraglutide or d. Empagliflozin Let s discuss this change!! Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes Diabetes Care 2018; 41 (Suppl. 1): S73-S85 Cardiovascular Outcome Trials (CVOT) In 2008 the FDA stated that all new antidiabetic therapies for type 2 DM should demonstrate no unacceptable increase in CV risk. They are designed and powered to assess non-inferiority versus placebo in addition to standard of care in a high risk CVD patient population (prior CVD ± high risk patients without proven CVD). Major endpoint composite of Major Adverse Cardiovascular Events: - Usual is 3 point MACE new nonfatal MI, new stroke, CV death based on careful adjudication to confirm accuracy of the events. Key understandings: - Powered for safety. - Studied population provides data on SECONDARY PROTECTION. - Not powered for subgroup analysis. - Cannot directly compare results of one study to another.

13 Possible Choices for Additional Antihyperglycemic Therapy Insulin: - ORIGIN trial (Glargine U-100). - DEVOTE trial (Degludec vs. Glargine U-100). Thiazoledinediones: - PROACTIVE trial (Pioglitazone). - RECORD trial (Rosiglitazone). DPP-4 inhibitor: - SAVOR TIMI (Saxagliptin). - EXAMINE (Alogliptin). - TECOS (Sitagliptin) CVD Safety CVD Safety Heart Failure CVD Safety Heart Failure DPP-4 Inhibitor CVD Outcome Trials Agent Population Composite Outcome Key Finding Heart Failure Saxagliptin SAVOR TIMI CVD or risk factors 3 point MACE Safety HR 1.00 Increased HR 1.27 Alogliptin EXAMINE CVD 3 point MACE Safety HR 0.96 Unchanged Sitiglipitin TECOS CVD 4 point MACE Safety HR 0.98 Unchanged Scirica BM et al. N Engl J Med. 2103;369: White WB et al. N Engl J Med. 2013;369: White WB et al. N Engl J Med. 2015;373: Pfeffer MA et al. N Engl J Med. 2015;373(23): SGLT2 Inhibitors

14 Empagliflozin and Cardiac Outcomes in Type 2 Diabetes EMPA REG Trial Primary Outcome Death Any Cause Death CVD Causes Hospitalization Heart Failure 7020 patients treated with 2 doses of empagliflozin or placebo for a median 3.1 years. Inclusion all had established CVD Primary outcome composite of death from CVD, nonfatal MI, or nonfatal stroke. With empagliflozin: - 14% reduction 3-point MACE. - 38% reduction CVD death. - 32% reduction death from any cause. - 35% reduction in hospitalization for heart failure. Zinman B et al. N Engl J Med. 2015;373: Hospitalization for Heart Failure in Type 2 Diabetes EMPA REG Trial HR 0.65 (95% CI 0.50, 0.85) p= % N=7020 Zinman B et al. N Engl J Med. 2015;373: Lowered Progression of Kidney Disease with Empagliflozin EMPA REG Trial Change in GFR Over 192 weeks Post Hoc Renal Composite Outcome Wanner C et al. N Engl J Med. 2016;375:

15 Individual Outcomes with Canagliflozin in Type 2 Diabetes CANVAS and CANVAS-R Trial Neal B et al. N Engl J Med. 2017;377: CVD-REAL Study Real world study of 6 countries (US, Norway, Denmark, Sweden, Germany, UK) for relative rates death and hospitalization for heart failure in pts. newly started on SGLT2i or matched controls (n=154,528 in both). - Baseline 3% HF, 13% CVD, 27% microvascular disease. - Canagliflozin 53%, Dapagliflozin 42%, Empagliflozin 5%. Lowered relative rates in SGLT2i patients: - Heart failure 0.61 (95% CI , p<0.001). - All cause death 0.49 (95% CI , p<0.001). No significant heterogeneity by country. Kosiborod M et al. Circulation : SGLT2 Inhibitor Therapy is a Good Choice for our Patient!! Class effects: - Dramatic and rapid reduction in clinically significant heart failure. - Dramatic reduction in onset and progression of chronic kidney disease. - Likely important reduction in overall death. Mechanisms of rapid effect on lowering heart failure: - Latest data suggests volume reduction (diuretic). Drug adverse effects: - Amputations with Canagliflozin - not yet seen with other agents. - Genital yeast infections in men and women. - Euglycemic DKA. Effects are only proven for preexisting cardiac disease: - We CANNOT assume there will be benefits in persons without CVD (primary prevention).

16 GLP-1 Receptor Agonists More Complicated Liraglutide LEADER Trial 9,340 type 2 DM patients high risk for CVD received Liraglutide versus placebo plus usual care for median 3.8 years. 81% with established CVD. Primary CV Outcome Death from CV Causes Marso SP et al. New Engl J Med 2016;375: Liraglutide LEADER Trial Hospitalization Heart Failure Marso SP et al. New Engl J Med 2016;375:

17 Lowered Progression of Kidney Disease with Liraglutide Leader Trial Mann JFE et al. N Engl J Med. 2017;377: Comparison of Major Outcome Relative Rates in LEADER, SUSTAIN 6 and EXSCEL Trials LEADER SUSTAIN 6 EXSCEL 3-point MACE Nonfatal MI Nonfatal Stroke Cardiac death Death any cause Hospital Heart Failure Nephropathy Retinopathy Red Color is statistically significant versus study control group. Liraglutide is a Good Choice for Our Patient Class effects Somewhat unclear - divergent CVD outcomes different agents. Liraglutide: -Reduction in 3 point MACE less cardiac and all cause death. -No improvement in heart failure. -Marked reduction in nephropathy. Mechanism of action: -Long duration (12-18 months) suggest modification of atherosclerosis along with improved CVD risk factors. High chance of attaining A1c goal <7% (at A1c 8.4%).

18 Final Thoughts - Firsts EMPA-REG FIRST CVOT showing PROTECTION effect. FDA gave the FIRST indication for CVD protection with a DM antihyperglycemic agent to empagliflozin. - To reduce the risk of cardiovascular death in adults with type 2 diabetes and established cardiovascular disease. - Liraglutide received indication to reduce the risk of major adverse cardiovascular (CV) events, heart attack, stroke, and cardiovascular death in adults with type 2 diabetes and established CV disease. ADA altered their treatment algorithm in 2018 to give their FIRST recommendation for specific antihyperglycemic agents following metformin therapy. Discussion Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes Diabetes Care 2018; 41 (Suppl. 1): S73-S85