How to Use the ADA Type 2 Diabetes Treatment Algorithm. Eric L. Johnson, MD Jay Shubrook, Jr., DO, FACOFP

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1 How to Use the ADA Type 2 Diabetes Treatment Algorithm Eric L. Johnson, MD Jay Shubrook, Jr., DO, FACOFP 8 ACOFP 55th Annual Convention & Scientific Seminars

2 ACOFP FULL DISCLOSURE FOR CME ACTIVITIES Please check where applicable and sign below. Provide additional pages as necessary. Name of CME Activity: ACOFP 55th Annual Convention and Scientific Seminars Dates and Location of CME Activity: March 22-25, 2018 JW Marriott Name of Faculty/Moderator: DISCLOSURE OF FINANCIAL RELATIONSHIPS WITHIN 12 MONTHS OF DATE OF THIS FORM A. Neither I nor any member of my immediate family has a financial relationship or interest with any proprietary entity producing health care goods or services. B. I have, or an immediate family member has, a financial relationship or interest with a proprietary entity producing health care goods or services. Please check the relationship(s) that applies. Research Grants Stock/Bond Holdings (excluding mutual funds) Speakers Bureaus* Ownership Consultant for Fee Employment Partnership Others, please list: Please indicate the name(s) of the organization(s) with which you have a financial relationship or interest, and the specific clinical area(s) that correspond to the relationship(s). If more than four relationships, please list on separate piece of paper: Organization With Which Relationship Exists Clinical Area Involved *If you checked Speakers Bureaus in item B, please continue: Did you participate in company-provided speaker training related to your proposed Topic? Yes: No: Did you travel to participate in this training? Yes: No: Did the company provide you with slides of the presentation in which you were trained as a speaker? Yes: No: Did the company pay the travel/lodging/other expenses? Yes: No: Did you receive an honorarium or consulting fee for participating in this training? Yes: No: Have you received any other type of compensation from the company? Please specify: Yes: No: When serving as faculty for ACOFP, will you use slides provided by a proprietary entity for your presentation and/or lecture handout materials? Yes: No: Will your Topic1 involve information or data obtained from commercial speaker training? Yes: No: DISCLOSURE OF UNLABELED/INVESTIGATIONAL USES OF PRODUCTS A. The content of my material(s)/presentation(s) in this CME activity will not include discussion of unapproved or investigational uses of products or devices. B. The content of my material(s)/presentation in this CME activity will include discussion of unapproved or investigational uses of products or devices as indicated below: I have read the ACOFP policy on full disclosure. If I have indicated a financial relationship or interest, I understand that this information will be reviewed to determine whether a conflict of interest may exist, and I may be asked to provide additional information. I understand that failure or refusal to disclose, false disclosure, or inability to resolve conflicts will require the ACOFP to identify a replacement. Signature: Date: Eric L. Johnson, MD Please this form to joank@acofp.org or fax to NO LATER THAN JANUARY 26, 2018

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4 How to Use ADA s Type 2 Diabetes Treatment Algorithm Jay H. Shubrook DO FACOFP Professor Primary Care Department Director of Clinical Research and Diabetes Services Touro University California Eric L. Johnson, M.D. Associate Professor University of North Dakota School of Medicine and Health Sciences Assistant Medical Director Altru Diabetes Center Disclosures Dr. Johnson: Numerous clinical multicenter diabetes studies at Altru Site since 2003 Novo Nordisk Speakers Bureau Medtronic Speakers Bureau Advisory panels Novo Nordisk, Sanofi I have type 1 diabetes and I use insulin products 1

5 Disclosures Jay H. Shubrook Advisory Board Eli Lilly Novo Nordisk Intarcia Clinical Trials Eli Lilly Astra Zeneca Theracos Management of Hyperglycemia in T2DM 1. Patient-centered care 2. Anti-hyperglycemic therapy 3. Implementation strategies 4. Other considerations 2

6 Learning Objectives Recognize drug-specific and patient factors of antihyperglycemic agents to support patientprovider shared decision making Demonstrate when and how to intensify therapy Identify opportunities to refer patients to Diabetes Self-Management Education Ominous Octet 3

7 Patient-Centered Approach...providing care that is respectful of and responsive to individual patient preferences, needs, and values - ensuring that patient values guide all clinical decisions. Gauge patient s preferred level of involvement Explore therapeutic choices Consider using decision aids Shared decision making Lifestyle choices ultimately lie with the patient Diabetes Care 2012;35: ; Diabetologia 2012;55: Glycemic Recommendations: Individualized Treatment A1C <7.0% * Preprandial capillary plasma glucose mg/dl * ( mmol/l) Peak postprandial capillary plasma glucose <180 mg/dl * (<10.0 mmol/l) * More or less stringent glycemic goals may be appropriate for individual patients. Goals should be individualized based on duration of diabetes, age/life expectancy, comorbid conditions, known CVD or advanced microvascular complications, hypoglycemia unawareness, and individual patient considerations. Postprandial glucose measurements should be made 1 2 h after the beginning of the meal, generally peak levels in patients with diabetes 4

8 Approach to the Management of Hyperglycemia Lifestyle Management Lifestyle management is a fundamental aspect of diabetes care and includes Diabetes self-management education (DSME) Diabetes self-management support (DSMS) Nutrition therapy Physical activity Smoking cessation counseling Psychosocial care American Diabetes Association Standards of Medical Care in Diabetes. 4. Lifestyle Management. Diabetes Care 2018;41(Suppl. 1): S38-S50 5

9 Anti-Hyperglycemic Therapy in T2DM Therapeutic options: Oral Agents & Non-Insulin Injectables Most Popular in U.S. and Europe Metformin SGLT-2 Inhibitors GLP-1 Receptor Agonists DPP-4 Inhibitors Thiazolidinediones Sulfonylureas Less Commonly Used Meglitinides A-Glucosidase Inhibitors Colesevelam Dopamine-2 Agonists Amylin Mimetics Metformin Efficacy Hypoglycemia Weight Change Cost Oral/SQ High No Neutral (Potential for Modest Loss) Low Oral 6

10 Metformin CV Effects Renal Effects ASCVD CHF Progression of DKD Dosing/Use Considerations Potential Benefit Neutral Neutral Contraindicated with egrf <30 Additional Considerations Gastrointestinal side effects common (diarrhea, nausea) Potential for B12 deficiency Sulfonylureas (2 nd Generation) Compounds: Glyburide; Glipizide; Glimepiride Efficacy Hypoglycemia Weight Change Cost Oral/SQ High Yes Gain Low Oral 7

11 Sulfonylureas (2 nd Generation) CV Effects Renal Effects ASCVD CHF Progression of DKD Dosing/Use Considerations Neutral Neutral Neutral Glyburide: not recommended Glipizide & glimepiride: initiate conservatively to avoid hypoglycemia Additional Considerations FDA Special Warning on increased risk of cardiovascular mortality based on studies of an older sulfonylurea (tolbutamide) SGLT-2 Inhibitors Compounds: Canagliflozin; Dapagliflozin; Empagliflozin Efficacy Hypoglycemia Weight Change Cost Oral/SQ Intermediate No Loss High Oral 8

12 SGLT-2 Inhibitors CV Effects Renal Effects ASCVD CHF Progression of DKD Dosing/Use Considerations Benefit: canagliflozin, empagliflozin Benefit: canagliflozin, empagliflozin Benefit: canagliflozin, empagliflozin Canagliflozin: Not recommended with egrf <45 Dapagliflozin: Not recommended with egrf <60; contraindicated with egrf <30 Empagliflozin: contraindicated with egrf <30 SGLT-2 Inhibitors Additional Considerations FDA Black Box: risk of amputation (canagliflozin) Risk of bone fractures (canagliflozin) DKA risk (all agents, rare in T2DM) Genitourinary infections Risk of volume depletion, hypotension Increase LDL cholesterol 9

13 GPL-1RAs Compounds: Exenatide; Exenatide extended release; lixisenatide, liraglutide; semaglutide; dulaglutide Efficacy High Hypoglycemia Weight Change Cost Oral/SQ No Loss High SQ GPL-1RAs CV Effects Renal Effects ASCVD CHF Progression of DKD Dosing/Use Considerations Neutral: lixisenatide, exenatide extended release Benefit: liraglutide Neutral Benefit: liraglutide Exenatide: not indicated with egrf<30 Lixisenatide: caution with egrf <30 Increased risk of side effects in patients with renal impairment 10

14 GPL-1RAs Additional Considerations FDA Black Box: Risk of thyroid c-cell tumors (liraglutide, dulaglutide, exenatide extended release) Gastrointestinal side effects common (nausea, vomiting, diarrhea) Injection site reactions Acute pancreatitis risk DPP-4 Inhibitors Compounds: Sitagliptin; Saxagliptin; Linagliptin; Alogliptin Efficacy Intermediate Hypoglycemia Weight Change Cost Oral/SQ No Neutral High Oral 11

15 DPP-4 Inhibitors CV Effects Renal Effects ASCVD CHF Progression of DKD Dosing/Use Considerations Neutral Potential Risk: saxagliptin, alogliptin Neutral Renal dose adjustment required; can be used in renal impairment Additional Considerations Potential risk of acute pancreatitis Joint pain Thiazolidinediones (TZDs) Compounds: Pioglitazone; Rosiglitazone Efficacy High Hypoglycemia Weight Change Cost Oral/SQ No Gain Low Oral 12

16 Thiazolidinediones (TZDs) CV Effects Renal Effects ASCVD CHF Progression of DKD Dosing/Use Considerations Potential Benefit: pioglitazone Increased Risk Neutral No dose adjustment required Generally not recommended in renal impairment due to potential fluid retention Thiazolidinediones (TZDs) Additional Considerations FDA Black Box: Congestive Heart Failure (pioglitazone, rosiglitazone) Fluid retention (edema; heart failure) Benefit in NASH Risk of bone fractures Bladder cancer (pioglitazone) Increase LDL cholesterol (rosiglitazone) 13

17 Insulin Efficacy Highest Hypoglycemia Weight Change Cost Oral/SQ Yes Gain Human Insulin: Low Analogs: High SQ Insulin CV Effects Renal Effects ASCVD CHF Progression of DKD Dosing/Use Considerations Neutral Neutral Neutral Lower Insulin doses required with a decrease in egrf; titrate per clinical response Additional Considerations Injection site reactions Higher risk of hypoglycemia with a human insulin (NPH or premixed formulations) vs. analogs 14

18 Individualizing Treatment Medical Care in Diabetes. Diabetes Care 2018; 41 (Suppl. 1): S73-S85 Considerations in Designing an Optimal Glucose Lowering Drug Regimen for Patients Age Weight Sex / racial / ethnic / genetic differences Comorbidities Coronary artery disease Heart Failure Chronic kidney disease Liver dysfunction Hypoglycemia-prone Identifying and addressing barriers to medication adherence Cost Side effects 15

19 Antihyperglycemic Therapy in Adults with T2DM Antihyperglycemic Therapy in Adults with T2DM 16

20 Antihyperglycemic Therapy in Adults with T2DM Case 1 JW is a 42 year old male who presents for a work physical. He denies any specific symptoms or concerns. You had mentioned a couple of years ago that he had pre-diabetes and he should lose weight and there was a class he could take but he has not found the time to do this. Med hx/surg hx: none Meds: omeprazole OTC prn Allergies: none 17

21 Case 1: Physical exam Obese male BMI 32 Bp 142/88 Mild athlete s foot Exam otherwise normal Labs HbA1c = 7.5% Glucose (fasting) 138 mg/dl High trigs (258) low HDL 28 Labs otherwise normal Case 1: Question 1 What is your A1c goal for this patient? A. < 6.5% B < 7.0% C. < 7.5% D < 8.0% 18

22 Case 1: Question 2 What is the treatment plan for this patient? We will assume that he will be offered diabetes educaton A. therapeutic lifestyle change (TLC) B. TLC + metformin C. TLC + other oral medication D. TLC + insulin Case 1: Question 3 Which of the following conditions would make you not want to use metformin? A. peripheral neuropathy B. Stage 3 CKD C. Stage 4 CKD D. Stage 3 heart failure E. Cirrhosis 19

23 Case 1: Question 4 What is your next pharmacologic option for this patient? If A1c not at goal in 3 months?) Sulfonylurea DPP-4 inhibitor GLP-1 RA SGLT-2 inhibitor TZD Alpha-glucosidase inhibitor What About The Patient with Established Atherosclerotic Cardiovascular Disease (ASCVD)? 20

24 Impact of Intensive Therapy for Diabetes: Summary of Major Clinical Trials Study Microvasc CVD Mortality UKPDS DCCT / EDIC* ACCORD ADVANCE VADT Kendall DM, Bergenstal RM. International Diabetes Center 2009 UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854. Holman RR et al. N Engl J Med. 2008;359:1577. DCCT Research Group. N Engl J Med 1993;329;977. Nathan DM et al. N Engl J Med. 2005;353:2643. Gerstein HC et al. N Engl J Med. 2008;358:2545. Patel A et al. N Engl J Med 2008;358:2560. Duckworth W et al. N Engl J Med 2009;360:129. (erratum: Moritz T. N Engl J Med 2009;361:1024). Writing Group for the DCCT/EDIC Research Group. JAMA. 2015;313(1): * in T1DM Initial Trial Long Term Follow-up Cardiovascular Benefit of Diabetes Medications 21

25 SUSTAIN-6 New GLP-1 agonist just approved December 2017, not on algorithm yet 26% risk reduction in the primary outcome, a composite of nonfatal heart attacks, nonfatal strokes, and cardiovascular death N Engl J Med. 2016;375(19): LEADER Liraglutide T2DM at higher CVD risk 22% risk reduction of cardiovascular death 22% risk reduction of nephropathy 12% risk reduction of non-fatal heart attacks,11% risk reduction of non-fatal strokes but neither statistically significant 13% reduction of primary CVD endpoints N Engl J Med 2016; 375:

26 EMPA-REG Empagliflozin T2DM patients with high CVD risk Reduced the primary major adverse cardiac event (MACE) end point (CV death, nonfatal myocardial infarction, nonfatal stroke) by 14% 38% reduction in CV mortality No significant decrease in nonfatal myocardial infarction or stroke. 35% reduction in hospitalization for heart failure without affecting hospitalization for unstable angina N Engl J Med 2015; 373: CANVAS Canagliflozin T2DM patients with high CV risk 14% reduction in CV endpoints 40% reduction in renal composite endpoints Higher risk of distal amputations N Engl J Med 2017; 377:

27 Pharmacologic Therapy For T2DM: ASCVD Recommendations In patients with T2DM and established ASCVD: antihyperglycemic therapy should begin with lifestyle management and metformin subsequently incorporate an agent proven to reduce major adverse CV events and CV mortality (currently empagliflozin and liraglutide), after considering drug-specific and patient factors (Table 8.1). A the antihyperglycemic agent canagliflozin may be considered to reduce major adverse CV events, based on drug-specific and patient factors (Table 8.1). C Case 2 MT is a 58 y/o Hispanic female Type 2 diabetes x 11 years with dyslipidemia, hypertension, albuminuria, non-painful peripheral neuropathy, obesity, NAFLD, history of MI 3 years ago Current medications: Metformin 1000mg BID Glipizide 10mg daily Pioglitazone 30mg daily Lisinopril 20mg daily Metoprolol XL 25mg daily Atorvastatin 80mg daily Aspirin 81mg daily 24

28 Case 2: Question 1 In this patient with established ASCVD, what should we consider beyond initial metformin therapy? A. TZD B. DPP-IV inhibitor C. GLP-1 RA (liraglutide) D. SGLT-2 inhibitor (canagliflozin, empagliflozin) E. either C or D Case 2: Question 2 In this patient with established ASCVD, what should we consider beyond initial metformin therapy? A. TZD B. DPP-IV inhibitor C. GLP-1 RA (liraglutide) D. SGLT-2 inhibitor (canagliflozin, empagliflozin) E. either C or D Answer: E 25

29 Case 2 Physical exam Nonproliferative retinopathy, normal heart and lung sounds, obese, decreased vibratory and filament sensation in otherwise healthy appearing feet Concerns Many blood sugars in 200 s-300 s, but occasional less than 70 mg/dl Fatigue Difficulty losing weight Labs A1C 10.2% Lipids target (on moderate statin dose), serum creatinine 0.9, GFR 54, hepatic function minor transaminase elevation, urine albumin 110 (normal <30) What next? Case 2 Recall current standards of care recommend SGLT-2 inhibitor (empagliflozin, canagliflozin) or GLP-1 agonist (liraglutide) in the setting of established cardiovascular disease Empagliflozin and liraglutide have FDA indication One of patients main complaints is difficulty losing weight, both of these drug classes are more weight-neutral or -loss 26

30 Case 2 Could do any of the following in the setting of established CVD Add liraglutide (GLP-1 RA) Add empagliflozin (or canagliflozin) (SGLT-2 inhibitor) Both GLP-1 RA or SGLT-2 inhibitor for maximal weight loss Would definitely Continue metformin (renal function is OK) Refer to diabetes educator and dietician Review activity level/exercise prescription Could consider Stop glipizide Stop pioglitazone Insulin Therapy in T2DM The progressive nature of T2DM should be regularly and objectively explained to T2DM patients. Avoid using insulin as a threat, describing it as a failure or punishment. Give patients a self-titration algorithm. 27

31 Combination Injectable Therapy in T2DM Therapeutic Options: Insulins Human Insulins Neutral protamine Hagedorn (NPH) Regular human insulin Insulin Analogues Basal analogues (glargine, detemir, degludec) Rapid analogues (lispro, aspart, glulisine) Biosimilar Insulin Basaglar (a biosimilar version of insulin glargine); long-acting Pre-mixed formulations Pre-mixed formulations Diabetes Care 2012;35: ; Diabetologia 2012;55: Diabetes Care 2015;38: ; Diabetologia 2015; /s

32 Insulin level 3/15/2018 Anti-Hyperglycemic Therapy: Insulins Rapid (Lispro, Aspart, Glulisine) Short (Regular) Long (Detemir) (Degludec) Long (Glargine) Hours After Injection Approach to Starting and Adjusting Insulin in T2DM 29

33 Approach to Starting and Adjusting Insulin in T2DM Approach to Starting and Adjusting Insulin in T2DM 30

34 Case 3 GM is a 64 y/o white male Diagnosed with type 2 diabetes after 2 fasting blood sugars of 154 mg/dl and 142 mg/dl and A1C of 6.8% Saw Diabetes Educator and Dietician at diagnosis Pre-existing HTN (on Lisinopril 10mg) Dyslipidemia (on atorvastatin 40mg) no history of ASCVD ASA 81 mg daily (over 50 + DM) Case 3 Physical Exam BP 132/78, pulse 80, BMI 34 Fundi normal Obese Feet healthy appearing other than benign calluses Lipids in target (measure of compliance), hepatic and renal chemistries all normal 31

35 Case 3 Current Diabetes Medications: Metformin 1000mg BID Glimepiride 4mg daily Basal insulin 40 units daily A1C 8.2% Fasting blood glucose values 110 s-130 s 2 hour post-prandial glucose values 220 s-250 s What next? Case 3 What would be an appropriate choice for this patient? A. DPP-IV inhibitor B. Higher dose of sulfonylurea C. GLP-1 RA D. Rapid acting insulin 32

36 Case 3 What would be an appropriate choice for this patient? A. DPP-IV inhibitor B. Higher dose of sulfonylurea C. GLP-1 RA D. Rapid acting insulin Answer: C or D Options Case 3 Add rapid acting insulin to largest meal of the day 33

37 Case 3 Add GLP-1 RA (or switch to combination GLP-1 RA + basal insulin) (lirglutide + degludec or lixisenatide + glargine) Switch to premix Case 3 Patient should see Diabetes Educator (again) and Dietician for regimen change/instruction and lifestyle evaluation If not reaching targets, consider multiple daily injections of insulin per algorithm Could consider stopping sulfonylurea may not be adding a lot of benefit, or could contribute to hypoglycemia 34

38 Key Points Individualize glycemic targets & BG-lowering therapies Lifestyle foundation of any T2DM therapy program Unless contraindicated, metformin is optimal first-line drug In patients with ASCVD and T2D, subsequent treatment should incorporate agent proven to CV events and/or CV mortality Ultimately, many patients will require insulin therapy alone or in combination with other agents to maintain BG control Shared decision making (focus on his/her preferences, needs & values) Comprehensive CV risk reduction - a major focus of therapy Diabetes Care 2012;35: ; Diabetologia 2012;55: Diabetes Care 2015;38: ; American Diabetes Association Standards of Medical Care in Diabetes. Diabetes Care 2018; 41 (Suppl. 1): S73-S85 Inzucchi SE et al. Diabetologia 2015;58(3): Case 4 TG, a 58-year-old African American, has had T2D for 8 years Currently being treated for hypertension (12 years) and dyslipidemia (10 years) Concerned about uncontrolled blood glucose level, a recent increase in weight (5 lbs) Non-smoker and only occasionally consumes alcohol Walks minutes, three times a week Diet has improved over last 5 years after consult with RD, but she admits to having a sweet tooth (Continued ) 35

39 Physical exam: Case 4 General examination normal, No pallor, cyanosis, clubbing or lymphadenopathy Height, 5 2 (157 cm); weight, 152 lbs (69 kg) BMI, 27.8 kg/m² BP, 132/86 mmhg Pulse 80/min, regular, peripheral pulses well felt Systemic examination- normal Foot examination is normal Fundus examination :Grade I non proliferative diabetic retinopathy Medication history: Glimepiride 2 mg daily BID Metformin sustained release preparations 1000 mg daily Telmisartan 40 mg daily Atorvastatin 10 mg at night Aspirin 81 mg at night (Continued ) Labs: A1C 8.3 % Case 4 Lipids TC 190, TG s 210, HDL 35, LDL 101 Fasting blood glucose values 130 s-160 s Post-prandial blood glucose values 190 s-220 s GFR 65, serum creatinine 1.2, hepatic chemistries normal Urine normal (no albuminuria) 36

40 Case 4 From the lab results, which plasma glucose patterns of hyperglycemia are present? A. Fasting B. Preprandial C. Postprandial D. Nocturnal E. B and C above Case 4 A drug from which of the following drug classes could you suggest to intensify Mrs. G s treatment to manage her hyperglycemia? A. GLP-1 receptor agonist B. DPP-4 inhibitor C. SGLT2 inhibitor D. Basal insulin E. A, B, C, or D above 37

41 Case 4: Think-Pair-Share What option you would have tried first? Would you discontinue the sulfonylurea or add the GLP-1 receptor agonist to the metformin/sulfonylurea? What if this patient had chronic kidney disease (GFR <40)? What if this patient had ASCVD? Thank You! 38