Autumn Steen, PharmD, BCACP, CDE, CPP Diabetes Medications July 26, 2018 Autumn Steen, PharmD, BCACP, CDE, CPP

Disclosures to Participants Requirements for Successful Completion: For successful completion, participants are required to be in attendance in the full activity, complete and submit the program evaluation at the conclusion of the educational event. Conflicts of Interest and Financial Relationships Disclosures Planners: Autumn Steen, PharmD, CDE – None Kimberly Miller, MSN, RN, CDE – None Melanie Batchelor, MHS, RD, LDN, CDE – None Presenters: Autumn Steen, PharmD, CDE -- None Disclosure of Relevant Financial Relationships and Mechanism to Identify and Resolve Conflicts of Interest: No conflicts of interest Sponsorship/Commercial Support: Off-label Use: Participants will be notified by speakers to any product used for a purpose other than that for which it was approved by the Food and Drug Administration Activity-Type: Knowledge-based

Continuing Education Information American Association of Diabetes Educators – Provider is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's Commission on Accreditation. American Association of Diabetes Educators (AM001) is a Continuing Professional Education (CPE) Accredited Provider with the Commission on Dietetic Registration (CDR). CDR Credentialed Practitioners will receive 1.0 Continuing Professional Education units (CPEUs) for completion of this activities/materials. The American Association of Diabetes Educators is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This program provides 1.0 contact hours (.10 CEU’s) of continuing education credit. ACPE Universal Activity Number: Effective Date:

Objectives Describe the major classes of diabetes medicines and how they work Identify and mitigate common side effects Recognize appropriate and inappropriate diabetes therapy based on comorbidities Discuss appropriate counseling points for patients on insulin in order to ensure safe and effective use

2018 ADA Guidelines Diabetes Care 2018 Jan; 41(Supplement 1): S1-S159 Image taken from: http://care.diabetesjournals.org/content/diacare/suppl/2017/12/08/41.Supplement_1.DC1/DC_41_S1_Combined.pdf Diabetes Care 2018 Jan; 41(Supplement 1): S1-S159

2018 ADA Guidelines Diabetes Care 2018 Jan; 41(Supplement 1): S1-S159 Image taken from: http://care.diabetesjournals.org/content/diacare/suppl/2017/12/08/41.Supplement_1.DC1/DC_41_S1_Combined.pdf Diabetes Care 2018 Jan; 41(Supplement 1): S1-S159

2018 ADA Guidelines Diabetes Care 2018 Jan; 41(Supplement 1): S1-S159 Image taken from: http://care.diabetesjournals.org/content/diacare/suppl/2017/12/08/41.Supplement_1.DC1/DC_41_S1_Combined.pdf Diabetes Care 2018 Jan; 41(Supplement 1): S1-S159

Basal Insulin Diabetes Care 2018 Jan; 41(Supplement 1): S1-S159 Image taken from: http://care.diabetesjournals.org/content/diacare/suppl/2017/12/08/41.Supplement_1.DC1/DC_41_S1_Combined.pdf Diabetes Care 2018 Jan; 41(Supplement 1): S1-S159

Combo Injectable Therapy Image taken from: http://care.diabetesjournals.org/content/diacare/suppl/2017/12/08/41.Supplement_1.DC1/DC_41_S1_Combined.pdf Diabetes Care 2018 Jan; 41(Supplement 1): S1-S159

Intensive Insulin Diabetes Care 2018 Jan; 41(Supplement 1): S1-S159 Image taken from: http://care.diabetesjournals.org/content/diacare/suppl/2017/12/08/41.Supplement_1.DC1/DC_41_S1_Combined.pdf Diabetes Care 2018 Jan; 41(Supplement 1): S1-S159

Diabetes Care 2018 Jan; 41(Supplement 1): S1-S159 Image taken from: http://care.diabetesjournals.org/content/diacare/suppl/2017/12/08/41.Supplement_1.DC1/DC_41_S1_Combined.pdf Diabetes Care 2018 Jan; 41(Supplement 1): S1-S159

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Glucophage (metformin) Reduces insulin resistance at the liver and reduces liver’s response to glucagon Net result: Reduces hepatic glucose production at inappropriate times and reduces fasting blood sugar Lowers A1c by 1-2% Image taken from: https://islaslab.wikispaces.com/Anti-diabetes+Drug+Metformin+and+its+Use+as+a+Potential+Pancreatic+Cancer+Chemopreventive Endocrinol. 10, 143–156 (2014)

Glucophage (metformin) Extra Benefits Improves cholesterol Lowers BP Improves non-alcoholic fatty liver disease Improves PCOS Can reduce risk of developing diabetes in prediabetes population Can reduce risk of heart attack and stroke Potential anti-cancer benefits (?) Endocrinol. 10, 143–156 (2014)

Glucophage (metformin) Common Side Effects Diarrhea* Nausea and vomiting* Flatulence* B12 deficiency Anemia, neuropathy Monitor and supplement if needed Warnings and Precautions Lactic acidosis Renal impairment eGFR < 30 ml/min – don’t use eGFR 30-45 ml/min – half dose Iodinated contrast: discontinue if eGFR 30-60 ml/min *Happens less with XR Lexicomp

Class: Thiazolidinedione (TZD) Brand: Actos Generic: pioglitazone Reduces insulin resistance at the liver, muscle, and fat cells Net result: Improves fasting and post-prandial BGs Lowers A1c by 1-1.5% Image taken from: http://www.cmaj.ca/content/172/2/213 Current Pharmaceutical Design, 2009, 15, 529-536

Class: Thiazolidinedione (TZD) Brand: Actos Generic: pioglitazone Extra Benefits Improves cholesterol Lowers BP NAFLD PCOS Prevention of type 2 diabetes Reduces risk of CVD, stroke, death Preserves beta cell function Current Pharmaceutical Design, 2009, 15, 529-536 Diabetes, Obesity and Metabolism, 10, 2008, 617–625

Class: Thiazolidinedione (TZD) Brand: Actos Generic: pioglitazone Common Side Effects Warnings and Precautions Weight gain* Fluid retention Bone fractures (women) Pseudoanemia Heart failure Osteoporosis Bladder cancer Macular edema *Less likely with diabetes medications that cause weight loss (GLP-1 RAs, SGLT2-is) Lexicomp

Class: Sulfonylureas Generics: glimepiride, glipizide, glyburide Stimulates insulin secretion from the pancreas in a glucose-independent manner Net result: reduces blood glucose in 2-3 hours (glipizide XL in 6-12 hours) Lowers A1c by 1-2% UpToDate Lexicomp Image taken from: http://www.cmaj.ca/content/172/2/213

Class: Sulfonylureas Generics: glimepiride, glipizide, glyburide Extra Benefits Cheap Works quickly Established therapy UpToDate Lexicomp

Class: Sulfonylureas Generics: glimepiride, glipizide, glyburide Common Side Effects Warnings and Precautions Hypoglycemia Weight gain Sun sensitivity CVD risk Sulfa allergy Chronic kidney disease UpToDate

Class: DPP-IV Inhibitors Brands: Januvia, Onglyza, Tradjenta, Nesina Generics: sitagliptin, saxagliptin, linagliptin, alogliptin Increases endogenous levels of GLP-1 and GIP which stimulates post prandial insulin release Reduces post PPBGs Lowers A1c by 0.6-0.8% Image taken from: http://dhrcindia.com/diabetes_e_10.html Expert Opinion on Emerging Drugs, 21:4, 409-419

Class: DPP-IV Inhibitors Brands: Januvia, Onglyza, Tradjenta, Nesina Generics: sitagliptin, saxagliptin, linagliptin, alogliptin Extra Benefits Weight neutral (sometimes loss) No hypoglycemia Few side effects Safe in elderly population Weak evidence of preserving beta cell function Expert Opinion on Emerging Drugs, 21:4, 409-419

Warnings and Precautions Class: DPP-IV Inhibitors Brands: Januvia, Onglyza, Tradjenta, Nesina Generics: sitagliptin, saxagliptin, linagliptin, alogliptin Common Side Effects Warnings and Precautions Nasopharyngitis Arthralgia Headache Bullous pemphigoid Hypersensitivity Chronic Kidney Disease Except: linagliptin Pancreatitis (?) Bullous pemphigoid – report blisters or erosions, immunosuppressive therapy and referral to dermatology UpToDate

Stimulates receptor for GLP-1 Class: GLP-1 Receptor Agonists Brands: Byetta, Bydureon, Victoza, Trulicity, Adylxin, Ozempic Generics: exenatide, exenatide ER, liraglutide, dulaglutide, lixisenatide, semaglutide Stimulates receptor for GLP-1 Delayed gastric emptying Insulin secretion in response to food Decreased glucagon Increased satiety Decreased FBG and PPBGs Lowers A1c by 1-1.5% Image taken from: https://www.semanticscholar.org/paper/Cardiovascular-effects-of-Glucagon-like-peptide-1-Saraiva-Sposito/d24527396880f3bc7342194778280fdc5969b021/figure/0 Can J Diabetes 41 (2017) 13-24

Evidence in prediabetes Reduces CVD risk Reduces progression of CKD Class: GLP-1 Receptor Agonists Brands: Byetta, Bydureon, Victoza, Trulicity, Adylxin, Ozempic Generics: exenatide, exenatide ER, liraglutide, dulaglutide, lixisenatide, semaglutide Extra Benefits Weight loss Lowers BP Improves cholesterol Evidence in prediabetes Reduces CVD risk Reduces progression of CKD Preserves beta cell function Can J Diabetes 41 (2017) 13-24 Diabetes, 58 (2009) 773-795

Warnings and Precautions Class: GLP-1 Receptor Agonists Brands: Byetta, Bydureon, Victoza, Trulicity, Adylxin, Ozempic Generics: exenatide, exenatide ER, liraglutide, dulaglutide, lixisenatide, semaglutide Common Side Effects Warnings and Precautions Nausea Diarrhea Constipation Vomiting Headache Increased heart rate Chronic Kidney Disease Gastroparesis Pancreatitis (?) Thyroid tumors (?) Can J Diabetes 41 (2017) 13-24

Inhibits sodium-glucose linked transporter 2 Class: SGLT2 Inhibitors Brand: Invokana, Farxiga, Jardiance, Steglatro Generic: canagliflozin, dapagliflozin, empagliflozin, ertugliflozin Inhibits sodium-glucose linked transporter 2 Reduces glucose reabsorption, increases excretion into the urine Lowers FBG and PPBG Glucose in urine when BG >100 Reduces A1c by 0.8-1% Image taken from: https://ars.els-cdn.com/content/image/1-s2.0-S0928098716303141-fx1_lrg.jpg Postgraduate Medicine, 126:6, 33-48

Reduces progression of CKD Decreased serum uric acid Class: SGLT2 Inhibitors Brand: Invokana, Farxiga, Jardiance, Steglatro Generic: canagliflozin, dapagliflozin, empagliflozin, ertugliflozin Extra Benefits Weight loss Reduced BP Reduces CVD risk Reduces progression of CKD Decreased serum uric acid Postgraduate Medicine, 126:6, 33-48 Int J Clin Pract. 2017;71:e12937

Warnings and Precautions Class: SGLT2 Inhibitors Brand: Invokana, Farxiga, Jardiance, Steglatro Generic: canagliflozin, dapagliflozin, empagliflozin, ertugliflozin Common Side Effects Warnings and Precautions Genitourinary infections Increased urine output, thirst, dehydration Dizziness Hypotension Increased serum K+ Chronic kidney disease Osteoporosis Increased risk of amputations Fall risk Ketoacidosis Int J Clin Pract. 2017;71:e12937

First Do No Harm 60 year old male with T2DM, BMI 35 kg/m2 PMH: MI x 2, CHF, CKD, HTN, HLD Labs: A1c 8.3%, SCr 1.8 mg/dl (eGFR 42 ml/min), FLP: TC 200 LDL 80 TG 180 HDL 35 (all else WNL) Meds: atorvastatin 40 mg qday, metoprolol tartrate 100 mg BID, lisinopril 40 mg qday, aspirin 81 mg qday, metformin 500 mg BID

First Do No Harm His A1c goal is <7.5%. What would be the safest addition to his med profile? Actos (pioglitazone) – a TZD Invokana (canagliflozin) – SGLT2i Victoza (liraglutide) – GLP1 RA Glimepiride – sulfonylurea Tradjenta (linagliptin) – DPPIVi

Insulin

Definitions Basal Bolus Longer acting Stability overnight and between meals Shorter acting Corrects hyperglycemia to target Prevents postprandial hyperglycemia

Administration and Considerations   Type of Insulin Onset Max Effect Duration Administration and Considerations Rapid Acting Humalog® (Clear) 15 - 30 min 60-90 min 3-4 hours 15 minutes before a meal Novolog® (Clear) 10 - 20 min 3-5 hours Fiasp® (Clear) 12-18 min 90-122 min 5-7 hours 15 minutes before a meal, or up to 20 minutes after eating Afrezza (inhaled) Immediate 12-15 min 160-180 min Comes in 4 and 8 unit step dosing. Use immediately before meal. May be helpful for needle phobia. Short Acting (R) Regular (Clear) 30-60 min 2-3 hrs 4-12 hours 30 minutes before a meal. High variability Intermediate Acting (N) NPH (Cloudy) 2-4 hrs 6-10 hrs 14-24 hours Once or twice daily. Must be mixed by gently rolling. High variability. Long Acting Lantus® (Clear) 3-4 hrs --------- 24 hours Usually once daily. 60% of effect in first 12 hours Levemir® (Clear) 0.8 – 2 hrs 6-23 hours Usually twice daily to avoid wearing off effect. Toujeo® U-300 (Clear) 6 hours >24 hours Once daily. Less potent vs. Lantus. Should not be titrated more often than every 3-4 days. Tresiba® U-100 and U-200 (Clear) 1 hour 42 hours Once daily. Does not have to be the same time each day. Helpful for adherence. Should not be titrated more often than every 3-4 days. Mixtures Novolin® 70/30 (70% NPH, 30% Regular) See above for each type of insulin Twice daily 30 minutes before meals Humulin® 70/30 Humulin® 50/50 (50% NPH, 50% Regular) Novolog® Mix 70/30 (70% intermediate acting, 30% Novolog®) Twice daily 15 minutes before meals Humalog® Mix 75/25 (75% intermediate acting, 25% Humalog®) UpToDate

Example Insulin Regimen Basal: Lantus (glargine) 40 units at bedtime Bolus: Novolog (aspart) 10 units before each meal + SS Blood Glucose Level Units of Novolog Less than 150 151-200 2 201-250 4 251-300 6* 301-350 8* >350 10* *Call healthcare provider

Basal – Counseling Points Avoid confusion with bolus! Gently roll NPH, never shake Aim for stability (<30 mg/dl difference overnight) NPH: check BG 4-6 hours after evening dose Don’t take “at bedtime” – consistent time is best Exception: Tresiba (degludec) Once >0.5 units/kg, look at post prandial BGs Avoid using excessive basal to bring down PPBGs Scheiner 2011, p103-127

Bolus – Counseling Points Avoid stacking – Insulin On Board Can keep at room temperature Each check is an opportunity to correct Teach difference between meal dose and correction dose, may use separately! Meal: goal is stability (<30 mg/dl) pre and post meals Correction: goal is to bring BG to target Consistent dose = consistent carbs Otherwise best to do I:C ratio Scheiner 2011, p151-182

Patient Case 55 yof, T2DM, A1c 6.7% Meds: Lantus (glargine) 60 units qHS, metformin 1,000 mg BID, glimepiride 4 mg once daily Started seated exercises 30 mins 4 days/week but is still gaining weight Snacking more often, eats in the middle of the night when she feels like she can “eat the whole refrigerator” FBGs are usually 80s-100s

What would be your advice? Increase exercise to 5 days/week and take sleep aid Ask PCP to decrease dose of glimepiride and/or Lantus (glargine) Eat high protein snack before bed and take sleep aid Reduce calories in diet, slowly increase time of activity

Summary There are 7 main classes of diabetes medications Each have unique benefits and risks Choose second agent based on patient comorbidities and preferences Patient education can prevent hypoglycemia and save lives

References Standards of Medical Care in Diabetes. Diabetes Care 2018 Jan; 41(Supplement 1): S1-S159. Available at https://doi.org/10.2337/dc18-Sint01 AACE/ACE Comprehensive Type 2 Diabetes Management Algorithm 2018. Endocr Pract.2018,doi:10.4158/CS-2017-0153. Available at https://www.aace.com/publications/algorithm. Metformin – mode of action and clinical implications for diabetes and cancer. Pernicova, I and Korbonits, M. Nat. Rev. Endocrinol. 10, 143–156 (2014); published online 7 January 2014; doi:10.1038/nrendo.2013.256 Metformin: Drug Information. Lexicomp. Available at http://online.lexi.com/lco/action/api/find/globalid/6545?utd=1. “Effects of Thiazolidinediones Beyond Glycaemic Control”. Kalaitzidis RG, Sarafidis PA, and Bakris GL. Current Pharmaceutical Design, 2009, 15, 529-536. “Thiazolidinediones and the preservation of beta-cell function, cellular proliferation and apoptosis”. Decker M, Hofflich H, Elias AN. Diabetes, Obesity and Metabolism, 10, 2008, 617–625. doi: 10.1111/j.1463-1326.2007.00745. “Pioglitazone: Drug Information”. Lexicomp. Available at http://online.lexi.com/lco/action/search?q=pioglitazone&t=name&va=pio “Sulfonylureas and meglitinides in the treatment of diabetes mellitus”. McCulloch, DK. UpToDate. Available at https://www.uptodate.com/contents/sulfonylureas-and-meglitinides-in-the-treatment-of-diabetes-mellitus?search=sulfonylureas&source=search_result&selectedTitle=1~132&usage_type=default&display_rank=1 “Glipizide: Drug Information”. Lexicomp. Available at http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/6981?hl=6266.

References Avivit Cahn, Simona Cernea & Itamar Raz (2016) An update on DPP-4 inhibitors in the management of type 2 diabetes, Expert Opinion on Emerging Drugs, 21:4, 409-419, DOI: 10.1080/14728214.2016.1257608. Available at http://dx.doi.org/10.1080/14728214.2016.1257608 “Dipeptidyl peptidase-4 (DPP-4) inhibitors for the treatment of type 2 diabetes mellitus”. Dungan K and DeSantis A. UpToDate. Available at: https://www.uptodate.com/contents/dipeptidyl-peptidase-4-dpp-4-inhibitors-for-the-treatment-of-type-2-diabetes-mellitus?search=dpp4%20inhibitors&source=search_result&selectedTitle=1~60&usage_type=default&display_rank=1 Lovshin, JA. “Glucagon-like Peptide-1 Receptor Agonists: A Class Update for Treating Type 2 Diabetes”. Can J Diabetes 41 (2017) 13-24. Available at: https://www.canadianjournalofdiabetes.com/article/S1499-2671(16)30532-9/pdf DeFronzo, RA. “From the Triumvirate to the Ominous Octet: A New Paradigm for the Treatment of Type 2 Diabetes Mellitus”. Diabetes. 58 (2009) 773-795. Jaime A. Davidson & Louis Kuritzky (2014) Sodium Glucose Co-Transporter 2 Inhibitors and Their Mechanism for Improving Glycemia in Patients with Type 2 Diabetes, Postgraduate Medicine, 126:6, 33-48, DOI: 10.3810/pgm.2014.10.2819. Available at http://dx.doi.org/10.3810/pgm.2014.10.2819 Dandona P and Chaudhuri A. “Sodium-glucose co-transporter 2 inhibitors for type 2 diabetes mellitus: An overview for the primary care physician”. Int J Clin Pract. 2017;71:e12937. Available at: https://doi.org/10.1111/ijcp.12937.

References McCulloch DK. “General principles of insulin therapy in diabetes mellitus”. UpToDate. Available at https://www.uptodate.com/contents/general-principles-of-insulin-therapy-in-diabetes-mellitus?search=insulin%20activity%20profile&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1#H11 . Scheiner, G. “Think like a Pancreas”. Boston: Da Capo Press, 2004, 2011:103-182. Print.