Strategies for Choosing 2nd and 3rd Line Agents in Type 2 Diabetes To Insulin And Beyond! Strategies for Choosing 2nd and 3rd Line Agents in Type 2 Diabetes Emily Holm, Pharm.D, BCACP Ambulatory Care Clinical Pharmacist MN Academy of Physician Assistants May 11th 2018

Objectives Review current guidelines for Type 2 Diabetes Review classes of medications used for Type 2 Diabetes Learn various strategies for choosing the appropriate add-on agent for your patient Apply what we learn to a patient case

Patient Case E.G. 51 y.o. White Female Significant PMH Type 2 Diabetes Hyperlipidemia Hypertension OSA GERD Migraines (mild- once every 6 months) Obesity UTI (about once a year) Positive Family History of Type 2 DM and Heart Failure

E.G.’s Medications Type 2 DM Hyperlipidemia Hypertension GERD Metformin 1000mg AM and 1500mg PM w/ meals Glimepiride 8mg AM w/ breakfast Type 2 DM Atorvastatin 40mg at bedtime Hyperlipidemia Lisinopril 2.5mg daily Hypertension Omeprazole 40mg daily GERD Sumatriptan 50mg PRN Migraine Ondansetron 4mg Q8H PRN N/V associated with Migraine Migraines Aspirin 81mg at bedtime Women’s Multivitamin daily OTCs

E.G. BP: 130/76 mm Hg Ht: 152cm Wt: 112kg BMI: 48.4 kg/m2 A1c: 9.5% (12/2015) Was 6.8% (08/2015) Lipids TC: 166, TG: 154, HDL: 40, LDL 96 SCr: 0.7 mg/dL

What should we add next?

Let’s Review the Guidelines….

https://www.aace.com/files/aace_algorithm.pdf

Alpha-Glucosidase Inhibitors Spin the Wheel?!?!?!? TZDs SU or Glinides GLP-1 Agonists DPP-IV Inhibitors SGLT2 Inhibitors Alpha-Glucosidase Inhibitors Insulins Note: Synthetic Amylin was not Included on the wheel

Strategies for Choosing Agents Gather Data Consider Drug Classes Available Mechanism of Action A1c Reduction Side Effects/Patient Comorbidities Cost Patient Preference? Insurance Formularies

What Data Do You Need?? Blood Sugar Logs Ask for 1 to 2 weeks of data Medications for Type 2 DM act on Fasting Blood Sugar OR Post-Prandial Blood Sugar OR A Mix of Fasting and Post-Prandial Ask for 1 to 2 weeks of data AM Fasting Blood Sugar 2 hours after largest meal

Medication Chart Class/Drugs Action on Fasting, Post-Prandial, Or MIXED Onset of Action15-44 A1c Reduction Biguanides (Metformin) Fasting Blood Sugars Max effect in 2 weeks 1.0%-1.5%3 Sulfonylureas (glipizide, glimepiride, glyburide) MIXED Max effect in 1 week Meglitinides (repaglinide, nateglinide) Max effect in 1 to 2 weeks 0.5-1.0%3 DPP-4 Inhibitors (sitagliptin, saxagliptin, linagliptin, alogliptin) Post-Prandial** 0.5-1.0%3 (experts feel this range is lower – 0.7%) GLP-1 Analogs (albiglutide, dulaglutide, exenatide, liraglutide) Max effect in 4 weeks SGLT2 Inhibitors (canagliflozin, dapagliflozin, empaglifozin) Max effect in 1-2 weeks 0.5%-1.0%4

Medication Charts Class/Drugs Action on Fasting, Post-Prandial, or MIXED Onset of Action15-44 Key Points Thiazolidinediones (pioglitazone, rosiglitazone) MIXED Max effect in 12 weeks 0.5%-1.5%3 Alpha-glucosidase inhibitors (acarbose, miglitol) Post-Prandial Max effect in 8 weeks 0.5%-0.8%3 Basal Insulin (glargine, detemir, degludec) Fasting Days to 1 week 1.5%-3.5%5 Bolus Insulin (aspart, glulisine, lispro) MIXED*

Biguanide Metformin (Glucophage, Glucophage XR) MOA17 A1c Reduction3 ⇩ hepatic glucose production Improves insulin sensitivity ⇩ intestinal absorption of glucose A1c Reduction3 1.0%-1.5%

Biguanide (Metformin) Advantages13 No Hypoglycemia Weight Neutral Cost is less than $20 per month Disadvantages13 Diarrhea Cramping B12 Deficiency Lactic Acidosis (rare)

Sulfonylureas Glyburide* (Diabeta) Glipizide (Glucotrol, Glucotrol XL) Glimepiride (Amaryl) MOA30-32 Stimulates insulin release from Beta Cell in Pancreas A1C Reduction3 1.0%-1.5%

Sulfonylureas Advantages13 Good efficacy (initially) Cost is less than $10 per month Disadvantages13 Hypoglycemia Weight gain Reduced efficacy over time Hypoglycemia, especially w/ renal dysfunction Weight Gain: more with glyburide than with glipizide and glimepiride Pearls: For eldery – start low and go slow Discontinue when more complex insulin regimens are started

Meglitinides Nateglinide (Starlix) Repaglinide (Prandin) MOA26-27 Stimulates insulin release from Beta Cells in Pancreas A1c Reduction3 0.5%-1.0%

Meglitinides Advantages13 Can be used in place of SU in patients with irregular meals schedules or those who develop late hypoglycemia with SU Disadvantages13 Hypoglycemia Weight Gain Frequent Dosing Cost is $50-100 per month

DPP-4 Inhibitors Alogliptin (Nesina) Linagliptin (Tradjenta) Saxagliptin (Onglyza) Sitagliptin (Januvia) MOA18-21 Inhibits the degradation of endogenous incretins (GLP- 1 & GIP) A1c Reduction3 0.5%-1.0% Experts would say A1c reduction is ≤0.7% Resulting in increased insulin secretion response to elevate glucose, decreased glucagon secretion, slowed GE and increased satiety

DPP-4 Inhibitors Advantages13 No hypoglycemia w/ monotherapy Weight Neutral Generally well tolerated Disadvantages13 Renal dosing needed with all except linagliptin CYP3A4 interactions with saxagliptin and linagliptin May cause joint pain May be associated with pancreatitis Cost is $310-$340 per month

GLP-1 Agonists Albiglutide (Tanzeum) Dulaglutide (Trulicity) Exenatide (Byetta) Exenatide ER (Bydureon) Liraglutide (Victoza) MOA22-25 Enhances glucose dependent insulin secretion Decreases glucagon secretion during periods of hyperglycemia Slows gastric emptying and increases satiety Potential restoration/preservation of beta-cells A1c Reduction3 1%-1.5%

GLP-1 Agonists Advantages13 Low hypoglycemia risk with metformin or monotherapy Weight Loss Approved to be used with basal insulin Lowers Blood Pressure Disadvantages13 Injection Nausea May be associated with pancreatitis Associated with thyroid cell cancer in rodents Cost is $325-$480 per month

SGLT2 Inhibitors or “flozins” Canaglifozin (Invokana) Dapagliflozin (Farxiga) Empagliflozin (Jardiance) MOA28-30 Blocks glucose reabsorption in kidney, increases glucosuria A1c Reduction3 0.5%-1.0%

SGLT2 Inhibitors or “flozins” Advantages13 Weight Loss May reduce blood pressure Oral Disadvantages13 Genital fungal infections UTIs Increased urination Hypotension Increased LDL Renal adjustments needed Monitor for hyperkalemia Decrease BMD (canagliflozin) Possible ketoacidosis Cost ~$340+ per month Mention positive glucose on UA

Thiazolidinediones “TZDs” Pioglitazone (Actos) Rosiglitazone (Avandia)(REMS program) MOA33-34 Increases insulin sensitivity in muscle and fat A1c Reduction3 1.0%-1.5%

Thiazolidinediones “TZDs” Advantages13 Low hypoglycemia risk Improves HDL Reduced Triglycerides (pioglitazone) Pioglitazone is generic –Less than$20 per month Disadvantages13 Weight Gain Edema Congestive Heart Failure Increased fracture risk Increases LDL (rosiglitazone) Possible increase in risk of bladder cancer (pioglitazone) Avandia was on REMS program and is still a Brand Name

Alpha-glucosidase Inhibitors Acarbose (Precose) Miglitol (Glyset) MOA15-16 Slow intestinal carbohydrate digestion/absorption A1c Reduction3 0.5%-0.8%

Alpha-glucosidase inhibitors Advantages13 Low hypoglycemia risk Weight neutral Not absorbed Works on postprandial glucose Cost $45-$145 per month Disadvantages13 INTENSE FLATULENCE Diarrhea Only modest effect on A1c Need for TID dosing

Long and Ultra Long-Acting Insulin Insulin glargine (Lantus® and Toujeo®) Insulin detemir (Levemir®) Insulin degludec (Tresiba®) MOA38-41: Acts via specific membrane-bound receptors on target tissues to regular metabolism of carbohydrates, protein, and fats. A1c Reduction5 1.5%-3.5%

Insulin Glargine (Lantus®)14 1.1 Hr Onset No significant peak Peak 10.8 to >24 hours Duration SubQ once daily* Administration 100unit/ml in vials (10ml) and pens (3ml) Formulation 28 days room temp Stability $248/ 10ml vial & $372 / box of 5 pens Cost Lantus® Onset 1.1 hr Peak No significant peak Administration SubQ once daily (some will split the dose) pH is 4, could be painful Duration 10.8 to > 24 hours Formulations 100 units/ ml Pens and Vials Stability 28 days at room temp for both pens and vials Cost $248/10ml vial $372/ 5 of 3 ml pen

Insulin Glargine (Concentrated) Toujeo®14 Over 6 hours Onset No significant peak Peak >24 hours Duration SUBQ once daily* Administration 300 units/ml pen (1.5ml) Formulation 28 days room temp Stability $335 / box of 3 pens Cost May take at least 5 days to see maximum effect of selected dose. Do not increase the dose more often than every 3 to 4 days. Post marketing data reveals that patients switched from Lantus to Toujeo need their dose increased by about 20%. 1.5ml pen

Insulin Detemir (Levemir®)14 1.1 to 2 hours Onset No significant peak Peak 7.6 to >24 hours* Duration SUBQ once or twice daily Administration 100 unit/ml vial (10ml) or pen (3ml) Formulation 42 days room temp Stability $248/ 10ml vial or $372 /box of 5 pens Cost * Other sources say the max is 22 hours

Insulin degludec (Tresiba®)14 30 to 90 minutes Onset Minimal Peak 42 hours Duration SUBQ once daily at any time of the day Administration U-100 and U-200 pens (3ml) Formulation 56 days at room temp Stability $443 / box U-100, $532 / box of U-200 Cost Takes 3 days to reach steady-state Ensure at least 8 hours between dosing if a dose is missed

Long and Ultra-Long Acting Insulin Advantages13 Effective in all patients Reduced microvascular complications No max dose Disadvantages13 Only effective on fasting blood sugars Hypoglycemia Injection Weight gain Education/training Cost

Rapid Acting Insulin Insulin lispro (Humalog®) Insulin aspart (Novolog®) Insulin glulisine (Apidra®) MOA35-37 Acts via specific membrane-bound receptors on target tissues to regular metabolism of carbohydrates, protein, and fats A1c Reduction3 1.5% to 3.5%

Rapid Acting Insulin14 Name Humalog® Novolog® Apidra® Onset 15 -30 mins 10-20 mins 25 mins Peak 0.5 -2.5 hrs 40 – 50 mins 45-48 mins Duration 3 -6.5 hrs 3 -5 hrs 4 -5.3 hrs Administration SUBQ w/in 15 before meal or right after SUBQ w/in 10 mins before meal or right after SUBQ w/in 15 min before or w/in 20 after starting meal Formulation U-100, vials, pens, cartridge U-200 Pen U-100 vials, pens U-100 vials and pens Stability 28 days Cost $202/vial, $391 / box of pens $203/ vial, $392/ box of pens $203 / vial, $391 /box of pens

Rapid Acting Insulin Advantages13 Effective in all patients No max dose Meal time and correction coverage May utilize advanced dosing regimens Disadvantages13 Hypoglycemia Multi-injection Education/training Cost

Mixed Insulin42-45 Novolog 70/30 ® Humalog 75/25 ® Humalog 50/50 ® Humulin 70/30 ® (NPH/R) Novolin 70/30® (NPH/R)

Mixed Insulin Advantages Twice daily fixed dosing 1 copay Covers both fasting and post-prandial Disadvantages Hypoglycemia middle of the day and middle of the night Injection Cost

NPH and Regular Use of these are on the rise due to cost Dosing NPH SUBQ once or 2xday Regular SUBQ 2 to 3x day NPH/R 70/30 – SUBQ 2xday Dose conversion is generally unit to per unit Administration times may need to change based on regimen

New Combinations! Long-Acting Insulin + GLP-1 Xultophy® Soliqua® Insurance coverage is getting better Generally have “fail” a basal insulin Not for patients on doses >50 units of basal Tresiba + Victoza Lantus + Adlyxin (Lix –A-Sen-A-Tide

Back to the case!! E.G. 51 y.o. White Female Significant PMH Type 2 Diabetes Hyperlipidemia Hypertension OSA GERD Migraines (mild- once every 6 months) Obesity UTI (about once a year) Positive Family History of Type 2 DM and Heart Failure

E.G A1c: 9.5% (12/2015) Medications Blood Sugar Log Was 6.8% (08/2015) Metformin 1000mg AM and 1500mg PM Glimepiride 8mg AM with breakfast Blood Sugar Log Average AM fasting: 145mg/dL Average 2-hr post-prandial: 299mg/dL

Let’s pick some options! Mixed, but mostly a post-prandial issue Need ~ 2.5% reduction in A1c Consider the following DPP-4 GLP-1 SGLT2 TZD Insulin (basal, bolus, mixed)

What does the patient want? Willing to try injection* Wants to lose weight Wants medication to be effective Wants to discuss side effects Wants medication affordable via insurance Not 4xday injections

What could we eliminate? DPP-4 Inhibitor A1c reduction is only modest TZD Family History of Congestive Health Failure SGLT2 History of yearly UTI Basal Insulin Only effective on fasting blood sugars

What is left over? GLP-1 Bolus or Mixed Insulin Byetta®, Bydureon®*, Tanzeum®*, Trulicity®*, Victoza® GLP-1 Humalog®, Novolog®, Apidra 70/30, 75/25, 50/50 Bolus or Mixed Insulin * Denotes once weekly dosing

Insurance Formulary Pearls Find a Pharmacist to HELP YOU!!! Let Review the following Formulary Tiers Medication “Rules”

Insurance Formulary Pearls Drug Tiers Low cost generics Tier 1 High cost generics Tier 2 Formulary Brand Tier 3 Specialty Drugs Tier 4

Insurance Formulary Pearls Medication “Rules” Need to meet certain criteria for coverage Prior Authorization (PA) Needs patient to try one or more alternative medications first Step Therapy (ST) Only covered if patient is in a specific age range Age Edit (AE) Limits the amount of medication the patient can get per fill. Quantity Limit (QL)

Insurance Patient has HealthPartners PreferredRX 2016 Drug Formulary List

Plan Started Victoza® 0.6mg SQ once daily at bedtime x 7 nights, then 1.2mg SQ once daily at bedtime x 7 nights, then 1.8mg SQ once daily at bedtime thereafter. Copay was $25 per month (w/ copay coupon) Decrease the glimepiride by 50% Counseling points Bedtime Dosing Increased Satiety Nausea side effects

Follow Up Patient reported mild nausea during the first 3 weeks. A1c: 7.2% (02/2016) BP: 122/74 (02/2016) Wt: 109kg (02/2016)

What if? Patient wanted to start Mix Insulin? Novolog Mix® 70/30 0.4-0.6 Units/Kg 2/3 dose in the AM w/ breakfast 1/3 dose in PM w/ evening meal Start at 30 units in the AM and 15 units in the PM Discontinue Glimepiride The patient had low risk of UTI and refused injections? SGLT2 Inhibitor Jardiance 10mgmg daily (increase to 25mg if needed) May need to reduce glimepiride dose to prevent hypoglycemia

Summary Gather Blood Sugar Data Consider most effective options Discuss “Pros” and “Cons” of each medication with patient Drug Formulary/Coupon Cards for cost savings Follow up

Thank You!!!!

References 1. AACE/ACE Comprehensive Diabetes Management Algorithm, Endocr Pract. 2015;21 (No.4) https://www.aace.com/files/aace_algorithm.pdf. Accessed April 14, 2016 2. Cefalu W, Bakris G, Blonde L, et al. ADA-Standards of medical care in diabetes-2016. Diabetes Care 2016;S54 http://care.diabetesjournals.org/site/misc/2016-Standards-of-Care.pdf. Accessed April 14. 2016 3. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach. Diabetes Care 2012;35:1364-79. 4. AACE/ACE Comprehensive Type 2 Diabetes Management Algorithm 2016 Published in Endocr Pract.2016;22:84- 113. 5. Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2009;32:193-203. 6. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient- centered approach. Diabetes Care 2015;38:140-9. 7. Handelsman Y, Bloomgarden ZT, Grunberger G, et al. American Association of Clinical Endocrinologists and American College of Endocrinology-Clinical practice guidelines for developing a diabetes mellitus comprehensive care plan – 2015. Endo Pract 2015;21(Suppl 1):1-87. 8. Egan AG, Blind E, Dunder K, et al. Pancreatic safety of incretin-based drugs-FDA and EMA assessment. N Engl J Med 2014;370:794-7. 9. PL Detail-Document, Comparison of GLP-1 Agonists. Pharmacist’s Letter/Prescriber’s Letter. December 2014. 10. FDA. Invokana and Invokamet (canagliflozin): drug safety communication – new information on bone fracture risk and decreased bone mineral density. September 10, 2015. http://www.fda.gov/safety/medwatch/safetyinformation/safetyalertsforhumanmedicalproducts/ucm461876.htm. (Accessed April 20, 2016).

References 11. FDA. FDA drug safety communication: FDA warns that DPP-4 inhibitors for type 2 diabetes may cause severe joint pain. August 28, 2015. http://www.fda. gov/drugs/drugsafety/ucm459579.htm. (Accessed April 20, 2015). 12. Udell JA, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes and moderate or severe renal impairment: observations from the SAVOR-TIMI 53 trial. Diabetes Care 2015;38:696-705. 13. PL Detail-Document, Drugs for Type 2 Diabetes. Pharmacist’s Letter/Prescriber’s Letter. June 2015. 14. PL Detail-Document, Comparison of Insulins and Injectable Diabetes Meds. Pharmacist’s Letter/Prescriber’s Letter. March 2015 15.Acarbose. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 14, 2016 16. Miglitol. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 14, 2016. 17. Metformin. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 14, 2016. 18. Alogliptin. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 14, 2016. 19. Linagliptin. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 14, 2016. 20. Saxagliptin. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 14, 2016.

References 21. Sitagliptin. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 14, 2016. 22. Albiglutide. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 14, 2016. 23. Dulaglutide. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 14, 2016. 24. Exenatide. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 14, 2016. 25. Liraglutide. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 14, 2016. 26. Nateglinide. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 14, 2016. 27. Repaglinide. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 20, 2016. 28. Canagliflozin. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 20, 2016. 29 Dapagliflozin. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 20, 2016. 30. Empaglifozin. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 20, 2016. 30. Glyburide. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 20, 2016. 31. Glipizide. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 20, 2016. 32. Glimepiride. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 20, 2016. 33. Pioglitazone. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 20, 2016. 34. Rosiglitazone. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 20, 2016. 35. Humalog. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 20, 2016. 36. Novolog. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 20, 2016. 37. Apidra. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 20, 2016. 38. Lantus. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 20, 2016. 39. Levemir. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 20, 2016. 40. Toujeo. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 20, 2016. 41. Tresiba. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 20, 2016. 42 .Novolog 70/30. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 20, 2016. 43. Humalog 75/25. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 20, 2016. 44. Humalog 50/50. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 20, 2016. 45. Novolin 70/30. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 20, 2016. 46. HealthPartners® PreferredRx 2016 Drug Formulary. https://www.healthpartners.com/ucm/groups/public/@hp/@public/documents/documents/cntrb_039144.pdf. Accessed April 20, 2016