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 Migraines OTCs Metformin 1000mg AM and 1500mg PM w/ meals Glimepiride 8mg AM w/ breakfast Atorvastatin 40mg at bedtime Lisinopril 2.5mg daily Omeprazole 40mg daily Sumatriptan 50mg PRN Migraine Ondansetron 4mg Q8H PRN N/V associated with Migraine
Aspirin 81mg at bedtime Womens Multivitamin daily 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? Lets Review the Guidelines. https://www.aace.com/files/aace_algorithm.pdf Spin the Wheel?!?!?!? Insulins TZDs Insulins TZDs Alpha-Glucosidase SU or Glinides Inhibitors Alpha-Glucosidase SU or
Glinides Inhibitors SGLT2 GLP-1 Inhibitors Agonists DPP-IV SGLT2 GLP-1 Inhibitors Agonists DPP-IV Inhibitors Inhibitors Note: Synthetic Amylin was not Included on the wheel Strategies for Choosing Agents 1. 2.
3. 4. 5. 6. 7. 8. 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 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, PostPrandial, Or MIXED Onset of Action15-44 A1c Reduction
Biguanides Fasting Blood Sugars Max effect in 2 weeks 1.0%-1.5%3 Sulfonylureas MIXED Max effect in 1 week 1.0%-1.5%3 MIXED
Max effect in 1 to 2 weeks 0.5-1.0%3 Post-Prandial** Max effect in 1 week 0.5-1.0%3 1.0%-1.5%3 (Metformin) (glipizide, glimepiride, glyburide) Meglitinides
(repaglinide, nateglinide) DPP-4 Inhibitors (sitagliptin, saxagliptin, linagliptin, alogliptin) (experts feel this range is lower 0.7%) GLP-1 Analogs MIXED Max effect in 4 weeks SGLT2 Inhibitors MIXED
Max effect in 1-2 0.5%-1.0%4 weeks (albiglutide, dulaglutide, exenatide, liraglutide) (canagliflozin, dapagliflozin, empaglifozin) Medication Charts Class/Drugs Action on Fasting, PostPrandial, or MIXED Onset of Action15-44 Thiazolidinedione
s MIXED Max effect in 12 0.5%-1.5%3 weeks Alphaglucosidase inhibitors Post-Prandial Max effect in 8 weeks 0.5%-0.8%3 Fasting Days to 1 week
No Hypoglycemia Weight Neutral Cost is less than $20 per month 13 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 Advantages 13 Good efficacy (initially) Cost is less than $10 per
month Disadvantages 13 Hypoglycemia Weight gain Reduced efficacy over time Meglitinides Nateglinide (Starlix) Repaglinide (Prandin) MOA26-27 Stimulates insulin release from Beta Cells in Pancreas A1c Reduction3
0.5%-1.0% Meglitinides Advantages Disadvantages 13 Can be used in place of SU in patients with irregular meals schedules or those who develop late hypoglycemia with SU 13
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% 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
Advantages Disadvantages 13 Weight Loss May reduce blood pressure Oral
13 Genital fungal infections UTIs Increased urination Hypotension Increased LDL Renal adjustments needed Monitor for hyperkalemia Decrease BMD (canagliflozin) Possible ketoacidosis Cost ~$340+ per month 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 Disadvantages13 Low hypoglycemia risk Weight neutral Not absorbed Works on postprandial glucose Cost $45-$145 per month 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) Onset 1.1 Hr Peak
No significant peak Duration 10.8 to >24 hours Administration SubQ once daily* Formulation Stability Cost 14 100unit/ml in vials (10ml) and pens (3ml) 28 days room temp $248/ 10ml vial & $372 / box of 5 pens
Insulin Glargine (Concentrated) Toujeo 14 Onset Peak Duration Administration Formulation Over 6 hours No significant peak >24 hours SUBQ once daily* 300 units/ml pen (1.5ml) Stability 28 days room temp
Cost $335 / box of 3 pens Insulin Detemir (Levemir) Onset Peak Duration Administration Formulation Stability Cost 14 1.1 to 2 hours No significant peak 7.6 to >24 hours* SUBQ once or twice daily 100 unit/ml vial (10ml) or pen (3ml) 42 days room temp
$248/ 10ml vial or $372 /box of 5 pens Insulin degludec (Tresiba) 14 Onset 30 to 90 minutes Peak Minimal Duration 42 hours Administration Formulation Stability
Cost SUBQ once daily at any time of the day U-100 and U-200 pens (3ml) 56 days at room temp $443 / box U-100, $532 / box of U-200 Long and Ultra-Long Acting Insulin Advantages Effective in all patients Reduced microvascular complications No max dose 13 Disadvantages
13 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 Insulin 14 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 SUBQ w/in 15 mins before meal min before or or right after 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 28 days 28 days Cost $202/vial, $391 / box of pens $203/ vial, $392/ box of pens $203 / vial, $391 /box of pens Rapid Acting Insulin
Advantages Disadvantages 13 Effective in all patients No max dose Meal time and correction coverage May utilize advanced dosing regimens 13
1 copay Covers both fasting and postprandial 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 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) Was 6.8% (08/2015) Medications 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 Lets 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 to discuss side effects Wants medication to be effective
Wants medication affordable via insurance 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 Byetta, Bydureon*, Tanzeum*, Trulicity*, Victoza * Denotes once weekly dosing Bolus or Mixed Insulin
Humalog, Novolog, Apidra 70/30, 75/25, 50/50 Insurance Formulary Pearls Find a Pharmacist to HELP YOU!!! Let Review the following Formulary Tiers Medication Rules Insurance Formulary Pearls Drug Tiers Tier 1
Authorization (PA) Need to meet certain criteria for coverage Step Therapy (ST) Needs patient to try one or more alternative medications first Age Edit (AE) Only covered if patient is in a specific age range Quantity Limit (QL) Limits the amount of medication
the patient can get per fill. 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. Pharmacists Letter/Prescribers 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. Pharmacists Letter/Prescribers Letter. June 2015. 14. PL Detail-Document, Comparison of Insulins and Injectable Diabetes Meds. Pharmacists Letter/Prescribers 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
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