Objectives  Describe the current information concerning newly approved medications for diabetes mellitus.  Compare and contrast newly approved diabetes mellitus medications to existing therapies. Joshua Settle, PharmD  Describe potential complications from new Clinical Pharmacist antidiabetes products. Baptist Medical Center South  Determine appropriate dose conversions between [email protected] older and newer insulin products. (Technician) ALSHP Fall Meeting September 30, 2016

Disclosure Type 1 Diabetes Mellitus Treatments  Mainstay of therapy is insulin  I, Joshua Settle, have no actual or potential conflict of interest in relation to this program to disclose.  May add additional agents  Pramlinitide  Metformin  GLP‐1 agonists*  DPP‐IV Inhibitors* *Agents are not approved for Type 1 Diabetes treatments but are being investigated

Diabetes Care 2016

Type 2 Diabetes Mellitus Treatments Anticipated A1c Lowering Effects Lifestyle modifications and a patient centered approach  Insulins: 1.5 to 3.5%  Biguanide: 1 to 2% st 1 Line Options: Metformin and/or insulin  Sulfonylureas: 1 to 2%  A1c target not achieved after ~3 months Meglitinides: 0.5 to 1.5% Add a second drug  Thiazolidinediones (TZDs): 0.5 to 1.4%  Sodium‐Glucose Cotransporter 2 (SGLT2) Inhibitors: 0.7 to 1% A1c target not achieved after ~3 months  Glucagon‐Like Peptide‐1 (GLP‐1) Receptor Agonist: 0.5 to 1% Add a third drug  Bile Acid Sequesterants: 0.5 to 1%  A1c target not achieved after ~3 months Alpha‐Glucosidase Inhibitors: 0.5 to 0.8% Add injectable medications (GLP‐1 receptor agonists or insulin)  Dipeptidyl Peptidase IV (DPP‐IV) Inhibitors: 0.4 to 0.8%  Amylin agonists: 0.4 to 0.6% *Choice of medication based on patient or disease‐specific factors  Dopamine 2 Agonists: 0.1% Diabetes Care 2016 Lexi Comp 2016 New Agents Considerations for New Agents Drug: Form/Strength Good Option For:  Lixisenatide (Adlyxin) Lixisenatide • Subcutaneous • Hypoglycemia risk  GLP‐1 Receptor Agonist injection • Heart failure • 10 μg, 20 μg • Weight loss  Not released at this time Linagliptin • Tablet • Hypoglycemia risk  Linagliptin + Metformin (Jentadueto XR) • 2.5mg/1000mg , • Weight neutral + Metformin 5mg/1000mg  DPP‐IV Inhibitor and Biguanide Empagliflozin • Tablet • Hypoglycemia risk  Empagliflozin + Metformin (Synjardy) • 5mg/500mg, • Heart failure + Metformin 5mg/1000mg, • Weight loss  SGLT2 Inhibitor and Biguanide 12.5mg/500mg, • Elevated blood pressure 12.5mg/1000mg

Adlyxin PI, Jentadueto XR PI, Synjardy PI, Diabetes Metab J 2015

Lixisenatide Counseling Points Lixisenatide Concerns  Contraindications:  Once‐daily subcutaneous injection in adjunct to diet and  Hypersensitivity to the drug exercise  Major Concerns:  Inject dose within the hour prior to the first meal of the day  Antibody formation  Missed dose: inject dose within the hour prior to the next meal  GI symptoms (nausea, vomiting, diarrhea)  10 μg for 14 days then increase to 20 μg daily  Increased heart rate  Pre‐filled pen with 14 preset doses  Injection site reactions  Inspect prior to use  Pancreatitis  Only use if solution is clear, colorless and no particles are visible  Renal Impairment (extensively excreted through the kidney)  Storage:  Thyroid tumors (studies were done in rodents)  Refrigerate prior to use then keep at room temperature  Warnings:  Do not use if frozen  Gastroparesis  Discard pen after 14 days from opening  Lowers blood pressure  Recap pen to protect from light Adlyxin PI Adlyxin PI, Clinical Diabetes 2012

Linagliptin + Metformin Linagliptin + Metformin Concerns Counseling Points  Contraindications:  Once‐daily tablet  Hypersensitivity reactions  Severe renal impairment  Take with food at the same time each day  eGFR<30 mL/min/1.73m2 or SCr >1.4 mg/dL (females and  Avoid excessive alcohol use >1.5 mg/dL males  Metabolic acidosis (including diabetic ketoacidosis)  Caution in patients with heart failure  Major Concerns:  Iodinated contrast: Suspend for 48 hours then  Lactic acidosis assess eGFR  Arthralgia (debilitating)  Decrease in lymphocyte counts  Pancreatitis  Vitamin B12 deficiency Jentadueto XR PI Jentadueto XR PI Empagliflozin + Metformin Concerns Empagliflozin + Metformin  Contraindications:  Hypersensitivity reactions Counseling Points  Moderate to severe renal impairment, end‐stage renal disease or on dialysis  Twice‐daily tablet  eGFR<45 mL/min/1.73m2  Take with food  Metabolic acidosis (including diabetic ketoacidosis)  Avoid excessive alcohol use  Major Concerns:  Urinary tract infections leading to urosepsis and pyelonephritis  Cardiovascular benefits  Bone fracture  Suspend therapy with Iodinated contrast and  Ketoacidosis  Genital mycotic infections assess eGFR after 48 hours  Volume depletion/hypotension  Increase in LDL‐C  Impairment in renal function  Lactic acidosis Synjardy PI, Diabetes Care 2016  Vitamin B12 deficiency Synjardy PI

Self Assessment Self Assessment It can be hard to keep track of all the new agents on the Which of the following have become a major concern of market. Please identify the latest FDA approved SGLT2 Inhibitors? antidiabetes medication. A. Lixisenatide A. Diarrhea B. Empagliflozin + Linagliptin B. Hypoglycemia C. Linagliptin + Metformin C. Hypokalemia D. Alogliptin + Metformin D. Ketoacidosis

New Insulin Comparison New Injectable Insulins Drug Onset Peak Duration Discard Insulin 5‐15 min 1.5‐2 hours >24 hours 28 days  Insulin Degludec/Insulin Aspart (Ryzodeg 70/30) Degludec/Aspart  70% insulin degludec/30% insulin aspart Insulin Degludec ~1 hour ~9 hours 42 hours 56 days (minimal peak)  Not released in the US at this time Insulin Glargine 3 hours No peak ~24 hours 28 days  Insulin Degludec (Tresiba FlexTouch) Do not refrigerate after opening and protect from direct heat and light.  Insulin Degludec U‐100 and U‐200 Do not use if has been frozen.  Insulin Glargine (Basaglar KwikPen) Concerns: Contraindications:  Insulin Glargine 100 units/mL •Hypoglycemia •Hypersensitivity to the drug •Hypokalemia •During hypoglycemic episodes  Not released in the US at this time •Injection site reactions •Fluid retention and heart failure can occur if taken with TZDs Ryzodeg 70/30 PI, Tresiba PI, Basaglar PI, Pharmacist Letter 2015 Insulin Degludec/Insulin Aspart Insulin Degludec Counseling Points and Concerns Counseling Points and Concerns  Once daily  Once or twice daily dosing with any main meal  Ultra long acting basal insulin  Option for Type 1 or Type 2 DM trying to  Similar A1c lowering effects and similar or possibly a decrease the number of daily injections slightly lower hypoglycemia risks versus Lantus®  Continue short/rapid acting insulin for meals not  Good for those requiring large doses of basal insulin covered  Greater than 80 Units per day  Low risk of nocturnal hypoglycemia  Dosed on equivalent unit‐per‐unit basis  Dosing times are less strict  not concentrated  Dosing times are less strict  Dose anytime of the day but wait at least 8 hours between Ryzodeg 70/30 PI, Int J Clin Pract 2016 dosings Tresiba PI, Pharmacist Letter 2015

Insulin Glargine Self Assessment Counseling Points and Concerns  Not released until December 2016 If a patient is currently taking 50 units of insulin degludec and your formulary item is the currently available insulin  Similar pharmacokinetic profile as Lantus® glargine, what is the appropriate insulin glargine dose?  Once or twice daily A. 20 units  Long acting basal insulin B. 30 units  Anticipated to be a cheaper insulin glargine option C. 40 units  Solution should be clear and is not intended for IV, IM D. 50 units or insulin pump administration  Basaglar is the first insulin product approved through an abbreviated approval pathway

Basaglar PI, FDA

References References  Abdul‐Ghani M, Del Prato S, Chilton R, and DeFronzo RA. SGLT2 Inhibitors and Cardiovascular Risk: Lessons Learned From the EMPA‐REG OUTCOME  Son JW, Kim S. Dipeptidyl Peptidase 4 Inhibitors and the Risk of Study. Diabetes Care 2016 May; 39(5): 717‐725 . Cardiovascular Disease in Patients with Type 2 Diabetes: A Tale of Three  Lexi‐Comp, Inc. (Lexi‐Drugs®), Lexi‐Comp, Inc.; July 16, 2016. Studies. Diabetes Metab J. 2015 Oct;39(5):373‐83  Adlyxin Package Insert. Sanofi Aventis 2016. Available at:  Reid T. Choosing GLP‐1 Receptor Agonists or DPP‐4 Inhibitors: Weighing the http://products.sanofi.us/adlyxin/adlyxin.pdf. Accessed July 18, 2016. Clinical Trial Evidence. Clinical Diabetes 2012 Jan; 30(1): 3‐12.  Jentadueto XR Package Insert. Boehringer Ingelheim Pharmaceuticals, Inc.  Ryzodeg 70/30 Package Insert. FDA. 2016. Available at: 2016. Available at: http://docs.boehringer‐ http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/203313lbl.pd ingelheim.com/Prescribing%20Information/PIs/Jentadueto%20XR/Jentadu f. Accessed July 12, 2016. eto%20XR.pdf?DMW_FORMAT=pdf. Accessed July 28, 2016.  Tresiba FlexTouch Package Insert. Novo Nordis. 2016. Available at:  Synjardy Package Insert. Boehringer Ingelheim Pharmaceuticals, Inc. 2016. http://www.novo‐pi.com/tresiba.pdf. Accessed July 20, 2016. Available at http://docs.boehringer‐  Basaglar KwikPen Package Insert. Eli Lilly and Company. 2016. Available at: ingelheim.com/Prescribing%20Information/PIs/Synjardy/Synjardy.pdf. http://uspl.lilly.com/basaglar/basaglar.html#pi. Accessed July 20, 2016. Accessed August 1, 2016. References

 PL Detail‐Document, Comparison of Insulins and Injectable Diabetes Meds. Pharmacist’s Letter/Prescriber’s Letter. March 2015  Kumar A, Awata T, Bain SC, Ceriello A, et al. Clinical Use of the Co‐ formulation of Insulin Degludec and Insulin Aspart. Int J Clin Pract. 2016 Aug;70(8):657‐67.  FDA. FDA approves Basaglar, the first “follow‐on” insulin glargine product to treat diabetes. December 16, 2015. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm47 7734.htm.