3/22/2017. Type 2 Diabetes Pathophysiology and Pharmacology Review. Accreditation Statement

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1 Type 2 Diabetes Pathophysiology and Pharmacology Review Joshua J. Neumiller, PharmD, CDE, FASCP Vice Chair & Associate Professor, Department of Pharmacotherapy Washington State University Spokane, WA This educational activity is sponsored by Postgraduate Healthcare Education, LLC (PHE) and supported by an educational grant from Boehringer Ingelheim Pharmaceuticals Inc. and Lilly USA, LLC. Accreditation Statement PHARMACY Postgraduate Healthcare Education, LLC is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. UAN: L1-P H1-P Credits: 1. hour (.1 ceu) Type of Activity: Knowledge Media: Internet New Horizons in Diabetes Care: Reducing Cardiovascular Risks Through Advances in Pharmacotherapy This valuable and engaging 3-part webinar series was designed to inform and educate pharmacists in all practice settings who are involved in the care of patients with T2DM, bridging the gap of learning about the new classes of medications for T2DM, including their pathophysiologic basis of action across the continuum of care for patients with T2DM, while keeping in mind the cardiovascular safety of these -lowering medications. Attend one, two, or all three webinars and gain confidence in applying the results of recent studies to clinical practice. Part 1 - Type 2 Diabetes Pathophysiology and Pharmacology Review Wednesday, March 22, 217 at 1: PM EDT Part 2 Intensifying Therapy after Basal Insulin Optimization in Type 2 Diabetes Options for Targeting Postprandial Control Thursday, March 3, 217 at 1: PM EDT Part 3 Cardiovascular Outcome Trials (CVOTs): Practical Considerations for your Type 2 Diabetes Patients Wednesday, April 5, 217 at 1: PM EDT 1

2 Disclosures to Participants Conflicts of Interest and Financial Relationships Presenter and Program Chair: Joshua J. Neumiller, PharmD, CDE, FASCP Advisory Board/Consultant: Eli Lilly & Boehringer Ingelheim Research Grant Support to WSU: Novo Nordisk Content Reviewer: Tricia Russell, PharmD, BCPS, CDE has nothing to disclose. Learning Objectives After completing this webinar, participants will be able to: 1. Describe the clinical pharmacology of the dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and sodium- cotransporter-2 (SGLT-2) inhibitors 2. Understand the concept of implementing combination pharmacotherapy by addressing complementary pathophysiologic targets 3. Describe the role of DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT-2 inhibitors as monotherapy and in combination with other medications for the treatment of type 2 diabetes (T2DM) Normal Regulation of Glucose Homeostasis Glucagon (α-cell) Pancreas Insulin (β-cell) Glucose output Liver Normal blood Glucose uptake Muscle Porte D Jr, Kahn SE. Clin Invest Med. 1995;18(4): Kahn CR, Saltiel AR. Joslin s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 25:

3 Dysregulation of Glucose Homeostasis in T2DM Islet cell dysfunction Glucagon (α-cell) Pancreas * Reduced effect of insulin indicating insulin resistance Glucose output Insulin (β-cell) Hyperglycemia * Glucose uptake Liver Muscle Del Prato S, MarchettiP. Horm Metab Res. 24;36(11-12): Porte D Jr, Kahn SE. Clin Invest Med. 1995;18(4): Kahn CR, Saltiel AR. Joslin s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 25: Natural History of T2DM Years from diagnosis Diagnosis Onset Insulin resistance Insulin secretion Postprandial (PPG) Fasting (FPG) Pre-diabetes Microvascular complications Macrovascular complications T2DM Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26(4): Nathan DM. N Engl J Med. 22;347(17): Pathophysiologic Defects in T2DM Decreased incretin effect Impaired insulin secretion Islet b-cell lipolysis glucagon secretion Islet a- cell Hyperglycemia reabsorption hepatic production Decreased uptake Neurotransmitter dysfunction DeFronzo RA. Diabetes. 29;58(4):

4 Select Antihyperglycemic Pharmacotherapy Options Oral medications Biguanides Sulfonylureas Meglitinides Thiazolidinediones a-glucosidase inhibitors (AGIs) DPP-4 inhibitors SGLT-2 inhibitors Non-insulin injectable agents GLP-1 receptor agonists Amylin mimetic Insulin Prandial insulin Insulin lispro Insulin aspart Insulin glulisine Insulin human inhaled Regular human insulin Basal insulin Insulin NPH Insulin detemir Insulin glargine U-1 Insulin glargine U-3 Insulin degludec Cornell S, Dorsey VJ. Postgrad Med. 212;124(4): American Diabetes Association Standards of Medical Care in Diabetes. Approaches to glycemic treatment. Diabetes Care. 217;4(Suppl 1):S64-S74. Pathophysiologic Defects in T2DM Decreased incretin effect Impaired insulin secretion Islet b-cell lipolysis glucagon secretion Islet a- cell Hyperglycemia reabsorption hepatic production Decreased uptake Neurotransmitter dysfunction DeFronzo RA. Diabetes. 29;58(4):

5 Insulin (mu/l) Insulin (mu/l) 3/22/217 The Incretin Effect Control subjects (n = 8) People with T2DM (n = 14) Incretin effect Time (min) Time (min) 18 Oral load Intravenous infusion Nauck M, et al. Diabetologia. 1986;29(1): Endogenous GLP-1: Effects in Humans After food ingestion GLP-1 is secreted from L-cells of the jejunum and ileum GLP-1 then Stimulates -dependent insulin secretion Suppresses glucagon secretion Slows gastric emptying Increases satiety Drucker DJ. Curr Pharm Des. 21;7(14): Drucker DJ. Mol Endocrinol. 23;17(2): Drucker DJ. Cell Metab. 26;3(3): Pharmacological Strategies to Augment the Incretin Effect GLP-1 secretion is impaired in T2DM Natural GLP-1 has an extremely short half-life Block DPP-4 to slow the enzymatic degradation of GLP-1: Sitagliptin (Januvia) Saxagliptin (Onglyza) Linagliptin (Tradjenta) Alogliptin (Nesina) Add GLP-1 analogues with longer half-life: Exenatide (Byetta) Liraglutide (Victoza) Lixisenatide (Adlyxin) Once-weekly Exenatide (Bydureon) Albiglutide (Tanzeum) Dulaglutide (Trulicity) 5

6 Comparison of Incretin-based Therapies Select clinical properties of DPP-4 inhibitors and GLP-1 receptor agonists DPP-4 inhibitors GLP-1 receptor agonists Slow gastric emptying No Yes Effect on postprandial hyperglycemia Yes Yes (variable) Effect on weight Weight neutral Weight loss Route of administration Oral Subcutaneous injection Associated with hypoglycemia when used as monotherapy No No Neumiller JJ. Med Clin North Am. 215;99(1): Characteristic Hypoglycemia risk Initial dose (normal CrCl) Dose adjustment for renal impairment CrCl = creatinine clearance. Comparison of DPP-4 Inhibitors Currently Available in the United States (U.S.) Sitagliptin (Januvia) Saxagliptin (Onglyza) Linagliptin (Tradjenta) Alogliptin (Nesina) Low Low Low Low 1 mg daily 5 mg daily 5 mg daily 25 mg daily CrCl < 5 ml/min: 5 mg daily CrCl 3 ml/min: 25 mg daily CrCl 5 ml/min: 2.5 mg daily No adjustment recommended on the basis of renal function CrCl < 6 ml/min: 12.5 mg daily CrCl < 3 ml/min: 6.25 mg daily Sitagliptin prescribing information, 29. Saxagliptin prescribing information, 29. Linagliptinprescribing information, 212. Alogliptinprescribing information, 213. Effects of Currently Available DPP-4 Inhibitors Characteristic Average A1C lowering* Sitagliptin Saxagliptin Linagliptin Alogliptin (Januvia) (Onglyza) (Tradjenta) (Nesina).65% to.79%.36% to.82%.5% to.69%.47% to.85% Average weight change* +.3 to +1.2 kg -.51 to +1.3 kg +.33 to +1.1 kg +.14 to +.51 kg *PBO-subtracted change from baseline; baseline characteristics of study groups and concomitant medications varied among studies. A1C = Hemoglobin A1C. Neumiller JJ. Med Clin North Am. 215;99(1): Sitagliptin prescribing information, 29. Saxagliptin prescribing information, 29. Linagliptinprescribing information, 212. Alogliptinprescribing information,

7 Exenatide BID Exenatide QW Exenatide BID Exenatide QW Exenatide QW Liraglutide Exenatide BID Liraglutide Dulaglutide 1.5 mg Dulaglutide.75 mg Exenatide BID Liraglutide Dulaglutide 1.5 mg Lixisenatide Exenatide BID Liraglutide Albiglutide 3/22/217 Key Considerations for the Use of DPP-4 Inhibitors Oral administration Generally weight neutral Side effects: Headache Nasopharyngitis/upper respiratory tract infections Generally well tolerated Warnings/precautions: Pancreatitis Hypoglycemia (when added to secretagogues or insulin) Allergic reactions Heart failure? (saxagliptin & alogliptin) Comparison of A1C Reductions with GLP-1 Receptor Agonists Study DURATION-1 DURATION-5 DURATION-6 LEAD-6 AWARD-1 AWARD-6 GetGoal-X HARMONY Change in A1C (%) BID = twice daily; QW = once weekly. Adapted from Trujillo JM, et al. Ther Adv Endocrinol Metab. 215;6(1):19-28.; Erratum. 215;6(3): Madsbad S. Diabetes Obes Metab. 216;18(4): GLP-1 Receptor Agonists: Weight Change Ranges in Phase III Trials Lixisenatide 1-2 mcg QD -.28 to kg Albiglutide 3 mg QW +.28 to kg Dulaglutide 1.5 mg QW -1.3 to -3.3 kg Dulaglutide.75 mg QW +.21 to -2.6 kg Liraglutide 1.8 mg QD -.2 to -3.6 kg Liraglutide 1.2 mg QD +.3 to -2.6 kg Exenatide 2 mg QW -2. to -3.7 kg Exenatide 1 µg BID * -1.7 to -3.6 kg Weight reduction (kg) QD = once daily. Adapted from Triplitt C, Solis-Herrera C. Diabetes Educ. 215;41(suppl 1):32S-46S. 7

8 Comparison of Exenatide Products (3-week Data) Exenatide Exenatide BID extended-release suspension A1C reduction (%) FPG reduction (mg/dl) PPG reduction (mg/dl) Achievement of A1C < 7% 1.9 a 41 b 96 77% d c 61% Change in body weight (kg) a P =.23; b P <.1; c P =.124; d P =.39 versus comparator. Drucker DJ, et al. Lancet. 28;372(9645): Key Considerations for the Use of GLP-1 Receptor Agonists Subcutaneous administration Can result in weight loss Side effects: Nausea/vomiting Injection site reactions Contraindications: Personal/family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2 (long-acting products) Warnings/precautions: Pancreatitis Hypoglycemia (when added to secretagogues or insulin) Pathophysiologic Defects in T2DM Decreased incretin effect Impaired insulin secretion Islet b-cell lipolysis glucagon secretion Islet a- cell Hyperglycemia reabsorption hepatic production Decreased uptake Neurotransmitter dysfunction DeFronzo RA. Diabetes. 29;58(4):

9 Renal Glucose Reabsorption Under Normal Conditions ~18 grams of filtered per day SGLT-2 Reabsorption of ~9% of filtered Virtually no urinary excretion SGLT-1 Reabsorption of ~1% of filtered Neumiller JJ, et al. Drugs. 21;7(4): SGLT-2 Inhibition Small intestine SGLT-1 Blood vessel SGLT-1 Glucose ~9% of filtered is reabsorbed through SGLT-2 transporters in the early proximal tubule Glomeruli SGLT-2 SGLT-2 inhibitor Urine Inhibition of SGLT-2 transporters in the proximal tubule blocks the reabsorption of filtered, leading to increased excretion via urine Idris I, Donnelly R. Diabetes Obes Metab. 29;11(2): Canagliflozin versus Glimepiride as Add-on to Metformin: Change in A1C CANA = canagliflozin; GLIM = glimepiride. Cefalu WT, et al. Poster presented at the 73rd Scientific Session of the ADA. June 21-25, 213; Chicago, IL. 9

10 Canagliflozin versus Glimepiride as Add-on to Metformin: Change in Weight Cefalu WT, et al. Poster presented at the 73rd Scientific Session of the ADA. June 21-25, 213; Chicago, IL. Comparison of SGLT-2 Inhibitors Currently Available in the U.S. Characteristic Hypoglycemia risk (as monotherapy) Canagliflozin (Invokana) Dapagliflozin (Farxiga) Empagliflozin (Jardiance) Low Low Low Dose 1 mg daily before breakfast; increase to 3 mg daily, if needed 5 mg daily in the morning; increase to 1 mg daily, if needed 1 mg daily in the morning; increase to 25 mg, if needed Effect on weight Weight loss Weight loss Weight loss Renal Dose Adjustment of SGLT-2 Inhibitors Agent Canagliflozin (Invokana) Dapagliflozin (Farxiga) Empagliflozin (Jardiance) Dosing in CKD stages 3, 4 and 5 (non-dialysis) egfr 6 ml/min/1.73 m 2 No dosage adjustment needed egfr ml/min/1.73 m 2 Do not exceed 1 mg/day by mouth egfr < 45 ml/min/1.73 m 2 Do not initiate and discontinue in patients currently receiving drug Do not initiate; discontinue with egfr < 6 ml/min/1.73 m 2 egfr 45 ml/min/1.73 m 2 No dosage adjustment needed egfr < 45 ml/min/1.73 m 2 Do not initiate and discontinue in patients currently receiving drug egfr = estimated glomerular filtration rate. Canagliflozin prescribing information, 217. Dapagliflozin prescribing information, 216. Empagliflozin prescribing information, 216. Kohan DE, et al. Kidney Int. 214;85(4):

11 Canagliflozin: Less A1C Reduction with Declining egfr Woo V, et al. Poster presented at the 73rd Scientific Session of the ADA. June 21-25, 213; Chicago, IL. Key Considerations for the Use of SGLT-2 Inhibitors Unique mechanism of action Have been studied in combination with a variety of other medication classes Oral administration Low hypoglycemia risk as monotherapy Caution when used with secretagogues or insulin Can result in weight loss and modest decrease in blood pressure Side effects: Genital mycotic infections Urinary tract infections Orthostasis (especially in elderly, chronic kidney disease, diuretic use) Watch volume status levels of low-density lipoproteins Euglycemic diabetic ketoacidosis American Diabetes Association Standards of Medical Care in Diabetes. Approaches to glycemic treatment. Diabetes Care. 217;4(Suppl 1):S64-S74. 11

12 Blood (mmol/l) ΔA1C (%) ΔFPG (mmol/l) ΔBody weight (kg) 3/22/217 Comparison of Glucose-lowering Abilities of T2DM Pharmacotherapy Options Monotherapy Route of administration Targets insulin resistance Target : FPG or PPG A1C reduction* (%) Sulfonylurea Oral No Both Metformin Oral Yes FPG 1.5 Glitazones Oral Yes Both Meglitinides Oral No PPG.5 2. AGIs Oral No PPG.5 1. DPP-4 inhibitors Oral No PPG.5.7 Bile acid sequestrant Oral No PPG.4 Dopamine agonists Oral No PPG.4 SGLT-2 inhibitors Oral toxicity Both GLP-1 receptor agonists Injectable No Short-acting PPG Long-acting Both Amylin analogs Injectable No PPG.6 Insulin Injectable toxicity *A1C reduction data are not from head-to-head comparative studies. Basal FPG Bolus PPG as much as needed Unger J, Parkin CG. Postgrad Med. 21;122(3): Cornell S, Dorsey VJ. Postgrad Med. 212;124(4): Once FBG is optimized, start addressing PPG excursions: Add GLP-1 receptor agonist or Add 1 rapid-acting insulin injection to largest meal or Change to premixed insulin twice daily American Diabetes Association Standards of Medical Care in Diabetes. Approaches to glycemic treatment. Diabetes Care. 217;4(Suppl 1):S64-S74. GLP-1 Receptor Agonist vs. Bolus Insulin in Patients with T2DM and Optimized Basal Insulin Weeks since randomization a a a a a a a a Weeks since randomization 3 Insulin lispro Exenatide BID Pre Post Pre Post Pre Post 3AM Breakfast Lunch Dinner b b b b b Weeks since randomization b b b 3 a p <.1 for exenatide BID vs. insulin lispro b p <.1 for exenatide BID vs. insulin lispro Exenatide caused more gastrointestinal issues (47% vs. 13%) but fewer non-nocturnal episodes of hypoglycemia (15% vs. 34%) than insulin lispro Diamant M, et al. Diabetes Care. 214;37(1):

13 Reprinted with permission from American Association of Clinical Endocrinologists 217 AACE. Garber AJ, Abrahamson MJ, Barzilay JI, et al. AACE/ACE comprehensive type 2 diabetes management algorithm 217. Endocr Pract.217;23: Reprinted with permission from American Association of Clinical Endocrinologists 217 AACE. Garber AJ, Abrahamson MJ, Barzilay JI, et al. AACE/ACE comprehensive type 2 diabetes management algorithm 217. Endocr Pract.217;23: Reprinted with permission from American Association of Clinical Endocrinologists 217 AACE. Garber AJ, Abrahamson MJ, Barzilay JI, et al. AACE/ACE comprehensive type 2 diabetes management algorithm 217. Endocr Pract.217;23:

14 Don t Miss the Upcoming Webinars in This Series! Intensifying Therapy after Basal Insulin Optimization in Type 2 Diabetes Options for Targeting Postprandial Control Presenter: Dr. Susan Cornell Cardiovascular Outcome Trials (CVOTs): Practical Considerations for Your Type 2 Diabetes Patients Presenter: Dr. Curtis Triplitt Thank you! Special Thanks: Postgraduate Healthcare Education, LLC Susan Cornell, PharmD Curtis Triplitt, PharmD How To Earn Credit Click through the URL After reviewing the information, click on the Take Evaluation button located at the bottom of the page Sign in with your username and password Fill out the two screen evaluation form and click submit Your credit will be automatically uploaded to CPE Monitor IMPORTANT: In order to claim credit you must have been in attendance through the live event platform and watched and listened to the event in its entirety. Postgraduate Healthcare Education, LLC has the right to deny credit to individuals that have not attended and participated in this webinar in its entirety. Postgraduate Healthcare Education, LLC completes audits of attendees on a routine basis to ensure compliance with all ACPE standards. 14