1/15/2018. Disclosures. Current Diabetes Medications. Objectives NON-INSULIN AGENTS. Diabetes Med Classes. Mealtime

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1 Disclosures Current Diabetes Medications None Claire Baker, M.D. Diabetes & Endocrine Associates January 24, 2018 Objectives Identify categories of diabetes medications Understand the pharmacology of diabetes medications Current Diabetes Medications NON-INSULIN AGENTS Thiazolidinediones () Mealtime Fat Pancreas Gut 1

2 Fasting Glucose Old Paradigm: Components of Glycemic Defects in Diabetes demand supply Resistance Beta Cell Function Hyperglycemia New Paradigm: Ominous Octet Hyperglycemia Thiazolidinediones () Metformin Metformin: Available Meds Mechanism Inhibit hepatic gluconeogenesis (primary ) Decreases intestinal absorption of glucose Improves insulin sensitivity by improving peripheral glucose Renally cleared XR tablets will occasionally be eliminated in feces intact Metformin, Glucophage, Glumetza, Fortamet, Riomet (a liquid version) May be XR or ER With SU Metaglip (glipizide/metformin) Glucovance (glyburide/metformin) With ActoPlus Met (pioglitazone/metformin) Avandamet (rosiglitazone/metformin) With GLN Prandimet (repaglinide/metformin) With SGLT2 Synjardy (empagliflozin/metformin) Xigduo (dapagliflozin/metformin) Invokament (canagliflozin/metformin) With DPP4 Janumet (sitagliptin/metformin) Jentadueto (linagliptin/metformin) Kombiglyze (saxagliptin/metformin) Kazano (alogliptin/metformin) 2

3 Metformin Thiazolidinediones () Sulfonylureas (SU) Stimulate insulin release from beta cells Long duration of action: taken once or twice daily Hepatic metabolism with active metabolites that are renally cleared Glipizide (Glucotrol) Metaglip (glipizide/metformin Glyburide (Diabeta, Micronase, Glynase) Glucovance (glyburide/metformin Glimepiride (Amaryl) Duetact (pioglitazone/glimepiride Avandaryl (rosiglitazone/glimepiride) SU Metformin Thiazolidinediones () Dopamine Agonist (bromocriptine, BCR) Meglitinides (GLN) Stimulate insulin release from beta cells via different receptor than the SU Have rapid onset and short duration, so taken before each meal Hepatic metabolism with active metabolites that are renally cleared Repaglinide (Prandin) Prandimet (repaglinide/metformin) Nateglinide (Starlix) 3

4 pg/ml mg/dl μu/ml 1/15/2018 SU, GLN Metformin Thiazolidinediones () s Improve insulin sensitivity by acting on adipose tissue, muscle, and the liver Hepatic metabolism Pioglitazone (Actos) ActoPlus Met (pioglitazone/metformin) Duetact (pioglitazone/glimepiride) Oseni (pioglitazone/alogliptin) Rosiglitazone (Avandia) Avandamet (rosiglitazone/metformin) Avandaryl (rosiglitazone/glimepiride) SU, GLN Metformin, Thiazolidinediones () Response of and After a Meal in Persons Without Diabetes Carbohydrate meal Glucose Time (min) α-cells 30 MM Pancreatic islet Islet boundary β-cells Unger RH. N Engl J Med. 1971;285: Photomicrograph courtesy of Michael Sarras, PhD, Rosalind Franklin University of Medicine and Science. 4

5 (μu/ml) (pg/ml) Plasma Glucose (mg/dl) C-Peptide (nmol/l) 1/15/2018 Inappropriate and Responses to Glucose in Patients With Type 2 Diabetes Non-DM T2DM Time (min) Non-DM T2DM Difference in Response to Oral vs Intravenous Glucose Accounts for the Incretin Effect Oral glucose (50g) or isoglycemic infusion Time (min) * * * * * * IV glucose Oral glucose Time (min) * Muller WA, et al. N Engl J Med. 1970;283: Adapted from Nauck MA, et al. J Clin Endocrinol Metab. 1986;63: Mealtime Pancreas Mealtime Incretins Pancreas Gut Gut Fat Fat -Like Peptide1 Receptor Agonists Incretins: Therapeutic Use Increase glucose dependent insulin secretion Decrease hepatic glucose production via glucagon suppression Increase satiety Slow gastric emptying *This is postulated to be mediated through the central nervous system Adapted from Kolterman OG, et al. J Clin Endocrinol Metab. 2003;88: ; Adapted from Fehse F, et al. J Clin Endocrinol Metab. 2005;90: ; Adapted from Nielsen LL, et al. Regul Pept. 2004;117:77-88 See accompanying Prescribing Information and safety information included in this presentation GLP-1 is rapidly broken down by DPP-IV limiting its usefulness as a medicine Current therapeutic options: GLP-1 analogs/mimetics/receptor agonists, which resist degradation by DPP-IV DPP-IV inhibitors, which increase endogenous levels of incretins 5

6 GLP-1 Receptor Agonists Tanzeum (albiglutide) will be discontinued by July 2018 Byetta (exenatide) Twice a Day Two Doses (5 & 10 mcg) Bydureon (exenatide) Once a Week One Dose (2 mg) Victoza (liraglutide) Once a Day 3 Doses (0.6, 1.2, 1.8 mg) Trulicity (dulaglutide) Once a Week Two Doses (0.75 and 1.5 mg) Ozempic (semiglutide) Once a week 2 Doses (0.5 and 1 mg) GLP-1 and Combos Once Daily Injections Soliqua 100/33 Glargine / Lixisenitide Delivers units of glargine along with 5 20 mg of lixisenatide Xultophy 100/3.6 Tresiba (degludec) and Victoza (liraglutide) Delivers units of degludec and mg of liraglutide SU, GLN, Metformin,, Thiazolidinediones () DPP-4 Inhibitors Decrease metabolism of endogenous incretins, hence enhance typical incretin actions though to a lesser extent than the drugs Metabolism varies by drug Januvia (sitagliptin). Adjust dose based on GFR Janumet (sitagliptin/metformin) Tradjenta (linagliptin). Dose stable regardless of GFR Jentadueto (linagliptin/metformin) Glyxambi (linagliptin/empagliflozin) Onglyza (saxagliptin). Adjust dose based on GFR Kombiglyze (saxagliptin/metformin) Nesina (alogliptin). Adjust dose based on GFR Kazano (alogliptin/metformin) Oseni (alogliptin/pioglitazone) SU, GLN,, DPP4, DPP4 Metformin,,, DPP4 6

7 Thiazolidinediones () SGLT2 Inhibitors Increase glycosuria (and diuresis) via inhibition of SGLT2 in the proximal tubule Increase glucagon, which is unwanted and may be why these drugs increase risk of DKA Inive with CKD Invokana (canagliflozin) Invokamet (canagliflozin/metformin) Jardiance (empagliflozin) Synjardy (empagliflozin/metformin) Glyxambi (empagliflozin/linagliptin) Farxiga (dapagliflozin) Xigduo (dapagliflozin/metformin) SU, GLN,, DPP4, DPP4 Metformin,,, DPP4 SGLT2 Thiazolidinediones () Alpha Glucosidase Inhibitors (AGi) Inhibit the GI tract alpha glucosidases that convert complex polysaccharide carbohydrates into monosaccharides This slows absorption of glucose from the gut Metabolism varies. Contraindicated with CKD Precose (acarbose) Glyset (miglitol) 7

8 SU, GLN,, DPP4 SGLT2, DPP4 Metformin,,, DPP4, AGi Thiazolidinediones () Mealtime Pancreas Mealtime Pancreas Amylin Gut Gut Fat Fat Amylin Amylin Slows gastric emptying Secreted with insulin Suppresses glucagon secretion Secreted with insulin Increases satiety 8

9 Symlin (pramlintide) Amylin analogue (co-secreted with insulin) Effects similar to except no increase in insulin secretion Primarily reduces post-prandial glucose and increases satiety For type 1 and type 2 diabetics on insulin Injection prior to each meal, Pram SU, GLN,, DPP4 SGLT2, DPP4, Pram Metformin,,, DPP4, Pram, AGi Thiazolidinediones () Cycloset: Bromocriptine Quick Release (BQR) Bromocriptine is a dopamine agonist, usually used to treat hyperprolactinemia and Parkinsons A quick release version can be taken in the morning Reduces glucose, but exact mechanism uncertain Cycloset (bromocriptine QR) SU, GLN,, DPP4, Pram, BQR, DPP4, Pram Metformin,,, DPP4, Pram, AGi SGLT2 Thiazolidinediones () Dopamine Agonist (bromocriptine, BCR) 9

10 Welchol (Colesevelam) Bile acid sequestrant usually used for hypercholesterolemia Exact mechanism unknown Not hepatically or renally metabolized Welchol (colesevelam) SU, GLN,, DPP4, Pram, BQR, DPP4, Pram SGLT2 Metformin,,, DPP4, Pram, AGi, COLSVL Noninsulin Agents Available for T2D Class Primary Mechanism of Action Agent(s) Available as -Glucosidase inhibitors Amylin analogue Biguanide Delay carbohydrate absorption from intestine Decrease glucagon secretion Slow gastric emptying Increase satiety Decrease liver Increase glucose in muscle Acarbose Miglitol Pramlintide Metformin Decrease liver? Bile acid sequestrant Increase incretin levels? Colesevelam DPP4 inhibitors Increase glucose-dependent insulin Alogliptin secretion Linagliptin Saxagliptin Decrease glucagon secretion Sitagliptin Precose or generic Glyset Symlin Glucophage or generic WelChol Nesina Tradjenta Onglyza Januvia Dopamine-2 agonist Activates dopaminergic receptors Bromocriptine Cycloset Meglitinides Increase insulin secretion DPP4, dipeptidyl peptidase; HGP, hepatic. Garber AJ, et al. Endocr Pract. 2017;23: ADA. Diabetes Care. 2017;40:S64-S74. Nateglinide Repaglinide Starlix or generic Prandin Noninsulin Agents Available for T2D Class Primary Mechanism of Action Agent(s) Available as receptor agonists SGLT2 inhibitors Increase glucose-dependent insulin Albiglutide secretion Dulaglutide Decrease glucagon secretion Exenatide Exenatide XR Slow gastric emptying Liraglutide Increase satiety Semaglutide Increase urinary excretion of glucose Sulfonylureas Increase insulin secretion Thiazolidinediones Canagliflozin Dapagliflozin Empagliflozin Glimepiride Glipizide Glyburide Increase glucose in muscle Pioglitazone and fat Rosiglitazone Decrease HGP, glucagon-like peptide; HGP, hepatic ; SGLT2, sodium glucose cotransporter 2. Garber AJ, et al. Endocr Pract. 2017;23: ADA. Diabetes Care. 2017;40:S64-S74. Tanzeum Trulicity Byetta Bydureon Victoza Ozempic Invokana Farxiga Jardiance Amaryl or generic Glucotrol or generic Dia eta, Glynase, Micronase, or generic Actos Avandia Fixed-Dose Oral Combination Agents for Type 2 Diabetes Class Added Agent Available as DPP4 inhibitor + SGLT-2 inhibitor Metformin + DPP4 inhibitor Linagliptin + empagliflozin Saxagliptin + dapagliflozin Alogliptin Linagliptin Sitagliptin Glyxambi Qtern Kazano Jentadueto Janumet Metformin + glinide Repaglinide Prandimet Metformin + SGLT2 inhibitor Metformin + sulfonylurea Metformin + thiazolidinedione Canagliflozin Dapagliflozin Glipizide Glyburide Pioglitazone Rosiglitazone* Invokamet Xigduo XR Metaglip and generic Glucovance and generic ACTOplus Met Avandamet Thiazolidinedione + DPP4 inhibitor Pioglitazone + alogliptin Oseni Thiazolidinedione + sulfonylurea Pioglitazone Rosiglitazone Duetact Avandaryl Current Diabetes Medications INSULIN 10

11 Basal- Prandial Basal Prandial 1/15/2018 Current Options Type Basal s Prandial s Premixed s Human Humulin Novolin Relion Analog U-100 NPH U-100 regular human insulin U-500 regular human insulin Afrezza: inhaled insulin U-100 Lantus (glargine) U-100 Basaglar (glargine) U-100 Levemir (detemir) U-100 Tresiba (degludec) U-200 Tresiba (degludec) U-300 Toujeo (glargine) U-100 Humalog (lispro) U-100 Novolog (aspart) U-100 Apidra (glulisine) U-200 Humalog (lispro) U-100 Fiasp (aspart + Vit B3) U /30 U /50 Humalog U /30 Novolog U /25 Humalog Analogue insulins are associated with less hypoglycemia than human insulins, although these differences are not always statistically significant Pharmacokinetics of Available s Agent Onset (h) Peak (h) Duration (h) Considerations Greater risk of nocturnal hypoglycemia compared to NPH insulin analogs Glargine No Detemir ~1-4 pronounced Up to 24 Less nocturnal hypoglycemia compared to NPH Degludec peak* Inject 30 min before a meal Indicated for highly insulin resistant individuals Regular U ~ Use caution when measuring dosage to avoid inadvertent overdose Must be injected min before a meal Regular ~0.5-1 ~2-3 Up to 8 Injection with or after a meal could increase risk for hypoglycemia Aspart Can be administered 0-15 min before a meal Glulisine <0.5 ~ ~3-5 Less risk of postprandial hypoglycemia compared Lispro to regular insulin Inhaled insulin * Exhibits a peak at higher dosages. Dose-dependent. NPH, Neutral Protamine Hagedorn. Moghissi E et al. Endocr Pract. 2013;19: Humulin R U-500 (concentrated) insulin prescribing information. Indianapolis: Lilly USA, LLC. Pharmacology Long Acting Action Profiles Short Acting Action Profiles What s New With Ultra-rapid insulin Biosimilars More concentrations Inhaled insulins Patch delivery device 11

12 Fiasp (aspart) Fiasp (aspart + B3) vs Novolog (aspart) Ultra rapid acting insulin Aspart (Novolog) with niacinamide (vitamin B3) added Approved by FDA and will enter market soon Novorapid is the European and Canadian tradename for Novolog (aspart) What s New With Generic vs Biosimilar Ultra-rapid insulin Biosimilars More concentrations Inhaled insulins Patch delivery device Generic Copies of brand name drugs with the same chemical structure and active ingredient. Are the same in regards to dosage form, safety, strength, route of administration, performance characteristics, and intended use Generic and brand are bioequivalent and can be substituted for one another without intervention of HCP Biosimilar Biologic products made from living organisms, highly similar to reference product. Undergoes thorough structural and functional characterization of the product Intended to produce the same s Not identical copies of biologic products and cannot be substituted without authorization of HCP Biosimilar Glargine What s New With Original product: Lantus Available in vials and pens Biosimilar product: Basaglar Available in pens only Other biosimilars will be coming Ultra-rapid insulin Biosimilars More concentrations Inhaled insulins Patch delivery device 12

13 Concentrations Most insulins have been U-100. The U-100 indicates there are 100 units of insulin per every 1 ml. Nearly all insulin syringes are made for U-100 insulin. Concentration Types Units per ml U-100 Many 100 U-200 U-300 U-500 Humalog (lispro) Tresiba (degludec) Toujeo (glargine) Humulin Regular Units per Vial 1000 (10 ml vial) 200 No Vials 200 No Vials 300 No Vials ,000 (20 ml vial) Units per Pen 300 (3 ml pen) 600 (3 ml pen) 600 (3 ml pen) 450 (1.5 ml pen) 1500 (1.5 ml pen) Humulin U-500 Regular insulin at 5 X the typical concentration Action profile is a mix of Regular and NPH For patients with significant insulin resistance High risk of dosing error which is minimized with the U-500 pen and the dedicated U-500 syringe Only use a U-100 syringe or tuberculin syringe with the vial when everyone is aware of the dose and concentration What s New With Ultra-rapid insulin Biosimilars More concentrations Inhaled insulins Patch delivery device Afrezza: Technosphere Formulation of Human Inhaled human insulin which is very rapidly absorbed For mealtimes only 4, 8, and 12 unit cartridges What s New With Ultra-rapid insulin Biosimilars More concentrations Inhaled insulins Patch delivery device 13

14 V-Go Mechanical pump that patients fill with rapid acting insulin Changed daily Delivers 20, 30, or 40 units of background insulin over 24 hours 36 units are available for boluses, 2 units per click Questions? 14