5/1/17 Conflict of Interest I declare no conflict of interest in this presentation. History of Diabetes I am not financially connected with any of the products described, nor do I nor any member of my Treatments family work for the companies who produce those Michael Wright, R.Ph. products. All brand names are the property of the respective companies who produce the products. Insulin Insulin u Discovered in 1921 by Canadian scientists Fredrick Banting, Charles Best, u 1982 – Human R, N (Humulin®, Novolin®) U-100 and U-500 J.J.R. Macleod, and James Collip u 1985 – Human L (Humulin®, Novolin®) u 1922 – Bovine insulin given to humans by injection u 1987 – Human U (Humulin®, Novolin®) u Impurities and injection site issues were common. u 1996 – Lispro (Humalog®) u 1936 – Protamine used to develop slow release insulin (24-36 hr effect) u 2000 – Glargine (Lantus®, Basaglar®, Toujeo ®) u 1950 – Neutral Protamine Hagedorn (NPH) insulin (24 hr effect) u 2000 – Aspart (Novolog®) u 1951 – Lente, Semilente, and Ultralente insulin developed u 2004 – Glulisine (Apidra®) u 1951 – Durham-Humphrey Ammendment u 2005 – Detemir (Levemir®) u 1966 – Iletin I – Pork insulin approved by FDA u 2006 – Inhaled insulin (Exubera®, Afrezza®) u 1975 – Synthetic insulin synthesized Insulin Insulin u 2015 - Degludec (Tresiba ®) Type/Brand Onset Peak Duration u 2015 – Aspart/Degludec (Ryzodeg®) Lispro (Humalog®) 15-30 min 30-90 min 3-5 hours ® u 2016 – Glargine/Lixisenatide (Soliqua®) Aspart (Novolog ) 10-20 min 40-50 min 3-5 hours ® u 2016 – Degludec/Liraglutide (Xultophy®) Glulisine (Apidra ) 20-30 min 30-90 min 1-2.5 hours Type/Brand Onset Peak Duration Lantus®, Basaglar® Glargine (Toujeo ® ) 1-1.5 hours n/a 20-24 hours Detemir (Levemir®) 1-2 hours 6-8 hours Up to 24 hours Degludec (Tresiba ®) 1-1.5 hours n/a 42 hours 1 5/1/17 Insulin Sulfonylurea u Reduction in PPG: Moderate to Marked u First introduced in 1955 u Reduction in Fasting glucose: Moderate to Marked u Mechanism of action – stimulates the release of insulin from functioning pancreatic beta cells u Hypoglycemia: Moderate to Severe u Weight: Gain u Renal Dx: More Hypo risk u Liver Dx: N/A u Heart Failure: N/A – unless with TZD u GI side effects: N/A Sulfonylurea Sulfonylurea u First generation: u Reduction in PPG: Moderate u Chlorpropamide (Diabinese®) Problem: Binds to proteins u Reduction in Fasting glucose: Moderate u Tolbutamide (Orinase®) and can be kicked off – can lead to sharp decreases in ® u Tolazamide (Tolinase ) blood sugar. u Hypoglycemia: Moderate to Severe u Acetohexamide (Dymelor®) u Weight: Gain u Second generation: Do not bind to proteins, u Renal Dx: More Hypo risk u Glyburide (Micronase®, Diabeta®) fewer drug interactions u Liver Dx: Caution u Glipizide (Glucotrol®) u Heart Dx: N/A u Third generation: May also cause a mild u GI side effects: N/A u Glimepiride (Amaryl®) decrease in insulin resistance Biguanides Biguanides u 1995 – Metformin (Glucophage®) u Reduction in PPG: Mild u Mechanism of Action u Reduction in Fasting glucose: Moderate u Decrease sugar production in the liver u Decrease absorption of sugar in the intestines u Hypoglycemia: N/A u Increases peripheral glucose uptake and utilization u Weight: Slight loss u Lactic acidosis u Renal Dx: Contraindicated in Chronic Kidney Disease stage 3B, 4, 5 Stomach discomfort Muscle pain/cramping u Liver Dx: Greatly increases risk of lactic acidosis Decreased appetite Unusual sleepiness, tiredness Diarrhea Unusual weakness u Heart Dx: Use with caution Fast, Shallow breathing General discomfort/malaise u GI side effects: Moderate 2 5/1/17 Alpha-glucosidase inhibitors Alpha-glucosidase inhibitors u 1996 – Acarbose (Precose®) u Reduction in PPG: Moderate Miglitol (Glyset®) u Reduction in Fasting glucose: Neutral u Mechanism of Action u Blocks alpha-glucosidase, the enzyme that breaks down carbohydrates in the upper u Hypoglycemia: N/A part of the small intestine. u Weight: N/A u Taken with the first bite of a meal, treats rise in blood sugar after meals u Renal Dx: N/A u Can interfere with treatment of low blood sugar episodes u Liver Dx: N/A u Can cause bloating, nausea, diarrhea, and flatulence u Heart Dx: N/A u Titrating dose up can help minimize these, and they tend to diminish over time. u GI side effects: Marked Thiazolidinediones (TZD) Thiazolidinediones (TZD) Glitazones Glitazones u 1997 – Troglitazone (Rezulin®) u Reduction in PPG: Mild ® Rosiglitazone (Avandia ) u Reduction in Fasting glucose: Moderate Pioglitazone (Actos®) u Mechanism of action: u Hypoglycemia: N/A u Improves insulin sensitivity for fat and muscle cells and in the liver. u Weight: Gain u Fluid retention and edema, particularly if with insulin u Renal Dx: N/A u Troglitazone à liver damage, taken off the market in 2000 u Liver Dx: Risks u Rosiglitazone à increased risk of heart attack u Heart Dx: Contraindicated in class 3,4 CHF u Pioglitazone à increased risk of bladder cancer u GI side effects: N/A u Watch for fluid retention, shortness of breath, or muscle aches. Meglitinides Meglitinides Glinides Glinides u 1998 – Repaglinide (Prandin®) u Reduction in PPG: Moderate Nateglinide (Starlix®) u Reduction in Fasting glucose: Mild u Mechanism of action: u Increase insulin secretion from the pancreas. Like sulfonylureas, but faster u Hypoglycemia: Mild u Taken right before a meal, not taken if meal is skipped. u Weight: Gain u Can interact with gemfibrozil, warfarin, beta blockers, and NPH insulin u Renal Dx: More hypoglycemia risk with renal issues u Liver Dx: Risks u Heart Dx: Increased CHF risk u GI side effects: N/A 3 5/1/17 Amylin Analogs Amylin Analogs u 1998 – Pramlintide (Symlin®) u Reduction in PPG: Moderate to Marked u Mechanism of action u Reduction in Fasting glucose: Mild u Amylin analog u Decreases after-meal rise in glucagon u Hypoglycemia: N/A u Slows gastric emptying u Weight: Loss u Decreases appetite / increases feelings of fullness u Renal Dx: N/A u Nausea, vomiting, loss of appetite, tiredness u Liver Dx: N/A u Runny or stuffy nose, sore throat, cough, joint pain u Heart Dx: N/A u GI side effects: Moderate Glucagon-like peptide 1 (GLP-1) Glucagon-like peptide 1 (GLP-1) Receptor Agonists Receptor Agonists u 2005 – Exenatide (Byetta®) u Reduction in PPG: Moderate to Marked Liraglutide (Victoza®) u Reduction in Fasting glucose: Mild Albiglutide (Tanzeum ®) Dulaglutide (Trulicity ®) u Hypoglycemia: N/A u Mechanism of action u Weight: Loss u Activates GLP-1 receptors, but longer than GLP-1 does u Renal Dx: Exenatide not indicated in CrCl < 30 u Stimulates Insulin secretion Possible benefit from Liraglutide u Suppresses glucagon u Liver Dx: N/A u Slows gastric emptying u Heart Dx: Possible cardiovascular benefit u Nausea, vomiting, diarrhea. Rarely pancreatitis. u GI side effects: N/A* Dipeptidyl Peptidase 4 (DPP-4) Inhibitors Dipeptidyl Peptidase 4 (DPP-4) Inhibitors Gliptins Gliptins u 2006 – Sitagliptin (Januvia®) u Reduction in PPG: Moderate Vidagliptin (Galvus®) u Reduction in Fasting glucose: Mild Saxagliptin (Onglyza®) Linagliptin (Tradjenta ®) u Hypoglycemia: N/A u Mechanism of Action u Weight: N/A u Increases activity of GLP-1 (an incretin) by blocking its clearance by DPP-4 u Renal Dx: Dose adjustment necessary, except Linagliptin u Stimulates Insulin secretion u Liver Dx: N/A u Suppresses glucagon u Heart Dx: Possible CHF risk for Saxagliptin and Alogliptin u Slows gastric emptying u GI side effects: N/A* u Upper respiratory tract infections, facial swelling. Rarely pancreatitis. 4 5/1/17 Sodium-glucose cotransporter 2 inhibitor Sodium-glucose cotransporter 2 inhibitor SGLT-2 inhibitors “Gliflozins” SGLT-2 inhibitors “Gliflozins” u 2013 – Canagliflozin (Invokana®) u Reduction in PPG: Moderate ® Dapagliflozin (Farxiga ) u Reduction in Fasting glucose: Mild Empagliflozin (Jardiance®) u Mechanism of action: u Hypoglycemia: N/A u Blocks reabsorbption of glucose from the kidneys u Weight: Loss u Works unless blood sugars are > 200mg/dl u Renal Dx: Not indicated for eGFR < 45 mL/min/1.73m2 u Increased risk of UTI, vaginal infections u Liver Dx: N/A u Can cause dehydration u Heart Dx: Possible benefit from empagliflozin u Increased risk of diabetic ketoacidosis (DKA) especially with insulin u GI side effects: N/A u Canagliflozin à increased risk of bone fracture Bibliography http://www.diabetes.org/research-and-practice/student-resources/history-of-diabetes.html?referrer=https://www.google.com/ http://www.diabetesnet.com/about-diabetes/diabetes-medications/sulfonylureas https://es.slideshare.net/tania07/aace-algorithm-38999887 https://www.aace.com/files/aace_algorithm.pdf https://www.accessdata.fda.gov/ http://content.karger.com/produktedb/katalogteile/isbn3_8055/_83/_53/insulin_02.pdf https://www.fda.gov/downloads/drugs/resourcesforyou/consumers/buyingusingmedicinesafely/understandingover-the-countermedicines/ ucm093550.pdf http://www.webmd.com/diabetes/guide/diabetes-types-insulin#1 http://www.rxlist.com/glucophage-drug/clinical-pharmacology.htm http://www.mayoclinic.org/drugs-supplements/glyburide-and-metformin-oral-route/precautions/drg-20061991 https://www.diabetesselfmanagement.com/diabetes-resources/definitions/alpha-glucosidase-inhibitors/ https://www.ncbi.nlm.nih.gov/pubmed/11921433 https://www.diabetesselfmanagement.com/blog/diabetes-medicine-thiazolidinediones/ Bibliography https://www.diabetesselfmanagement.com/blog/diabetes-medicine-meglitinides/ http://www.rxlist.com/symlin-drug/clinical-pharmacology.htm http://www.rxlist.com/symlin-side-effects-drug-center.htm https://www.diabetesselfmanagement.com/blog/diabetes-drugs-glp-1-agonists/ https://www.diabetesselfmanagement.com/blog/diabetes-medicine-dpp-4-inhibitors/ https://www.diabetesselfmanagement.com/blog/updates-sglt2-inhibitors/ 5 .