1. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Chapter 57 Drugs for Diabetes Mellitus

2. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Diabetes Mellitus: Overview of the Disease and Its Treatment  Disorder of carbohydrate metabolism  Deficiency of insulin  Resistance to action of insulin  Sustained hyperglycemia, polyuria, polydipsia, ketonuria, and weight loss 2

3. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Types of Diabetes Mellitus  Type 1 diabetes (T1DM)  As a rule, type 1 diabetes develops during childhood or adolescence, and symptom onset is relatively abrupt  Can develop during adulthood  Accounts for 5% of all cases of diabetes mellitus  Primary defect is destruction of pancreatic beta cells due to autoimmune process  Trigger for this immune response is not entirely known, but genetic, environmental, and infectious factors likely play a role 3

4. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Types of Diabetes Mellitus  Type 2 diabetes (T2DM)  Most prevalent form of diabetes  Accounts for 90% to 95% of all cases of diabetes  Affects approximately 22 million Americans  Insulin resistance and impaired insulin secretion  Hyperinsulinemia  Insulin resistance  Strong family association 4

5. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Complications of Diabetes Short-Term  Hyperglycemia  Ketoacidosis  Hypoglycemia Long-Term  Macrovascular damage Heart disease Hypertension Stroke Hyperglycemia Altered lipid metabolism  Microvascular damage Retinopathy Nephropathy: Angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB) Sensory and motor neuropathy Gastroparesis Amputation secondary to infection Erectile dysfunction 5

6. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Diabetes and Pregnancy  Before insulin: Virtually all babies born to severely diabetic women died during infancy  Factors during pregnancy  Placenta produces hormones that antagonize the actions of insulin  Production of cortisol increases threefold  Glucose can pass freely from the maternal to the fetal circulation (fetal hyperinsulinemia) 6

7. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Diabetes and Pregnancy  Proper glucose levels are needed in the pregnant patient and in the fetus to prevent teratogenic effects  Fetal death frequently occurs near term  Earlier delivery is desirable 7

8. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Diabetes and Pregnancy  Gestational diabetes  Appears in the mother during pregnancy and subsides rapidly after delivery  Managed in much the same manner as any other diabetic pregnancy  Blood glucose should be monitored and controlled with diet and insulin  Diabetic state usually disappears almost immediately after delivery  If diabetic state persists beyond delivery, it is no longer considered gestational and should be rediagnosed and treated accordingly 8

9. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Diagnosis of Diabetes  Hemoglobin A 1c  Tests based on glucose:  Fasting plasma glucose (FPG) test  Casual plasma glucose test  Oral glucose tolerance test (OGTT) 9

10. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Prediabetes  Impaired fasting plasma glucose between 100 mg/dL and 125 mg/dL  Impaired glucose tolerance test  Increased risk for developing type 2 diabetes  May reduce risk with diet changes and exercise and possibly with certain oral antidiabetic drugs  Many people who meet criteria for “prediabetes” never develop diabetes, even if they do not take precautions against diabetes 10

11. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Overview of Diabetes Treatment  Primary goal is to prevent long-term complications  Tight control of blood glucose level is important  Controlling blood pressure and blood lipids also is important 11

12. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Type 1 Diabetes  Requires a comprehensive plan  Integrated program of diet, self-monitoring of blood glucose, exercise, and insulin replacement 12

13. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Type 1 Diabetes  Dietary measures  Evidence suggests no ideal percentage of calories that should be ingested from carbohydrate, fat, or protein  Macronutrient distribution for any given individual is based on the person’s current eating patterns, preferences, and goals  Glycemic index  Substituting low-glycemic-load foods for higher- glycemic-load foods may modestly improve glycemic control 13

14. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Type 1 Diabetes  Physical activity  Insulin replacement  Management of hypertension  An ACE inhibitor (for example, lisinopril) or an ARB (for example, losartan) can reduce the risk of diabetic nephropathy  Dyslipidemia  Statins (for example, atorvastatin ) 14

15. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Type 2 Diabetes  Similar to type 1, requires comprehensive plan  Patient should be screened and treated for:  Hypertension, nephropathy, retinopathy, neuropathy, dyslipidemias  Glycemic control with:  Modified diet and physical activity  Drug therapy 15

16. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Tight Glycemic Control Inappropriate  Long-standing type 2 diabetes  Advanced microvascular or macrovascular complications  Extensive comorbid conditions  History of severe hypoglycemia  Limited life expectancy 16

17. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Monitoring Treatment  Self-monitoring of blood glucose (SMBG)  Common target values for blood glucose 70-130 mg/dL before meals 100-140 mg/dL at bedtime 17

18. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Monitoring Treatment  Hemoglobin A 1c  Also called glycosylated hemoglobin or glycated hemoglobin  Provides an index of average glucose levels over the prior 2 to 3 months  A 1c goal of below 7% is good for most patients  Goal below 8% may be appropriate for patients with a history of severe hypoglycemia, limited life expectancy, or advanced microvascular or macrovascular complications 18

19. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Insulin  Preparations: “High alert” agents  Sources of insulin  Recombinant DNA technology  Human insulin: Identical to insulin produced by the human pancreas  Human insulin analogs: Modified forms of human insulin that have the same pharmacologic actions as human insulin but different time courses 19

20. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Types of Insulin  Short duration: Rapid acting  Insulin lispro [Humalog]  Insulin aspart [NovoLog]  Insulin glulisine [Apidra]  Short duration: Slower acting  Regular insulin [Humulin R, Novolin R]  Intermediate duration  Neutral protamine Hagedorn (NPH) insulin  Insulin detemir [Levemir]  Long duration  Insulin glargine 20

21. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Insulin Appearance  Except for NPH insulins, all insulins made in the United States are formulated as clear, colorless solutions  NPH insulin is a cloudy suspension  Patients should inspect their insulin before using it and should discard the vial if the insulin looks abnormal 21

22. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Insulin  Concentration  100 units/mL (U-100)  500 units/mL (U-500)  Mixing insulins  NPH with short-acting insulins  Short-acting insulin drawn first 22

23. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Administration  Subcutaneous injection  Syringe and needle  Pen injectors  Jet injectors  Subcutaneous infusion  Portable insulin pumps  Implantable insulin pumps  Intravenous infusion  Inhalation (approved but not used) 23

24. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Storage  Unopened vials should be stored under refrigeration until needed  Insulin should not be frozen  Insulin can be used until the expiration date if kept in the refrigerator  After opening, insulin can be kept up to 1 month without significant loss of activity  Insulin should be kept out of direct sunlight and extreme heat 24

25. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Storage  Mixtures of insulin in vials are stable for 1 month at room temperature and for 3 months under refrigeration  Mixtures in prefilled syringes should be stored in a refrigerator for at least 1 week; they should be stored vertically with the needle pointing up 25

26. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Insulin: Therapeutic Use  Indications  Principal: Diabetes mellitus  Required by all patients with T1DM and by many patients with T2DM  Most insulin sold is used by people with type 2 diabetes, largely because T2DM accounts for 90% to 95% of all cases of diabetes  IV insulin for diabetic ketoacidosis  Gestational diabetes  Hyperkalemia: Can promote uptake of potassium  Aids in the diagnosis of growth hormone (GH) deficiency 26

27. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Insulin Therapy of Diabetes  Dosage  Dosing schedules  Three dosing schedules Twice daily premixed insulin regimen Intensive basal/bolus strategy Continuous subcutaneous insulin 27

28. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Achieving Optimal Glucose Control  Careful attention to all elements of the treatment program (diet, exercise, insulin replacement therapy)  A defined glycemic target  Self-monitoring of blood glucose according to the patient’s individualized management plan  A high degree of patient motivation  Extensive patient education  The responsibility for managing diabetes rests with the patient 28

29. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Complications of Insulin Treatment  Hypoglycemia: Blood glucose below 70 mg/dL  Drug interactions  Blood glucose below 70 mg/dL Rapid treatment mandatory Conscious patients: Fast-acting oral sugar (for example, glucose tablets, orange juice, sugar cubes, nondiet soda) If swallowing reflex or gag reflex is suppressed:  Nothing should be given by mouth  IV glucose or parenteral glucagon is the preferred treatment 29

30. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Complications of Insulin Treatment  Lipohypertrophy  Allergic reactions  Hypokalemia  Drug interactions  Hypoglycemic agents  Hyperglycemic agents  Beta-adrenergic blocking agents 30

31. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Oral Hypoglycemics  Biguanides  Metformin [Glucophage]  Sulfonylureas  Thiazolidinediones (also known as glitazones)  Rosiglitazone [Avandia]  Pioglitazone [Actos]  Meglitinides (also known as glinides)  Repaglinide [Prandin]  Nateglinide [Starlix] 31

32. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Non-Insulin Injectable Drugs  Pramlintide  Amylin mimetic 32

33. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Non-Insulin Injectable Drugs  GLP-1 receptor agonists (also called incretin mimetics)  Slow gastric emptying, stimulate glucose- dependent release of insulin, inhibit postprandial release of glucagon, and suppress appetite  Exenatide [Byetta] Adverse effects: Hypoglycemia and gastrointestinal effects, including pancreatitis Drug interactions 33

34. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Non-Insulin Injectable Drugs  GLP-1 receptor agonists (incretin mimetics) (Cont.)  Liraglutide [Victoza] May cause medullary thyroid carcinoma (MTC)  Amylin mimetics  Pramlintide [Symlin] Reduces postprandial levels of glucose by delaying gastric emptying and suppressing glucagon secretion Adverse effects: Hypoglycemia and nausea, injection site reactions Drug interactions 34

35. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Acute Complications of Poor Glycemic Control  Diabetic ketoacidosis (DKA)  Hyperosmolar hyperglycemic state (HHS)  Cardinal features of both conditions: Hyperglycemic crisis and associated loss of fluid and electrolytes  Both conditions can be life-threatening  Differences  Hyperglycemia more severe in HHS  Ketoacidosis characteristic of DKA, absent in HHS Treatment of the two disorders is similar 35

36. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Diabetic Ketoacidosis  Severe manifestation of insulin deficiency  Symptoms evolve quickly within hours or days  Most common complication in pediatric patients and leading cause of death  Characteristics  Hyperglycemia  Ketoacids  Hemoconcentration  Acidosis  Coma 36

37. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Diabetic Ketoacidosis  Altered glucose metabolism  Hyperglycemia  Water loss  Hemoconcentration  Altered fat metabolism  Production of ketoacids 37

38. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Diabetic Ketoacidosis  Treatment  Insulin replacement  Bicarbonate for acidosis  Water and sodium replacement  Potassium replacement  Normalization of glucose levels 38

39. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Hyperosmolar Hyperglycemic State (HHS)  Also called hyperglycemic hyperosmolar nonketotic syndrome (HHNS)  Large amount of glucose excreted in urine  Results in dehydration and loss of blood volume  Increases blood concentrations of electrolytes and nonelectrolytes (particularly glucose); also increases hematocrit  Blood “thickens” and becomes sluggish 39

40. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. HHS  Little or no change in ketoacid levels  Little or no change in blood pH  No sweet or acetone-like smell to urine or breath  Occurs most frequently with type 2 diabetes with acute infection, acute illness, or some other stress 40

41. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. HHS  Can evolve slowly  Metabolic changes begin a month or two before signs and symptoms become apparent  If left untreated, can lead to coma, seizures, and death  Management  Correct hyperglycemia and dehydration with IV insulin, fluids, and electrolytes 41

42. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Glucagon for Treatment of Severe Hypoglycemia  Preferred treatment is IV glucose  Immediately raises blood glucose level  Glucagon can be used if IV glucose is not available  Delayed elevation of blood glucose  Cannot correct hypoglycemia resulting from starvation Promotes glycogen breakdown, and the malnourished have little glycogen left 42