Chapter 60 Drugs for Diabetes Mellitus 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 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 Types of Diabetes Mellitus (Cont.) 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 Complications of Diabetes Short-term Hyperglycemia Ketoacidosis Hypoglycemia 5 Complications of Diabetes (Cont.) Long-term Macrovascular damage • Heart disease • Hypertension • Stroke • Hyperglycemia • Altered lipid metabolism 6 Complications of Diabetes (Cont.) 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 7 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) 8 Diabetes and Pregnancy (Cont.) 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 9 Diabetes and Pregnancy (Cont.) 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 10 Diagnosis of Diabetes Hemoglobin A1c Tests based on glucose: Fasting plasma glucose (FPG) test Casual plasma glucose test Oral glucose tolerance test (OGTT) 11 Prediabetes Impaired fasting plasma glucose between 100 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 12 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 13 Type 1 Diabetes Requires a comprehensive plan Integrated program of diet, self-monitoring of blood glucose, exercise, and insulin replacement 14 Type 1 Diabetes (Cont.) 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 higherglycemic-load foods may modestly improve glycemic control 15 Type 1 Diabetes (Cont.) Physical activity Insulin replacement Management of hypertension An ACE inhibitor (eg, lisinopril) or an ARB (eg, losartan) can reduce the risk of diabetic nephropathy Dyslipidemia Statins (eg, atorvastatin) 16 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 17 Type 2 Diabetes (Cont.) Step 1 Step 2 Step 3 Step 4 18 Benefits of Glycemic Control Type 1 diabetes Type 2 diabetes 19 Tight Glycemic Control Inappropriate Long-standing type 2 diabetes Advanced microvascular or macrovascular complications Extensive comorbid conditions History of severe hypoglycemia Limited life expectancy 20 Monitoring Treatment Self-monitoring of blood glucose (SMBG) Common target values for blood glucose • 70 to 130 mg/dL before meals • 100 to 140 mg/dL at bedtime 21 Monitoring Treatment (Cont.) Hemoglobin A1c Also called glycosylated hemoglobin or glycated hemoglobin Provides an index of average glucose levels over the prior 2 to 3 months A1c 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 22 Insulin: Physiology Biosynthesis Secretion Metabolic actions Metabolic consequences of insulin deficiency Catabolic mode Increased glycogenolysis Increased gluconeogenesis Reduced glucose utilization 23 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 24 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 Long duration Insulin glargine Insulin determir [Levemir] 25 Short-Duration, Rapid-Acting Insulin Insulin lispro [Humalog] Analog of human insulin Rapid onset (10 to 20 minutes) Short duration (3 to 5 hours) Administered immediately before eating or even after eating 26 Short-Duration, RapidActing Insulin (Cont.) Insulin aspart [NovoLog] Insulin lispro [Humalog] Rapid-acting analog of regular insulin Onset: 15 to 30 minutes after subcutaneous (subQ) injection Duration: 3 to 6 hours Usual route is subQ via injection or use of an insulin pump Acts faster than regular insulin but has a shorter duration of action Should be injected 5 to 10 minutes before meals 27 Short-Duration, RapidActing Insulin (Cont.) Insulin glulisine [Apidra] Synthetic analog of natural human insulin Rapid onset (10 to 15 minutes) Short duration (3 to 5 hours) Should be administered close to the time of eating 28 Short-Duration, Slower-Acting Insulin Regular insulin [Humulin R, Novolin R] Unmodified human insulin Four approved routes: SubQ injection, subQ infusion, intramuscular (IM) injection (used rarely), and oral inhalation (approved but not currently used) Effects begin in 30 to 60 minutes Peak in 1 to 5 hours Duration up to 10 hours Clear solution 29 Short-Duration, SlowerActing Insulin (Cont.) U-100 (100 units/mL) U-500 (500 units/mL) 30 Intermediate-Duration Insulin NPH insulin [Humulin N, Novolin N] Drug is injected twice or 3 times daily to provide glycemic control between meals and during the night NPH insulin is the only one suitable for mixing with short-acting insulins Allergic reactions are possible NPH insulins are cloudy suspensions that must be agitated before administration NPH insulins are administered by subQ injection only 31 Long-Duration Insulin Insulin glargine [Lantus] Modified human insulin Prolonged duration of action (up to 24 hours) Once-daily subQ dosing to treat adults and children with type 1 diabetes and adults with type 2 diabetes Clear solution 32 Long-Duration Insulin (Cont.) Insulin detemir [Levemir] Human insulin analog Slow onset and dose-dependent duration of action Used to provide basal glycemic control Clear, colorless solution Dosing: Once or twice daily by subQ injection Do not mix with other insulins Must not be given IV 33 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 34 Insulin Concentration 100 units/mL (U-100) 500 units/mL (U-500) Mixing insulins NPH with short-acting insulins Short-acting insulin drawn first 35 Administration Subcutaneous injection Syringe and needle Pen injectors Jet injectors Subcutaneous infusion Portable insulin pumps Implantable insulin pumps Intravenous infusion Inhalation 36 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 37 Storage (Cont.) 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 38 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 39 Insulin Therapy of Diabetes Dosage Dosing schedules Three dosing schedules • Twice daily premixed insulin regimen • Intensive basal/bolus strategy • Continuous subcutaneous insulin 40 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 41 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 (eg, 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 42 Complications of Insulin Treatment (Cont.) Lipohypertrophy Allergic reactions Hypokalemia Drug interactions Hypoglycemic agents Hyperglycemic agents Beta-adrenergic blocking agents 43 Oral Hypoglycemics Biguanides Metformin [Glucophage] Sulfonylureas Thiazolidinediones (also known as glitazones) Rosiglitazone [Avandia] Pioglitazone [Actos] Meglitinides (also known as glinides) Repaglinide [Prandin] Nateglinide [Starlix] 44 Oral Hypoglycemics (Cont.) Biguanides Metformin [Glucophage] • Drug of choice for initial therapy in most patients with type 2 diabetes • Most common side effects: Gastrointestinal (GI) disturbances • Lactic acidosis, a potentially fatal complication, is rare • Prevention of type 2 diabetes • Gestational diabetes • Polycystic ovary syndrome (PCOS) • Drug interactions 45 Oral Hypoglycemics (Cont.) Sulfonylureas First oral antidiabetics available Promote insulin release Can be used only for type 2 diabetes Major side effects: Hypoglycemia, weight gain First generation Second generation Cardiotoxicity Drug interactions 46 Oral Hypoglycemics (Cont.) Meglitinides (glinides) Repaglinide [Prandin] • Generally well tolerated • Adverse effect: Hypoglycemia • Drug interactions: Gemfibrozil [Lopid] Nateglinide [Starlix] • Pharmacology nearly identical to that of repaglinide 47 Oral Hypoglycemics (Cont.) Thiazolidinediones (glitazones) Reduce glucose levels primarily by decreasing insulin resistance Only indication is type 2 diabetes, mainly as an addon to metformin Rosiglitazone [Avandia]: Restricted use Pioglitazone [Actos] 48 Oral Hypoglycemics (Cont.) Pioglitazone [Actos] Reduces insulin resistance and may also decrease glucose production Indication: Adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes Adverse effects: Generally well tolerated; most common reactions are upper respiratory tract infection, headache, sinusitis, and myalgia Drug interactions 49 Oral Hypoglycemics (Cont.) Alpha-glucosidase inhibitors Act in the intestine to delay absorption of carbohydrates Indication: Type 2 diabetes Acarbose [Precose] • Adverse effects: Frequently causes flatulence, cramps, abdominal distention, borborygmus, and diarrhea, liver dysfunction 50 Oral Hypoglycemics (Cont.) Miglitol [Glyset] • Especially effective among Latinos and African Americans • Adverse effects: Flatulence, abdominal discomfort, and other GI effects • Has not been associated with liver dysfunction 51 Oral Hypoglycemics (Cont.) DPP-4 inhibitors (also called gliptins) Promote glycemic control by enhancing the actions of incretin hormones Stimulate glucose-dependent release of insulin Suppress postprandial release of glucagon Sitagliptin [Januvia] 52 Oral Hypoglycemics (Cont.) Saxagliptin [Onglyza] • Most common adverse effects: Upper respiratory infection, urinary tract infection, and headache Linagliptin [Tradjenta] Alogliptin [Nesina] 53 Oral Hypoglycemics (Cont.) Sodium-glucose co-transporter 2 (SGLT-2) inhibitors Block reabsorption of filtered glucose in the kidney, leading to glucosuria Indication: Type 2 diabetes mellitus Canagliflozin [Invokana] • Side effects: Genital fungal infections in female patients, urinary tract infections, increased urination 54 Oral Hypoglycemics (Cont.) Dapagliflozin [Farxiga] 55 Other Drugs Colesevelam [Welchol] Bromocriptine 56 Non-Insulin Injectable Drugs Pramlintide Amylin mimetic 57 Non-Insulin Injectable Drugs (Cont.) 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 58 Non-Insulin Injectable Drugs (Cont.) Liraglutide [Victoza] • May cause medullary thyroid carcinoma (MTC) 59 Non-Insulin Injectable Drugs (Cont.) 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 60 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 61 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 62 Diabetic Ketoacidosis (Cont.) Altered glucose metabolism Hyperglycemia Water loss Hemoconcentration Altered fat metabolism Production of ketoacids 63 Diabetic Ketoacidosis (Cont.) Treatment Insulin replacement Bicarbonate for acidosis Water and sodium replacement Potassium replacement Normalization of glucose levels 64 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 65 HHS (Cont.) 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 66 HHS (Cont.) 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 67 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 68 Question 1 A patient is prescribed insulin glargine [Lantus]. Which statement should the nurse include in the discharge instructions? A. B. C. D. The insulin will have a cloudy appearance in the vial. The insulin should be injected twice daily (before breakfast and dinner). The patient should mix Lantus with the intermediateacting insulin. The patient will have less risk of hypoglycemic reactions with this insulin. 69 Question 2 A patient is prescribed NPH insulin. Which statement should the nurse include in the discharge instructions? A. B. C. D. The insulin will have a cloudy appearance in the vial. The onset of action is rapid. The patient should not mix Lantus with short-acting insulin. The patient will have no risk of allergic reactions with this insulin. 70 Question 3 A patient is prescribed metformin. Which statement about metformin does the nurse identify as true? A. B. C. D. Metformin increases absorption of vitamin B12. Metformin can delay the development of type 2 diabetes in high-risk individuals. Metformin causes patients to gain weight. Metformin use predisposes patients to alkalosis. 71