Drugs for Diabetes Mellitus Chapter 57 Drugs for Diabetes Mellitus 1

Diabetes Mellitus: Overview of the Disease and Its Treatment Greek word for “fountain” Latin word for “honey” Disorder of carbohydrate metabolism Deficiency of insulin (IN TYPE I DIABETES) Resistance to action of insulin (TYPE II DIABTES) Sustained hyperglycemia, polyuria, polydipsia, ketonuria, and weight loss in DM I 2

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Types of Diabetes Mellitus Type 1 diabetes 5% to 10% of all cases Also called insulin-dependent diabetes mellitus (IDDM) Or called juvenile-onset diabetes mellitus Primary defect is destruction of pancreatic beta cells 4

Types of Diabetes Mellitus Type 2 diabetes Most prevalent form of diabetes Approximately 19 million Americans have it Also called non–insulin-dependent diabetes mellitus (NIDDM) Or called adult-onset diabetes mellitus Obesity is almost always present Insulin resistance and impaired insulin secretion 5

Complications of Diabetes Short-term Hyperglycemia (from the disease)and hypoglycemia (from the meds) Long-term Macrovascular damage Heart disease Hypertension Stroke Hyperglycemia Altered lipid metabolism 6

Complications of Diabetes Long-term (cont’d) Microvascular damage Retinopathy Nephropathy Neuropathy Gastroparesis Amputations secondary to infections Erectile dysfunction 7

Diagnosis of Diabetes Excessive plasma glucose is diagnostic of diabetes Patient must be tested on two separate days, and both tests must be positive Three tests Fasting plasma glucose (FPG): this test is preferred, 126 mg/dl is diagnostic Casual plasma glucose Oral glucose tolerance test (OGTT) Hemoglobin A1c, oral glucose tolerance test 8

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 and exercise and possibly certain oral antidiabetic drugs 9

Overview of Diabetes Treatment Primary goal is to prevent long-term complications Tight control of blood glucose level is important (reduces CV, kidney, eye, nerve damage) Also important to control blood pressure and blood lipids 10

Type 1 Diabetes Requires comprehensive plan Integrated program of diet, self-monitoring of blood glucose, exercise, and insulin replacement Dietary measures Total carbohydrates – not the type of carbohydrates – are most important Glycemic index 11

Type 2 Diabetes Like type 1, requires comprehensive plan Should be screened and treated for: Hypertension, nephropathy, retinopathy, neuropathy, dyslipidemias Glycemic control with: Diet and exercise Drug therapy 12

Monitoring Treatment Self-monitoring of blood glucose (SMBG) Glycosylated hemoglobin: Hgb A1c- THIS TEST INDICATES AVERAGE SERUM GLUCOSE OVER THE PAST 3 MONTHS 13

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Seven 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) Regular insulin used in hospital “sliding scale” Intermediate duration Neutral protamine Hagedorn (NPH) insulin Insulin detemir (Levemir) Long duration Insulin glargine (GIVEN QHS, FOR NEXT DAY COVERAGE) 15

Fig. 56-2. Time-effect relationship for different types of insulin following subcutaneous injection. 16

Insulin Concentration Mixing insulins 100 units/mL (U-100) NPH with short-acting insulin (Note: NPH can be mixed with any SHORT-ACTING insulin, this saves the patient an extra injection) Short-acting insulin drawn first 17

Administration Subcutaneous injection (abdomen most consistent absorption, thigh is acceptable) Syringe and needle Pen injectors Jet injectors Subcutaneous infusion Portable insulin pumps Implantable insulin pumps Intravenous infusion- short acting insulin can be used, hospitals use regular insulin for operative and NPO patients 18

Storage Unopened vials should be stored under refrigeration until needed Should not be frozen Can be used until expiration date if kept in refrigerator After opening, can be kept up to 1 month without significant loss of activity Keep out of direct sunlight and extreme heat 19

Complications of Insulin Treatment Hypoglycemia (this can be fatal, treat with oral glucose or IV dextrose, depending on the patient’s status) Lipodystrophies Allergic reactions Hypokalemia Drug interactions Hypoglycemic agents (oral hypoglycemic agents are often used concurrently) Hyperglycemic agents Beta adrenergic blocking agents (mask symptoms of hypoglycemia and decrease ability of the body to respond to hypoglycemia) 20

Oral Hypoglycemics (used only for type II DM) Biguanides Metformin (Glucophage) Sulfonylureas Tolbutamide (Orinase) Thiazolidinediones (glitazones) Rosiglitazone (Avandia) Pioglitazone (Actos) Glinides (meglitinides) Repaglinide (Prandin) Nateglinide (Starlix) 21

Oral Hypoglycemics Alpha-glucosidase inhibitors Acarbose (Precose) Miglitol (Glyset) Muraglitazar (Pargluva) Gliptins (Sitagliptin/Januvia) Combination products 22

Metformin Trade names: Glucophage, Glucophage XR, Fortamet, Glumetza, Riomet MOA Inhibits glucose production in liver Reduces glucose absorption slightly in gut Sensitizes insulin receptors in target tissues 23

Metformin May be used as monotherapy or with a sulfonylurea, a glitazone, or exenatide More effective in combination Well suited for patients who skip meals (no hyppoglycemia) Prevention of type 2 diabetes Gestational diabetes PCOS 24

Metformin Side effects Toxicity – lactic acidosis, may be deadly Decreased appetite, nausea, diarrhea Decreases absorption of B12 and folic acid Patients lose average of 7-8 pounds Toxicity – lactic acidosis, may be deadly Alcohol, cimetidine (Tagamet), and iodinated radiocontrast media may intensify acidosis Drug shouldn’t be given to those with active, serious liver or kidney disease, alcoholics 25

Sulfonylureas (glyburide is our prototype) First oral hypoglycemic agents Promote insulin release Major side effect is hypoglycemia First-generation controversy Cardiovascular toxicity Second-generation agents Much more potent than first-generation drugs Significant drug-drug interactions less common 26

Sulfonylureas Drug interactions Alcohol- disulfuram-type reaction and hypoglycemia NSAIDs-hypoglycemia Sulfonamides-hypoglycemia Cimetidine-hypoglycemia Beta-adrenergic blocking agents-mask signs of hypoglycemia and block glycogen breakdown 27

Meglitinides (Repaglinide is prototype) Mechanism: like sulfonylureas, they increase insulin release Adverse effects: major one is hypoglycemia, like sulfonylureas

Glitazones Rosiglitazone (Avandia) and pioglitazone (Actos) Reduce glucose levels by decreasing insulin resistance Not related chemically or functionally to sulfonylureas, biguanides, or alpha-glucosidase inhibitors 29

Pioglitazone (Actos) Only minor side effects Drug interactions Renal retention of fluid In general avoid glitazones in patients with heart failure because of fluid retention/pulmonary edema risk Raises levels of plasma lipids Drug interactions Insulin also promotes fluid retention, hence the combination poses increased risk for heart failure Gemfibrozil (Lopid) can raise plasma levels of rosiglitazone 30

Sitagliptin (Januvia) Enhances the actions of incretin hormones Stimulates glucose dependent release of insulin Suppresses postprandial release of glucagon Monotherapy or combination Generally well tolerated URI, headache, inflammation throat/nasal 31

New Injectable Drugs for Diabetes Exenatide (Byetta)- analog of incretin Adjunctive therapy to improve glycemic control in patients with type 2 diabetes Adverse effects Hypoglycemia Gastrointestinal effects 32

Colesevelam (Welchol) Bile-acid sequestrant – used to lower plasma cholesterol Can also help lower blood glucose FDA-approved for type 2 treatment in 2008 Many diabetic patients have high cholesterol 33

DKA and HHNS Diabetic ketoacidosis (DKA) and hyperglycemic hyperosmotic nonketotic syndrome (HHNS) – both conditions are hyperglycemic crises DKA occurs in type I, HHNS in type II Hyperglycemia is more severe in HHNS No ketoacidosis in HHNS 34

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Diabetic Ketoacidosis (occurs in type I DM) Severe manifestation of insulin deficiency Symptoms evolve quickly – period of hours or days Most common complication in pediatric patients and leading cause of death Characteristics Hyperglycemia (sugars may be in 600-800 range) Ketoacids (in serum and urine) Hemoconcentration (elevated Hct) Acidosis (low pH on arterial blood gas, low serum bicarbonate Coma 36

Diabetic Ketoacidosis Treatment Insulin replacement (IV, not subQ) Bicarbonate for acidosis Water and sodium replacement (will likely need immediate quick replacement with LARGE amounts of normal saline) Potassium replacement (insulin therapy drives potassium into cells) Normalization of glucose levels 37

HHNS Hyperglycemia may be extreme Large amount of glucose excreted in urine Dehydration and loss of blood volume Increases the blood concentrations of electrolytes and nonelectrolytes (particularly glucose Blood “thickens” and becomes sluggish (increased Hct) 38

HHNS Little or no change in ketoacid levels Little or no change in blood pH No sweet or acetone-like smell to urine or breath HHNS occurs most frequently with type 2 DM with acute infection, acute illness, or some other stress 39

HHNS Can evolve slowly Metabolic changes begin a month or two before signs and symptoms become apparent If untreated, HHNS can lead to coma, seizures, and death Management Correct hyperglycemia and dehydration with IV insulin, fluids, and electrolytes 40