Chapter 57

Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

Chapter 57

Drugs for Diabetes Mellitus

2Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

Diabetes Mellitus: Overview of the Disease and Its Treatment

Diabetes mellitus Greek word for “fountain” Latin word for “honey”

Disorder of carbohydrate metabolism Deficiency of insulin Resistance to action of insulin

Sustained hyperglycemia, polyuria, polydipsia, ketonuria, and weight loss


Types of Diabetes Mellitus Type 1 diabetes

5%–10% of all cases Also called insulin-dependent diabetes mellitus

(IDDM) or juvenile-onset diabetes mellitus Primary defect is destruction of pancreatic beta

cells


Types of Diabetes Mellitus Type 2 diabetes

Most prevalent form of diabetes Approximately 22 million Americans have it Also called non–insulin-dependent diabetes

mellitus (NIDDM) or adult-onset diabetes mellitus Insulin resistance and impaired insulin secretion


Complications of Diabetes Short-term

Hyperglycemia and hypoglycemia Long-term

Macrovascular damage• Heart disease• Hypertension• Stroke• Hyperglycemia• Altered lipid metabolism


Complications of Diabetes Long-term (cont’d)

Microvascular damage• Retinopathy• Nephropathy• Neuropathy• Gastroparesis• Amputation secondary to infection


Diabetes and Pregnancy Before insulin: many babies born to severely

diabetic women died 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)


Diabetes and Pregnancy Proper glucose levels needed in pregnant

patient and in fetus to prevent teratogenic effects

Fetal death frequently occurs near term Earlier delivery is desirable Gestational diabetes


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) Casual plasma glucose Oral glucose tolerance test (OGTT)

Hemoglobin A1c, oral glucose tolerance test


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


Overview of Diabetes Treatment Primary goal is to prevent long-term

complications Tight control of blood glucose level is

important Also important to control blood pressure and

blood lipids


Type 1 Diabetes Requires comprehensive plan Integrated program of diet, self-monitoring of

blood glucose, exercise, and insulin replacement

Dietary measures Total number of carbohydrates, not the type of

carbohydrates, is most important Glycemic index


Type 2 Diabetes Similar to type 1, requires comprehensive

plan Should be screened and treated for:

Hypertension, nephropathy, retinopathy, neuropathy, dyslipidemias

Glycemic control with: Modified diet and exercise Drug therapy


Monitoring Treatment Self-monitoring of blood glucose (SMBG) Hemoglobin A1c


Insulin: Physiology Biosynthesis Secretion Metabolic actions Metabolic consequences of insulin deficiency


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)

Intermediate duration Neutral protamine Hagedorn (NPH) insulin Insulin detemir (Levemir)

Long duration Insulin glargine


Insulin Concentration

100 units/mL (U-100) 500 units/mL (U-500)

Mixing insulins NPH with short-acting insulins Short-acting insulin drawn first


Administration Subcutaneous injection

Syringe and needle Pen injectors Jet injectors

Subcutaneous infusion Portable insulin pumps Implantable insulin pumps (experimental)

Intravenous infusion


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


Storage Mixtures of insulin in vials are stable for 1

month at room temperature and for 3 months under refrigeration

Mixtures in pre-filled syringes should be stored in refrigerator for at least 1 week and should be stored vertically with needle pointing up


Insulin: Therapeutic Use Indications

Principal: diabetes mellitus Required by all type 1 and some type 2 patients IV insulin for DKA Hyperkalemia: can promote uptake of potassium Aids in the diagnosis of GH deficiency


Insulin Therapy of Diabetes Dosage Dosing schedules

Conventional therapy Intensive conventional therapy Continuous subQ infusion

Achieving tight glucose control


Complications of Insulin Treatment Hypoglycemia Lipohypertrophy Allergic reactions Hypokalemia Drug interactions

Hypoglycemic agents Hyperglycemic agents Beta-adrenergic blocking agents


Oral Hypoglycemics Biguanides

Metformin (Glucophage) Sulfonylureas Thiazolidinediones (glitazones)

Rosiglitazone (Avandia) Pioglitazone (Actos)

Meglitinides (Glinides) Repaglinide (Prandin) Nateglinide (Starlix)


Oral Hypoglycemics Alpha-glucosidase inhibitors

Acarbose (Precose) Miglitol (Glyset)

Gliptins Combination products


Combination Products Metformin/Glyburide Metformin/Glipizide Metformin/Saxagliptin Metformin/Pioglitazone Metformin/Repaglinide Metformin/Sitagliptin Pioglitazone/Glimepiride Rosiglitazone/Glimepiride Rosiglitazone/Metformin Sitagliptin/Simvastatin


Injected Drugs (Other than Insulin) Exenatide

Adjunctive therapy to improve glycemic control in patients with type 2 diabetes

Adverse effects• Hypoglycemia• Gastrointestinal effects

Liraglutide Pramlintide


Acute Complications of Poor Glycemic Control

Diabetic ketoacidosis (DKA) and hyperglycemic hyperosmotic nonketotic syndrome (HHNS): Both conditions are hyperglycemic crises

Hyperglycemia is more severe in HHNS No ketoacidosis in HHNS


Diabetic Ketoacidosis Severe manifestation of insulin deficiency Symptoms evolve quickly in a period of hours

or days Most common complication in pediatric

patients and leading cause of death Characteristics

Hyperglycemia Ketoacids Hemoconcentration Acidosis Coma


Diabetic Ketoacidosis Altered glucose metabolism

Hyperglycemia Water loss Hemoconcentration

Altered fat metabolism Production of ketoacids


Diabetic Ketoacidosis Treatment

Insulin replacement Bicarbonate for acidosis Water and sodium replacement Potassium replacement Normalization of glucose levels


HHNS Large amount of glucose excreted in urine Dehydration and loss of blood volume Increases the blood concentrations of

electrolytes and nonelectrolytes (particularly glucose); also increases hematocrit

Blood “thickens” and becomes sluggish


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

diabetes mellitus with acute infection, acute illness, or some other stress


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


Glucagon for Insulin Overdose 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 Will not work in starvation

• Promotes glycogen breakdown and the malnourished have little glycogen left

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