1. Drugs for Diabetes Mellitus
Chapter 57
Drugs for Diabetes Mellitus 1

2. 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

3. 3

4. 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

5. 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

6. 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

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

8. 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

9. 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

10. 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

11. 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

12. 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

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

14. 14

15. 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

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

17. 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

18. 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

19. 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

20. 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

21. 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

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

23. 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

24. 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

25. 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

26. 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

27. 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

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

29. 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

30. 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

31. 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

32. 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

33. 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

34. 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

35. 35

36. 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 range)
Ketoacids (in serum and urine)
Hemoconcentration (elevated Hct)
Acidosis (low pH on arterial blood gas, low serum bicarbonate
Coma 36

37. 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

38. 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

39. 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

40. 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