Oral Diabetes Medications

Carol Cordy, MD Swedish Family Practice Residency January 14, 2003

Goals
Understand how type 2 diabetes affects many organs and how this changes over the course of the illness Understand how each class of oral diabetes medications works Using the above, be able to pick the best medication or combination of medications for our patients with type 2 diabetes

Progression of Type 2 Diabetes

Normal Glu Intol DM - HI DM - LI
OGTT mg/dL 100 150 250 350 Insulin uU/mL 80 140 100 20 Glu uptake mg/m2xmin 70 30 20 20

Organs Affected in Diabetes

Pancreas and Liver Muscle and Fat

Insulin Resistance
Muscle = Postprandial Hyperglycemia Fat = Increased FFA Concentration and Hepatic VLDL-TG

Increased Liver Glucose Production = Increase in Fasting Hyperglycemia

b-Cell Dysfunction = Decrease in Insulin Production

Insulin Resistance and Type 2 Diabetes

40% of older people are insulin resistant mostly secondary to obesity and inactivity (important in prevention and treatment) 20% of the elderly have type 2 diabetes 8.5% of all adults have type 2 diabetes 90% of diabetics are managed in primary care

Classes of Oral Medications

Drugs that help the body use insulin (sensitizers) Drugs that stimulate the pancreas to release more insulin (secretagogues) Drugs that block the breakdown of starches and sugars (a-glucosidase inhibitors)

UK Study - 1998
Traditional glycemic control (secretagogues) reduced microvascular complications Retinopathy -29% Nephropathy -33% Neuropathy -40% But not macrovascular complications MIs -16% Stroke +11% Deaths -6%

UK Study 1998
Metformin decreased macrovascular complicatons (lower insulin levels) MI -39% Coronary Deaths -50% Diabetes Related Deaths -42% All Cause Mortality -36%

First Line Drug for Type 2 Diabetes

Biguanide Metformin (Glucophage and Glucophage XR) Decreases hepatic glucose output Increases insulin sensitivity Decreases LDL and triglycerides Decreases C-reactive protein Causes weight loss or stabilization No risk of hypoglycemia Causes nausea, cramps and diarrhea Lactic acidosis rare (contraindications CHF, renal impairment, age greater than 80)

Second Line Drugs for 2 Type Diabetes

Thiazolidinediones (Glitazones) Increase muscle uptake of glucose, decrease FFA, increase HDLs, decrease triglycerides, may cause weight gain and edema, may increase LFTs, decrease C-reactive protein Sulfonylureas and Meglitinides Increase pancreatic insulin release, cause weight gain and hypoglycemia a-Glucose Inhibitors Decrease absorbtion of carbohydrates in the small intestine, increase LFTs, cause flatulance

Tripod Study - 2001

Troglitazone prevented the development of diabetes in patients with a history of gestational diabetics (age 35, BMI 30) by 54% Early treatment with b-cell rest may delay onset of diabetes Thiazolidinediones may be more effective than metformin in prevention and treatment of diabetes

Insulin Resistance
Muscle = Postprandial Hyperglycemia Fat = Increased FFA Concentration and Hepatic VLDL-TG

Increased Liver Glucose Production = Increase in Fasting Hyperglycemia

b-Cell Dysfunction = Decrease in Insulin Production

Progression of Type 2 Diabetes

Normal Glu Intol DM - HI DM - LI
OGTT mg/dL 100 150 250 350 Insulin uU/mL 80 140 100 20 Glu uptake mg/m2xmin 70 30 20 20

One Approach to Selecting Medication for Type 2 Diabetics

Check a fasting insulin C-peptide level If high or high-normal use an insulin sensitizer biguanine or glitazone or a combination of the two If low or low-normal use an insulin secretagogue Consider changing patients who were put on insulin before the new oral diabetes medications to insulin sensitizers

Affect on Blood Glucose

Reduce fasting glucose metformin and sulfonylureas Reduce postprandial glucose meglitinides and a-glucosidase inhibitors Reduce fasting and postprandial glucose - glitazones

Goal for Glycemic Control

HbA1C less than 7% (6.5%?) Fasting sugars less than 110 Two-hour postprandial sugars less than 140 Blood pressure less than 130/80 (125/75 if renal impairment)

Case #1
30 y.o. woman with a history of gestational diabetes with her first pregnancy at age 21 presents with frequent urination, thirst, weight loss and a random glucose of 250. She has an IUD in place. Her BMI is 33. BP is 140/80. Is this enough information to diagnose diabetes? What other tests would you order?

Test Results
HbA1C 9.2 Alb/Cr 0.010 Cr 0.6 LFTs WNL CBC WNL TSH 2.3 Fasting Insulin C-peptide 3.5 b-HCG Neg

What will you do now?

Educate your patient about diabetes and set goals together for her care Refer to a nutritionist for diabetic diet counseling and a weight loss program Refer to a diabetes educator for education in use of a glucose meter Refer to PT for an exercise program

Anything else?
Refer to ophthalmologist Do microfilament check for neuropathy See frequently to reinforce diet, exercise, home glucose monitering Start Metformin XL Treat BP with ACEI if remains over 130/80

Eight Months Later

Despite modest weight loss and compliance with her medications your patient still has a HbA1C of 8.0. Her blood pressue is 120/75 and her Alb/Cr is 0.012. LFTs remain normal. What would you do now?

Second Oral Medication

Add a Glitazone or Sulfonylurea

Summary
Type 2 diabetes affects many organs Type 2 diabetes changes over time Diabetes treatment changes over time Medications can now be selected to work where the problem is Combinations of medications, because they work at different sites, in the body usually work better than monotherapy