1. Oral Diabetes Medications Carol Cordy, MD

2. 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

3. Progression of Type 2 Diabetes OGTTInsulinGlu uptake mg/dLuU/mL mg/m2xmin Normal 100 80 70 Glu Intol 150 140 30 DM - HI 250 100 20 DM - LI 350 20 20

4. Organs Affected in Diabetes Pancreas and Liver Muscle and Fat

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

6. Increased Liver Glucose Production = Increase in Fasting Hyperglycemia  -Cell Dysfunction = Decrease in Insulin Production

7. 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

8. 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 (  -glucosidase inhibitors)

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

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

11. 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)

12. Second Line Drugs for 2 Type Diabetes Thiazolidinediones (Glitazones) Increase muscle uptake of glucose, decrease FFA, increase HDL’s, decrease triglycerides, may cause weight gain and edema, may increase LFT’s, decrease C-reactive protein Sulfonylureas and Meglitinides Increase pancreatic insulin release, cause weight gain and hypoglycemia  -Glucose Inhibitors Decrease absorbtion of carbohydrates in the small intestine, increase LFT’s, cause flatulance

13. 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  -cell rest may delay onset of diabetes Thiazolidinediones may be more effective than metformin in prevention and treatment of diabetes

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

15. Increased Liver Glucose Production = Increase in Fasting Hyperglycemia  -Cell Dysfunction = Decrease in Insulin Production

16. Progression of Type 2 Diabetes OGTTInsulinGlu uptake mg/dLuU/mL mg/m2xmin Normal 100 80 70 Glu Intol 150 140 30 DM - HI 250 100 20 DM - LI 350 20 20

17. 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

18. Affect on Blood Glucose Reduce fasting glucose – metformin and sulfonylureas Reduce postprandial glucose – meglitinides and  glucosidase inhibitors Reduce fasting and postprandial glucose - glitazones

19. 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)

20. 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?

21. Test Results HbA1C 9.2 Alb/Cr 0.010 Cr 0.6 LFT’s WNL CBC WNL TSH 2.3 Fasting Insulin C-peptide 3.5  HCGNeg

22. 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

23. 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

24. 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. LFT’s remain normal. What would you do now?

25. Second Oral Medication Add a Glitazone or Sulfonylurea

26. 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