Oral Diabetes Medications

1. Oral Diabetes Medications Carol Cordy, MD Swedish Family Practice Residency January 14, 2003

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

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

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

6. Increased Liver Glucose Production = Increase in Fasting Hyperglycemia • b-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 (a-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 a-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 withb-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 • b-Cell Dysfunction = Decrease in Insulin Production

16. Progression of Type 2 Diabetes OGTT Insulin Glu uptake mg/dL uU/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 a-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 b-HCG Neg

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