1.5 mg/dL,>1.4 mg/ dL (women), CHF, radiographic contrast studies, seriously ill patients, acidosis2.Glucosidase inhb. (Acarbose, MiglitolQ)|Glucose absorption |lpostprandial digestion and absorp starch&disaccharides)0.Reduce post- prandialGI flatulence, LFTs glycemiaRenal/liver disease3.Dipeptidyl peptidase IV inhibitors (Sitagliptin)Prolong endogenous GLP-1 action Does not cause hypoglycemiaReduce dose with renal disease4. Insulin secretagogues: Sulfonylurea- first generation Chlorpropamide, Tolazamide, Tolbutami second generation Glimepiride, Glipizide Glipizide, Glyburide|Insulin secretion deLower fasting blood glucoseHypoglycemia, weight gainRenal/ liver disease5.Insulin secretagogues Nonsulfonylureas e.g., Repaglinide Nateglinide| Insulin secretionShort onset of action, lowers postprandial glucoseHypoglycemiaRenal/liver disease6. Thiazolidinediones (Rosiglitazone, Pioglitazone). Pioglitazone has PPAR-a as well as PPAR-g activity0| Insulin utilizationLower insulin requirements. Lowers TG levels & causes slight | in HDL & LDLEdema, CHF macular edema; weight gain, fractures, rosiglitazone may | risk of MlCHF, liver diseaseParenteral1. InsulinShort-acting, subcutaneousLispro, AspartGlulisine, RegularLong-acting: NPH,Detemir, Glargine| Glucose utilization and other anabolic actions-Known safetyInjection, profile weight gain, hypoglycemia2. GLP-1 agonist(Exenatide Q)| Insulin, slow gastric emptyingWeight loss nausea,Injection, agents that T risk of hypoglycemia with insulin secretagoguesRenal disease, slow GI motility3. Amylin agonist(Pramlintide )Slow gastric emptying, | GlucagonReduce post- prandial glycemia, weight loss.Injection, nausea, | risk of hypoglycemia with insulin *Approved for use in type 1 DM also.Agents that also slow GI motilitySeveral drug classes (biguanides, thiazolidinediones ) increase insulin sensitivity.THIAZOLIDINEDIONES# MOA- Thiazolidinediones (Tzds) act to | insulin resistance.- Primary action is the regulation of genes involved in glucose and lipid metabolism and adipocyte differentiation (PPAR receptors).- In persons with diabetes, a major site of Tzd action is adipose tissue, where the drug promotes glucose uptake and utilization and modulates synthesis of lipid hormones or cytokines and other proteins involved in energy regulation.- In addition to targeting adipocytes, myocytes, and hepatocytes, Tzds also have significant effects on vascular endothelium, the immune system, the ovaries, and tumor cells. Some of the responses may be independent of the PPAR-g pathway.0- Tzds also regulate adipocyte apoptosis and differentiation.# Currently available:- Pioglitazone and rosiglitazone (Troglitazone withdrawn from the market because of hepatic toxicity).- Pioglitazone (PPAR-a as wel as PPAR-g activity):It is absorbed within 2 hours of ingestion;* Food may delay uptake, but total bioavailability is not affected.* Pioglitazone is metabolized by CYP2C8 and CYP3A4 to active metabolites.* The bioavailability of numerous other drugs also degraded by these enzymes may be affected by pioglitazone therapy, including estrogen-containing OC pills.* Pioglitazone may be taken once daily; the usual starting dose is 15-30 mg.* The triglyceride lowering effect is more significant than that observed with rosiglitazone, presumably because of its PPAR-a binding characteristics.* Pioglitazone therapy reduces mortality and macrovascular events (myocardial infarction and stroke).* Pioglitazone is approved as a monotherapy and in combination with metformin, sulfonylureas, and insulin for the treatment of type 2 diabetes.- Rosiglitazone* Is rapidly absorbed and highly protein-bound.* It is metabolized in the liver to minimally active metabolites, predominantly by CYP2C8 and to a lesser extent by CYP2C9.* It is administered once or twice daily; 4-8 mg is the usual total dose.* Rosiglitazone shares the common Tzd adverse effects but does not seem to have any significant drug interactions.* The drug is approved for use in type 2 diabetes as monotherapy or in combination with a biguanide, sulfonylurea, in combination with a biguanide and sulfonylurea, and insulin.Adverse Effects# Fluid retention, which presents as a mild anemia and peripheral edema.# Some reports have suggested an increased risk of heart failure.# Rarely, macular edema has been reported in association with rosiglitazone treatment.# Should not be used during pregnancy or in the presence of significant liver disease (ALT more than 2.5 upper limit of normal), or if there is a concurrent diagnosis of heart failure.# Anovulatory women may resume ovulation and should be counseled on the increased risk of pregnancy.# Hepatotoxicity has not been associated with rosiglitazone or pioglitazone.# Thiazolidinediones have an emerging benefit in the prevention of type 2 diabetes and gestational diabetes.">