1. Antidiabetic and Antilipid drugs and renal failure DR M.MORTAZAVI NEPHROLOGIST

2. Goal To understand the use and side effects of anti-diabetic medications and be able to educate patients.

3. Guidelines for Glycemic, BP, & Lipid Control American Diabetes Assoc. Goals HbA1C < 7.0% (individualization) Preprandial glucose 70-130 mg/dL (3.9-7.2 mmol/l) Postprandial glucose < 180 mg/dL Blood pressure < 130/80 mmHg Lipids LDL: < 100 mg/dL (2.59 mmol/l) < 70 mg/dL (1.81 mmol/l) (with overt CVD) HDL: > 40 mg/dL (1.04 mmol/l) > 50 mg/dL (1.30 mmol/l) TG: < 150 mg/dL (1.69 mmol/l) ADA. Diabetes Care. 2012;35:S11-63 HDL = high-density lipoprotein; LDL = low-density lipoprotein; PG = plasma glucose; TG = triglycerides.

4. Nine to Know  Brand & Generic Name  Mechanism of action  Therapeutic effect  Relevant pharmacokinetics and pharmacodynamics  Dosing by route  Adverse reactions and contraindications  Monitoring parameters  Drug-drug and drug food interactions  Comparisons between agents w/in the same class of drugs

5. +   peripheral glucose uptake hepatic glucose production pancreatic insulin secretion pancreatic glucagon secretion Main Pathophysiological Defects in T2DM gut carbohydrate delivery & absorption incretin effect HYPERGLYCEMIA ? Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011

6. Type 2 Diabetes High blood glucose 1.Defective beta cell function Diminished phase 1 insulin release Delayed phase 2 insulin release 2. Overproduction of glucagon Impaired GI motility 1.Tissues less sensitive to insulin 2.Liver produces excess glucose Image Obtained From: Diabetes 101: Overview of Drug Therapy by Jennifer Danielson, RPh, CDE Type 2 Video from diabetes.com

7. ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 3. ANTI-HYPERGLYCEMIC THERAPY Therapeutic options: Oral agents & non - insulin injectables - Metformin - Sulfonylureas - Thiazolidinediones - Meglitinides -  - glucosidase inhibitors - Bile acid sequestrants Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

8. Biguanides Metformin Glucophage500, 850, 1000 mgtablets (Glucophage XR)500, 750 mg XRtablets Indication Type II Diabetes Mellitus, Antipsychotic-induced weight gain MOA Decrease hepatic glucose production, decrease intestinal absorption of glucose and increase insulin sensitivity therefore increasing peripheral glucose uptake

9. Biguanides (cont) Patient Info  Upset stomach/dyspepsia – take with food  Metallic taste  Minimal Weight Loss  Alcohol may increase likelihood of lactic acidosis  Does not cause hypoglycemia

10. Biguanides (cont) Special Population Considerations:  Geriatric: limited data suggests starting doses should be 33% lower for geriatric patients than that of an adult dose. Titration should also to a lower limit. Cautions/Severe Adverse Reactions  Black Box Lactic Acidosis: D/C immediately and notify practitioner if: myalgia, malaise, hyperventilation, unusual somnolence.  Alcohol potentiates this reaction

11. Biguanides (cont) CONTRAINDICATIONS  Renal disease or renal dysfunction (Scr > 1.5 mg/dL in males, >1.4 mg/dL in females)  Abnormal Scr from any cause including: shock, acute MI, or septicemia  Metabolic acidosis (including diabetic ketoacidosis (DKA))  Heart failure requiring pharmacologic therapy; active liver failure

13. Sulfonylureas Gliclazid 80 mg Glipizide (Glucotrol, Glucotrol XL) (2.5), 5, 10 mg (XL) tablets Glyburide (DiaBeta)1.25, 2.5, 5 mgtablets Indications Adjuncts to diet and exercise to lower blood glucose in patients w/ type II diabetes mellitus MOA Stimulating insulin release from beta-cells of pancreatic islets

15. Where does it work? Image Obtained From: Diabetes 101: Overview of Drug Therapy by Jennifer Danielson, RPh, CDE

16. Sulfonylureas (cont) Patient Info  Hypoglycemia  GI upset/abdominal pain  Dizziness  Weight gain  Heartburn/epigastric fullness  Onset: glucose lowering effect: 30 minutes with peak at 1.5-3 hours lasting 24 hours

17. Sulfonylureas (cont) Special Population Considerations:  Pediatric: safety and efficacy not established for pts under age 16  Hepatic/Renal Dysfunction: conservative dosing and titration recommended. Caution/Severe Adverse Reactions  Syndrome of Inappropriate Anti-diuretic Hormone (SIADH) CONTRAINDICATIONS  Diabetes complicated by ketoacidosis  Type I DM  Diabetes w/ pregnancy. Pregnancy Cat: C (except glyburide: B)

18. Thiazolidinediones (TZD) Pioglitazone (Actos) 15, 30, 45 mgtablets Rosiglitazone (Avandia) 2, 4, 8 mgtablets Indications As adjunct to diet and exercise for type II diabetes MOA Increase insulin sensitivity by affecting PPAR-γ (peroxisome proliferators-activated receptor) at adipose tissue, skeletal muscle and in the liver.

19. Where does it work? Image Obtained From: Diabetes 101: Overview of Drug Therapy by Jennifer Danielson, RPh, CDE

20. TZD (cont) Patient Info  Weight gain  Edema  Hypoglycemia esp. when used with other antidiabetic medications and insulin (not w/ metformin)  May cause or exacerbate heart failure with risk of fluid retention  Myalgia  Headache

21. TZD (cont) Cautions/Severe Adverse Reactions  Black Box: Heart Failure (for all thiazolidinediones, mainly due to rosiglitazone)  Hepatic failure  Anemia  Bone loss  Ovulation in premenopausal women  Pregancy Cat: C

22. TZD (cont) Special Populations Considerations:  Congestive Heart Failure: should be initiated at lowest approved dose with longer intervals between dose increases for NYHA class II. Use is not recommended in patients with NYHA Class III or IV CHF CONTRAINDICATIONS  NYHA Class III-IV heart failure  Active liver disease (ALT > 2.5 upper limit of normal)

23. Insulin Indications Type I diabetes mellitus, type II diabetes mellitus, hyperkalemia, DKA/diabetic coma MOA Stimulating peripheral glucose uptake and inhibiting hepatic glucose production Patient Info  Hypoglycemia (BG < 70 mg/dL) esp with higher doses  Anxiety, blurred vision, palpitations, shakiness, slurred speech, sweating  Weight gain

24. Indication for insulin therapy:

25. Where does it work? Image Obtained From: Diabetes 101: Overview of Drug Therapy by Jennifer Danielson, RPh, CDE Insulin: the Movie from diabetes.org

26. Insulin (cont) Administration:  Subcutaneous injection  Rotate site  Check blood sugars regularly Storage:  Refrigerate until use  Once vial is punctured, it is good for 28 days and can be left at room temperature (except for glargine which is 90 days)

27. Insulin (cont) Dosing:  Starting daily dose: 0.5-1 unit/kg/day in divided doses  Adjust according to fasting (premeal) blood glucose of 80-130 mg/dL and peak postprandial blood glucose < 180 mg/dL  Provide 50% as long acting insulin and 50% as prandial insulin  1 unit of can account for 30 grams of carbohydrate (14-50)  1 unit can lower 50 mg/dL blood glucose (10-100) Special Population Consderations:  Renal dysfunction  CrCl 10-50 mL/min: 75% of normal dose  CrCl < 10 ml/min: 25-50% of normal dose; monitor closely  Exercise??? ---- Acute Stress???

28. ADA-EASD Position Statement: Management of Hyperglycemia in T2DM Long (Detemir) Rapid (Lispro, Aspart, Glulisine) Hours Long (Glargine) 0 2 4 6 8 10 12 14 16 18 20 22 24 Short (Regular) Hours after injection Insulin level 3. ANTI-HYPERGLYCEMIC THERAPY Therapeutic options: Insulin Intermediate (NPH)

29. Insulin Dosing Normal insulin secretion Long-acting Long-acting & Short-acting 70/30 pre-mixed

30. Insulin Comparison Chart courses.washington.edu/pharm504/Insulin%20Chart.pdf

31. ClassMechanismAdvantagesDisadvantagesCost Biguanides Activates AMP-kinase  Hepatic glucose production Extensive experience No hypoglycemia Weight neutral ?  CVD Gastrointestinal Lactic acidosis B-12 deficiency Contraindications Low SUs / Meglitinides Closes KATP channels  Insulin secretion Extensive experience  Microvasc. risk Hypoglycemia Weight gain Low durability ? Ischemic preconditioning Low TZDs PPAR-  activator  insulin sensitivity No hypoglycemia Durability  TGs,  HDL-C ?  CVD (pio) Weight gain Edema / heart failure Bone fractures ?  MI (rosi) ? Bladder ca (pio) High  -GIs Inhibits  glucosidase Slows carbohydrate absorption No hypoglycemia Nonsystemic  Post-prandial glucose ?  CVD events Gastrointestinal Dosing frequency Modest  A1c Mod. Table 1. Properties of anti-hyperglycemic agents Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

32. ClassMechanismAdvantagesDisadvantagesCost DPP-4 inhibitors Inhibits DPP-4 Increases GLP-1, GIP No hypoglycemia Well tolerated Modest  A1c ? Pancreatitis Urticaria High GLP-1 receptor agonists Activates GLP-1 R  Insulin,  glucagon  gastric emptying  satiety Weight loss No hypoglycemia ? Beta cell mass ? CV protection GI ? Pancreatitis Medullary ca Injectable High Amylin mimetics Activates amylin receptor  glucagon  gastric emptying  satiety Weight loss  PPG GI Modest  A1c Injectable Hypo w/ insulin Dosing frequency High Bile acid sequestrants Bind bile acids  Hepatic glucose production No hypoglycemia Nonsystemic  Post-prandial glucose  CVD events GI Modest  A1c Dosing frequency High Dopamine-2 agonists Activates DA receptor Modulates hypothalamic control of metabolism  insulin sensitivity No hypoglyemia ?  CVD events Modest  A1c Dizziness/syncope Nausea Fatigue High Table 1. Properties of anti-hyperglycemic agents Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

33. ClassMechanismAdvantagesDisadvantagesCost Insulin Activates insulin receptor  peripheral glucose uptake Universally effective Unlimited efficacy  Microvascular risk Hypoglycemia Weight gain ? Mitogenicity Injectable Training requirements “Stigma” Variable Table 1. Properties of anti-hyperglycemic agents Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

34. ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 4. OTHER CONSIDERATIONS Comorbidities -Coronary Disease -Heart Failure -Renal disease -Liver dysfunction -Hypoglycemia  Metformin: CVD benefit (UKPDS)  Avoid hypoglycemia  ? SUs & ischemic preconditioning  ? Pioglitazone &  CVD events Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

35. ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 4. OTHER CONSIDERATIONS Comorbidities -Coronary Disease -Heart Failure -Renal disease -Liver dysfunction -Hypoglycemia  Metformin: May use unless condition is unstable or severe  Avoid TZDs Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

36. ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 4. OTHER CONSIDERATIONS Comorbidities -Coronary Disease -Heart Failure -Renal disease -Liver dysfunction -Hypoglycemia  Increased risk of hypoglycemia  Metformin & lactic acidosis  US: stop @SCr ≥ 1.5 (1.4 women)  UK:  dose @GFR <45 & stop @GFR <30  Caution with SUs (esp. glyburide) Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

37. ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 4. OTHER CONSIDERATIONS Comorbidities -Coronary Disease -Heart Failure -Renal disease -Liver dysfunction -Hypoglycemia  Most drugs not tested in advanced liver disease  Pioglitazone may help steatosis  Insulin best option if disease severe Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

38. ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 4. OTHER CONSIDERATIONS Comorbidities -Coronary Disease -Heart Failure -Renal disease -Liver dysfunction -Hypoglycemia  Emerging concerns regarding association with increased mortality  Proper drug selection in the hypoglycemia prone Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

42. Antilipid Drugs DR.M.MORTAZAVI NEPHROLOGIST

43. Lipoproteins  Low-density lipoproteins (LDL):  Elevation of LDL:  Atherosclerotic plaque formation  Increases the risk for heart disease  High-density lipoproteins (HDL):  Take cholesterol from the peripheral cells and transport it to the liver

44. Cholesterol Levels  HDL cholesterol: Protects against heart diseases  Higher the LDL level: Greater the risk for heart disease  Drugs used to treat hyperlipidemia:  Bile acid sequestrants  HMG-CoA reductase inhibitors  Fibric acid derivatives  Niacin

45. HMG-CoA Reductase Inhibitors: Actions  Statins**  HMG-CoA reductase:  An enzyme that is a catalyst during the manufacture of cholesterol  Inhibits the manufacture of cholesterol or promotes the breakdown of cholesterol  Lowers the blood levels of cholesterol and serum triglycerides  Increases blood levels of HDLs

47. HMG-CoA Reductase Inhibitors: Uses  As adjunct to diet in the treatment of hyperlipidemia  For primary prevention of coronary events  MI  For secondary prevention of cardiovascular events  TIA/stroke

48. HMG-CoA Reductase Inhibitors: Adverse Reactions  Central nervous system reactions:  Headache, blurred vision, dizziness, insomnia  Gastrointestinal reactions:  Flatulence, abdominal pain, cramping, constipation, nausea  Other:  Elevated CPK level, Rhabdomyolysis with possible renal failure  Pharyngitis with use of rosuvastatin/Crestor

49. HMG-CoA Reductase Inhibitors: Contraindications And Precautions  Contraindicated in patients:  With hypersensitivity to the drugs, serious liver disorders  During pregnancy and lactation  Used cautiously in patients with:  History of alcoholism, acute infection, hypotension, trauma, endocrine disorders, visual disturbances, and myopathy

50. Nursing alert  Pts taking cyclosporine, Asians and those with severe renal insufficiency are at risk for myopathy/rhabdomyolysis when taking rosuvastatin/Crestor

51. HMG-CoA Reductase Inhibitors: Interactions Interactant Drug Effect of Interaction Macrolides, erythromycin, clarithromycin Increased risk of severe myopathy or rhabdomyolysis AmiodaroneIncreased risk for myopathy and for severe myopathy or rhabdomyolysis NiacinIncreased risk for severe myopathy or rhabdomyolysis

52. Bile Acid Sequestrants: Actions and Use  Bile: Manufactured, secreted by liver -Stored in the gallbladder, emulsifies fat, lipids  Used to treat: Hyperlipidemia; Pruritus associated with partial biliary obstruction

54. Bile Acid Sequestrants: Adverse Reactions  Constipation  Aggravation of hemorrhoids  Abdominal cramps  Nausea  Increased bleeding tendencies related to vitamin K malabsorption, and vitamin A and D deficiencies

55. Bile Acid Sequestrants: Contraindications And Precautions  Contraindicated in patients :  With known hypersensitivity to the drugs  With complete biliary obstruction  With liver disease  Used cautiously in patients:  With liver disease, kidney disease  During pregnancy and lactation

56. Bile Acid Sequestrants : Interactions Drug Interactant Effect of Interaction AnticoagulantsDecreased effect of the anticoagulant (cholestyramine) Thyroid hormoneLoss of efficacy of thyroid; also hypothyroidism (particularly with cholestyramine) UrsodiolReduced absorption of ursodiol (particularly cholestyramine and colestipol)

57. Fibric Acid Derivatives: Actions  Clofibrate:  Stimulates liver to increase breakdown of very–low-density lipoproteins (VLDLs) to low- density lipoproteins (LDLs); Decreases liver synthesis of VLDLs and inhibites cholesterol formation  Fenofibrate:  Reduces VLDL; Stimulates catabolism of triglyceride-rich lipoproteins; Decreases plasma triglyceride, cholesterol

59. Fibric Acid Derivatives: Actions (cont’d)  Gemfibrozil:  Increases excretion of cholesterol in the feces  Reduces the production of triglycerides by the liver  Lowers serum lipid levels

60. Fibric Acid Derivatives: Uses  Clofibrate and gemfibrozil:  Used to treat individuals with very high serum triglyceride levels who are at risk for abdominal pain, pancreatitis  Fenofibrate:  Used as adjunctive treatment for reducing LDL, total cholesterol, triglycerides in patients with hyperlipidemia

61. Fibric Acid Derivatives  Adverse Reactions:  Nausea, vomiting, GI upset, diarrhea, cholelithiasis or cholecystitis  Contraindicated in patients:  With hypersensitivity to the drugs and those with significant hepatic or renal dysfunction or primary biliary cirrhosis  Used cautiously in patients with:  Peptic ulcer disease, diabetes, during pregnancy and lactation

62. Miscellaneous Antihyperlipidemic Drugs: Niacin  Action: Lowers blood lipid levels  Uses: Adjunctive therapy for lowering very high serum triglyceride levels in patients who are at risk for pancreatitis  Adverse reactions:  Gastrointestinal reactions: Nausea, vomiting, abdominal pain, diarrhea  Other reactions: Severe generalized flushing of the skin, sensation of warmth,

63. Miscellaneous Antihyperlipidemic Drugs: Contraindications And Precautions  Contraindicated in patients:  With known hypersensitivity to niacin, active peptic ulcer, hepatic dysfunction, and arterial bleeding  Used cautiously in patients with:  Renal dysfunction, high alcohol consumption, unstable angina, gout, pregnancy

65. Thank you