1. BOOK OF POTIONS UPDATE ON TYPE 2 DIABETES MEDICATIONS CHRISTINE SUCHAN, APRN APRIL 29, 2016

2. DISCLOSURES NONE

3. OBJECTIVES Identify insulin resistance versus insulin deficiency. Identify AACE and ADA guidelines in Diabetes treatment. Identify new classes of diabetes medications and their mechanism of action.

4. TRIUMVIRATE MUSCLE LIVER BETA CELL

5. PRIOR TO 2009 INSULIN RESISTANCE IN THE MUSCLE AND LIVER PLUS BETA CELL FAILURE REPRESENTED THE CORE DEFECTS IN TYPE 2 DIABETES

6. NOW

7. THE OMINOUS OCTECT

9. OMINOUS OCTET MUSCLE LIVER BETA CELL FAT CELL GI TRACT ALPHA CELL KIDNEY BRAIN

10. MUSCLE CELL IMPAIRED GLUCOSE TRANSPORT ON THE SURFACE OF THE MUSCLE CELL RESULT IN DECREASED GLUCOSE UPTAKE

11. LIVER Liver is responsible for 50% of serum glucose in a fasting state (Gluconeogenesis) Liver has inappropriate response Releases glucose inappropriately = increased glucose release in a fasting and fed state.

12. BETA CELL Aware of body’s sensitivity Adjusts it’s insulin secretion to maintain normoglycemia. Failure occurs earlier and more severe than previously thought. First = loss of beta cell mass Second = decrease in cell function

13. BETA CELL At Diagnosis: 80% beta cell loss Cause:1) aging 2) genetic INSULIN RESISTANCE IS THE INVERSE OF INSULIN SENSITVITY

14. FAT CELL Has 3 friends: muscle, liver and beta cell. Dysfunctional fat cell results in: Increased free fatty acid concentration Increased gluconeogenesis Inflammatory response = decrease adiponectin Lipid overflow to muscle, liver and beta cell

15. GI TISSUE Secretes 2 Hormones : GLP-1, GIP GLP-1 Glucose Like Peptide 1 GIP – Gastrin Inhibitory Polypeptide

16. GLP-1 Secreted by the L cells of the distal small intestine. Known to be deficient in Type 2 Diabetes. It is a potent INHIBITOR of glucagon secretion.

17. GIP Secreted by the K cells of the proximal small intestine. Elevated GIP results in decreased insulin levels = beta cell resistance.

18. PANCREATIC ALPHA CELL Responsible for glucagon secretion. Defective in Type 2 diabetes resulting in: increased glucagon concentration results in liver hypersensitivity = fasting hyperglycemia

19. KIDNEY Kidney filters around 162 grams of glucose daily. 90% of glucose is reabsorbed by the SGLT -2 in the proximal tubule and 10% reabsorbed by the SGLT-1 transporter in proximal tubule. RESULT- NO GLUCOSE IN THE URINE. Diabetic kidney is maladaptive so instead of dumping glucose into the urine it reabsorbs more.

20. BRAIN Now believed that insulin resistance in the liver, and muscle also extends to the brain tissue. Insulin is known to be appetite suppressant This dysfunction contributes to increased food uptake and increases obesity. (Leading to increased insulin resistance).

21. IMPLICATIONS FOR TREATMENT ADA GUIDELINES AACE GUIDELINES BOTTOM LINE- MAKE A1C GOAL INDIVIDUALIZED TO PATIENT

25. TREATMENTS FOR HYPERGLYCEMIA Medications that act on Sulfonylurea Receptor Complex Medications that act on Insulin Target Cells Medications that effect Glucose Absorption Medications that act on the Beta Cell Medications that block Glucose Reabsorption Drugs that Replace Insulin

26. MEDICATIONS THAT ACT ON SULFONYLUREA RECEPTOR COMPLEX Sulfonylureas Meglitinide Analogs Phenylalanine Derivatives

27. SULFONYLUREAS Stimulate the Beta Cell to produce more insulin. Metabolized in the liver, excreted by the kidney and in the bile. Contraindicated in liver disease and severe kidney disease. Side Effects: Weight Gain, Hypoglycemia

28. SULFONYLUREAS Glyburide – 1.25, 2.5, 5mg tablets Maximum Dose: 10 mg as single dose Half Life – 1-2 hours but biologic effect up to 24 hours as it enters the beta cell as well as binds to the receptor. Use cautiously in elderly patient because of beta cell binding

29. SULFONYLUREAS Glipizide- 5mg and 10 mg tablets Also available ER. Maintenance Dose: 20-40mg daily Half Life: 1 hour Preferable in elderly because of shorter half life.

30. SULFONYLUREAS Glimepiride – 1, 2 and 4mg scored tablets. Maintenance Dose: 8 mg – can be dosed 4mg twice daily or 8mg daily. Half –Life : 5 hours

31. MEGLITINIDE ANALOGS Binds to the sulfonylurea receptor =beta cell secretes more insulin for short period of time. Metabolized in the liver, excreted in urine. Side effects: Weight gain, hypoglycemia Useful in patients with kidney disease or sulfa allergy.

32. MEGLITINIDE ANALOGS Repaglinide (Prandin) 0.5, 1 and 2mg tablets. Half-Life: 1 hour Administer 15 minutes prior to meal or snack. Maximum Dose: 16 mg day Better to use in patients with kidney impairment because of half-life.

33. MEGLITINIDE ANALOG-PHENYLALANINE DERIVATIVE Nateglinide (Starlix): 60 and 120 mg tablet. Half-Life: 1-1/2 hours. Maximum Dose: 120 mg three times a day Better to use in patients with kidney impairment.

34. MEDICATIONS THAT ACT ON INSULIN TARGET CELLS Biguinides Thalizolidinediones

35. BIGUINIDES Metformin: IR 500, 850, 1000mg tablets; ER 500 and 750 mg tablets Maximum Dose: IR – 2500 mg in divided doses (2000 usually) ER 2000mg once a day. Half-Life: 1.5-3 hours Tip: Give with food to increase absorption and decrease GI SE Side Effects: Anorexia, nausea, flatulence, bloating, diarrhea, LACTIC ACIDOSIS, macrocytic anemia secondary to decreased B12 absorption. Use cautiously in history of CHF, alcohol abuse.

36. THALIZOLIDINEDIONES (TZD) Activates nuclear receptor(PPARy): increases glucose transport into the cell, decreases fatty acid levels, decreases hepatic glucose output decreases resistin release from adipocytes. Metabolized in Liver, excreted in urine and feces. Side Effects: Edema, weight gain (central). Contraindicated in Liver Disease, Class III and IV Heart Failure.

37. TZD Rosiglitazone (Avandia): 4 and 8mg tablets. Half-Life: 3-4 hours. Maximum Dose: 8 mg. Pioglitazone (Actos): 15, 30, 45 mg tablets. Half-Life: 3-7 hours – Metabolite 24 hours Maximum Dose: 45 mg.

38. MEDICATIONS THAT AFFECT GLUCOSE ABSORPTION Inhibits glucose absorption at brush border in the intestine. Metabolized: GI tract. Excreted: Excreted Feces and Urine. SE: Flatulence, diarrhea, abdominal pain, increased LFT’s, ileus Contraindicated: GI disease, Malabsorption Syndromes, Cirrhosis and Creatinine >2.0.

39. ALPHA GLUCOSIDASE INHIBITORS Acarbose (Precose): 50 and 100 mg tablets. Given start of each meal. Maximum Dose: 100 mg three times daily. Miglitol (Glycet): 25, 50, 100 mg tablets. Start 25mg three times daily for 4-8 weeks Maximum Dose: 100 mg three times daily.

40. INCRETINS Increases gut hormone = increases post meal insulin secretion Need a functioning beta cell. Natural occurring GLP-1 half-life is only 1-2 minutes. 2 Classes of medications: GLP-1 Receptor Analogs and DDP4 Inhibitors.

41. DPP-4 INHIBITORS DPP-4 = Dipeptidyl Peptidase IV Inhibits the enzyme which breaks down GLP-1. Increases longer action of natural GLP-1 and GIP. Increases insulin synthesis. Metabolized: Liver, Excreted Urine. Side Effects: Nasopharyngitis, URI, Pancreatitis. Contraindicated: Type 1 Diabetes, DKA, Pancreatitis, or History of Pancreatitis.

42. DPP-4 INHIBITORS Sitagliptin(Januvia): 25, 50, 100mg tablets. Maintenance: 100 mg, decrease to 50 if Cr Cl 30-50; 25 if <30. Half-Life: 12.4 hours Saxagliptin(Onglyza): 2.5, 5 mg tablet. Maintenance: 2.5 or 5mg, decrease to 2.5mg if Cr Cl <50. Half-Life: 2.5 hr, Metabolite 3.1hr.

43. DPP-4 INHIBITORS Linagliptin(Tradjenta): 5mg tablets. Half-Life: 12 hours. Safe for Cr Cl <50. Alogliptin (Nesina): 6.25, 12.5, 25 mg tablets. Half-Life: 21 hours Maintenance: 25 mg daily, 12.5 mg CrCl 30-59; 6.25mg CrCl <30.

44. GLP-1 ANALOGS Injectable only. Increases GLP-1 to super-physiologic levels. Reduces hepatic glucose production. Augment beta cell function. Stimulates brain to reduce appetite.

45. GLP-1 ANALOGS Exenetide (Byetta) 5mg or 10 mg pen, twice daily 60 minutes before the meal. Half-Life: 2.4 hours SE: Nausea, vomiting, diarrhea, headache, nephrotoxicity, pancreatitis, weight loss Contraindicated: GI disease, Gastroparesis, history of pancreatitis, Cr Cl <30, Type 1 Diabetes

46. GLP-1 ANALOGS Exendrin 4 (Bydureon): 2mg Reconsituted Pen. Once weekly – same day Half-Life: ~2 weeks SE:: same as Byetta, also “bumps” at injection site. Takes 6-8 weeks to get to steady state.

47. GLP1 ANALOGS Liraglutide(Victoza): 1.8mg pen Given SQ daily, begin at 0.6mg titrate weekly. Half-Life: 11 hours Excreted in urine. Contraindications: same as GLP-1 class, history of medullary thyroid cancer, family history of medullary thyroid cancer or MEN2

48. GLP-1 ANALOG Abiglutide (Tanzeum): 30mg; 50mg pen – needs reconstitution. Once weekly injection. Half-Life 5 days. Contraindications: Same as Liraglutide.

49. GLP-1 ANALOGS Dulaglutide (Trulicity): 0.75 and 1.5mg pen SQ weekly. Half-Life: 5 days Contraindications: Same as Liraglutide.

50. MEDICATIONS THAT BLOCK GLUCOSE REABSORPTION Inhibits the sodium-glucose cotransporter 2 (SGLT2) = 1) reduction in the amount of glucose reabsorption 2) increases urinary excretion of glucose Canafliflozin(Invokana) ; Dapagliflozin(Farxiga); Empagliflozin (Jardiance)

51. SGLT-2 Canagliflozin (Invokana): 100 and 300mg tablets. Administer before first meal. Half-Life: 10.6-13.1 hours Metabolized in the liver, excreted urine and feces. SE: Hyperkalemia, genital mycotic infections, hypoglycemia, UTI, hypotension, pancreatitis, elevated creatinine, possible DKA. Contraindications: Type 1 Diabetes, Volume Depletion, GFR <45

52. SGLT-2 Dapagliflozin (Farxiga): 5 and 10 mg tablet. Half-Life: 12.9 hours. Do not use if GFR less than 60. Contraindications: Same as Canagliflozin.

53. SGLT-2 Empagliflozin (Jardiance): 10 and 25 mg tablet. Half-Life: 12 hours. Discontinue if GFR <45. Contraindications: Same as Canagliflozin.

54. OTHER MEDICATIONS Pramlintide Bromocriptine Colesevelam Insulin

55. PRAMLINTIDE TRADE NAME: SYMLIN - Type 1 and Type 2 Diabetes An amylin mimetic: 1) suppresses plasma glucagon secretion from the liver, 2) slows gastric emptying 3) promotes satiety (similar to GLP-1) Half-Life: 48 minutes Administer SQ before meals. T1- 60 mg tid, T2 120 mg tid. Contraindications: Gastroparesis, A1c >9.0% hypoglycemia unawareness SE: nausea, headache, anorexia, arthralgias, hypoglycemia, dizziness.

56. BROMOCRIPTINE Trade Name: Cyclocet Mechanism of Action: 1) stimulates Dopamine receptorsin brain 2) inhibits anterior pituitary prolactin, 3) BUT precise mechanism of action in Diabetes is unknown. Supplied: 8 mg tablet given with food within 2 hours of awakening. Max Dose: 4.8 mg daily Half-Life: 4-4.5 hours, Metabolite 15 hours. SE: Hypotension, syncope, hypoglycemia, nausea, rhinitis, dyspepsia, somnolence. Contraindications: Migraines, syncope, breastfeeding, psychosis, renal impairment.

57. COLESVELAM Trade Name: Welchol Mechanism of Action: Binds intestinal bile acids, in DM unknown. Supplied: 625mg tablets, 1875 or 3750 mg powder packets. Administer: 4 hours after all medications, either BID or 3750 QD. No systemic absorption. SE: Rash, oral blisters, intestinal obstruction, fecal impaction, pancreatitis. Contraindications: GI obstruction, GI motility disorders

61. Case Studies Martina is a 38 yo Latino female Diagnosed 2 years ago History of gestational 4 years ago, diet controlled (baby 8# 3oz) Ht: 66 inches, Wt: 179#; BMI 29 kg/m2 PMH: Irritable bowel with diarrhea dominant (no treatment) FMH: DM2 (F, S, S) Non-Smoker Works Full Time as Dentist (50 hrs weekly) Today: A1c is 7.1%. BP: 132/70 ; P76 THOUGHTS FOR TREATMENT

62. CASE STUDY James is a 69 yo AA male Diabetes for 15 years Complications of retinopathy, polyneuropathy History CAD (MI 11 Years ago) Current Meds: Metformin 1000mg twice daily; Pioglitazone 30 mg daily, Glimepiride 4mg Daily A1c today is 7.9%. GFR 63 ml/min; Cr. 1.2 THOUGHTS

63. SOURCES AACE Comprehensive Diabetes Management Algorithm 2015 ADA Standard of Medical Care in Diabetes 2015, Diabetes Care, 2015 Diabetes Best Clinical Practice and Research Compendium, 2006 Elsevier From the Triumvirate to the Ominous Octet; Ralph DeFronzo, Diabetes, April 2009, Vol 54 Greenspan’s Basic & Clinical Endocrinology, 9 th Edition; 9 th Edition, David Gardner, Dolores Shoback