Update on the Pharmacological Treatments for Diabetes Mellitus

1. Update on the Pharmacological Treatments for Diabetes Mellitus Scott K. Stolte, Pharm.D. Chair, Department of Pharmacy Practice Bernard J. Dunn School of Pharmacy Shenandoah University This program has been made possible by an education grant from Pfizer Labs.

2. Objectives • At the completion of this program, the participant will be able to: • Identify the mechanisms of action, pharmacology and the other important information for the medications used to treat both types of diabetes. • Apply information about diabetes that has application in the daily practice of pharmacy. • Enhance the understanding of new treatment approaches for diabetes.

3. Background • About 18.2 million people with DM • Approximately 33% undiagnosed • 6.3% of US adults have DM • Higher prevalence: • Ethnic Groups – AA, NA, Latino • Increased age and weight

4. Background • Incidence • 625,000 cases diagnosed each year • Impact • Leading cause of adult blindness (25x), renal failure (17x), nontraumatic amputation (5x) • 5th leading cause of death due to disease • Direct and indirect medical costs > 50 billion

5. Pharmacotherapy • Oral Hypoglycemics • Sulfonylureas • Meglitinides • Alpha-glucosidase inhibitors • Biguanides • Thiazolidinediones • Insulin

6. Sulfonylureas • Pancreatic Actions • Stimulates insulin release from pancreatic β-cells – Primary acute mechanism • Down-regulation of this affect over time • No stimulation of insulin release in chronic therapy – How do they continue to work? • Explanation not clear • Reduced plasma glucose may allow circulating insulin to have pronounced effects on target tissues • Chronic hyperglycemia impairs insulin secretion

7. Sulfonylureas • Other pancreatic actions: • Reduce hepatic clearance of insulin • Suppress glucagon release slightly • Stimulate somatostatin release

8. Sulfonylureas • Extrapancreatic effects • Responsible for long-term efficacy • Reduce hepatic gluconeogenesis • May increase insulin receptor sensitivity and number • Potentiation of post-receptor insulin effects - Stimulate synthesis of glucose transporters

9. Sulfonylureas • Two categories based on potency, duration of action, and drug interaction/side effect profiles • First Generation • Tolbutamide (ORINASE), Chlorpropamide (DIABINESE) , Tolazamide (TOLINASE) , Acetohexamide (DYMELOR) • Second Generation • Glyburide (DIABETA, GLYNASE), Glipizide (GLUCOTROL), Glimepiride (AMARYL)

10. Sulfonylureas • Characteristics • Administered orally • Few therapeutic differences among agents • Should be administered 30 min. before breakfast for maximal absorption • Dose can be increased every 1-2 weeks • Metabolized in liver, mainly excreted in urine (glyburide – 50% in feces)

11. Sulfonylureas * - Doses above 15 mg/day should be divided and administered twice daily

12. Sulfonylureas • Adverse effects • Hypoglycemia – fairly common • Skin reactions (3%) – rashes, pruritis • GI • Rare hematologic reactions • Drug Interactions • Increase in concentration from liver metabolism inhibition or protein binding displacement – fluconazole, warfarin • Decrease in effect by increasing liver metabolism or inhibiting insulin release - rifampin, beta-blockers

13. Meglitinides • Repaglinide (PRANDIN) • Nonsulfonylurea moiety of glyburide • Nateglinide (STARLIX) • Amino acid derivative • Pharmacologic effect is the same as sulfonylureas • Shorter duration of action

14. Repaglinide • Absorbed rapidly from the GI tract • Peak serum concentrations obtained within 1 hour • Half-life is about 1 hour • Metabolized mainly by the liver – metabolites are inactive • 10% metabolized by the kidney

15. Repaglinide • Starting Dose – 0.5 mg po tid taken immediately before eating each meal • Can increase dose every week • Maximum dose = 4 mg po tid • Main adverse effect is hypoglycemia • Drug Interactions • Metabolized by CYP450 3A4 • May interact with inhibitors or inducers of that enzyme • Erythromycin, Azole antifungals, cimetidine, etc.

16. Nateglinide • Starting and maintenance dose – 120 mg po tid 1-30 minutes before meals • Dose should be skipped if meal is skipped • Highly bound to plasma proteins • Clinical significance unknown • Metabolized in the liver by CYP450 2C9 and 3A4 • Clinically significant interactions unknown

17. Alpha-Glucosidase Inhibitors • Acarbose (PRECOSE) • Miglitol (GLYSET) • Mechanism of Action • Inhibition of membrane bound intestinal brush border alpha glucosidase enzyme • Membrane-bound intestinal alpha-glucosidases hydrolyze oligosaccharides and disaccharides to glucose and other monosaccharides in the brush border of the small intestine • Enzyme inhibition results in delayed glucose absorption and lowering of postprandial hyperglycemia

18. Acarbose • Not absorbed from the GI tract • Will not induce hypoglycemia with monotherapy • Onset – 0.5 hrs. • Half-life – 1 to 2 hrs. • Duration – 4 hrs. • Recommended starting dose – 25 mg/d with first bite of main meal, possibly 25 mg po tid • Max. dose/day – 300 mg

19. Miglitol • Dose-dependent absorption from the GI tract • Absorption not related to therapeutic efficacy • Excreted in urine as unchanged drug (95%) • Initial dose – 25 mg po tid with first bite of each main meal, some may need lower dose to minimize GI adverse events • Max. daily dose – 100 mg po tid

20. Adverse Events • Mainly GI • Abdominal pain – 11% • Diarrhea – 29% • Flatulence – 42% • Abdominal pain and diarrhea diminish with continued treatment • AE’s minimized by starting at low dose and utilizing slow dosage titration • Skin rash – 4.3%

21. Other Considerations • Not recommended for patients with inflammatory bowel disease • May alter liver function at high doses • Diet and activity may have to be altered to limit production of gas • Often used in combination with other antidiabetic agents

22. Biguanides • Metformin (GLUCOPHAGE) • Mechanism of action • Decreases hepatic glucose production – reduces gluconeogenesis • Decreases intestinal absorption of glucose • Improves insulin sensitivity (increases peripheral glucose uptake and utilization) • Does not produce hypoglycemia as monotherapy

23. Metformin • Absolute bioavailability is 50-60% - fasting • Not bound to plasma proteins • Excreted unchanged in the urine • Does not undergo hepatic metabolism • Starting dose – 500 mg bid with morning and evening meals • Can be increased at rate of 1 tab/week • Maximum daily dose – 2550 mg/day

24. Metformin • Adverse reactions • GI • N/V/D, bloating, flatulence, anorexia • Resolve spontaneously with continued treatment • Decreased with gradual dose escalation and administration with food • Asymptomatic subnormal Vit. B12 concentrations-reversed by calcium supp. • Unpleasant metallic taste (3%)

25. Metformin • Drug Interactions • Cationic drugs that are excreted by renal tubular secretion • Compete with metformin for excretion • Could increase metformin concentrations • Cimetidine, amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, and vancomycin • Theoretical except for cimetidine

26. Metformin Precautions • Lactic acidosis • Rare, but very serious (50% mortality) • Occurs due to metformin accumulation • Plasma levels > 5 mcg/mL • 0.03 cases/1000 patient years • Increased risk with significant renal insufficiency, CHF • Hepatic disease increases risk – not often used • Excessive alcohol intake • Metformin should be D/C’d prior to radiocontrast dye and held for 24 hours after administration

27. Metformin Precautions • Renal function • Should be assessed prior to starting metformin and at least yearly thereafter • Not generally used in patients with SrCr above upper limits of normal for age (SrCr > 1.5 for males, 1.4 for females) • Caution with elderly patients • Contraindicated in CHF requiring drug therapy

28. Thiazolidinediones • Pioglitazone (ACTOS) • Rosiglitazone (AVANDIA) • Mechanism of Action • Improve glycemic control by improving insulin sensitivity • Highly selective and potent agonists for the peroxisome proliferator-activated receptor-gamma (PPARg) • P.A. receptors are found in key target tissues for insulin action such as adipose tissue, skeletal muscle, and liver • Activation of PPARg nuclear receptors regulates transcription of insulin responsive genes involved in the control of glucose production, transport, and utilization • PPARg-responsive genes also participate in the regulation of fatty acid metabolism. • Require insulin to be present for action • May also lower liver glucose production

29. Rosiglitazone • Absolute bioavailability – 99% • Half-life – 3 to 4 hours • Peak concentration – 1 hr. • Maximal clinical effect in 6-12 weeks • Highly protein bound, mostly albumin • Extensively metabolized, no unchanged drug excreted (mostly CYP2C8, some 2C9) • Excreted in urine (64%) and feces (23%)

30. Rosiglitazone • Dose • Monotherapy or in combo. with metformin- 4 mg administered qd or divided bid, dose may be increased to 8 mg/day with inadequate response after 12 weeks • Taken without regard to meals • Hepatic Impairment • Therapy not initiated with evidence of active liver disease or increased ALT (>2.5x upper limit of normal) at baseline • No evidence of induced hepatotoxicity

31. Rosiglitazone • Adverse reactions • Edema and anemia – mild to moderate, did not require drug D/C • Drug Interactions – no clinically significant • Precautions • Ovulation - In premenopausal anovulatory patients, treatment may result in resumption of ovulation

32. Pioglitazone • Characteristics very similar to rosiglitazone • Therapy should not be initiated if clinical evidence of active liver disease or ALT exceeds 2.5 times the upper limit of normal • No evidence of drug-induced hepatotoxicity • Metabolized by CYP 2C8 and to some degree by CYP3A4 • Dose – 15 or 30 mg po qd, maximum 45 mg qd • Without regard to meals • Used in combination with sulfonylureas, metformin, insulin

33. Pioglitazine • Drug Interactions • Oral Contraceptives – troglitazine reduced plasma concs. of ethinyl estradiol and norethindrone by 30% • Due to 3A4 metabolism • May lead to loss of contraception • Pioglitazone not investigated • Ketoconazole – inhibits metabolism, monitor closely • Other potential 3A4 interactions – no studies

34. Insulin • Composed of two peptide chains • A chain – 21 AA’s • B chain – 30 AA’s • Molecular Mass – 5734 Daltons

35. Insulin • Actions • Increases glucose uptake by tissues (brain does not require insulin) • Increases liver glycogen production • Decreases glycogen breakdown • Increases fatty acid synthesis • Inhibits breakdown of fatty acids to ketone bodies • Promotes incorporation of AA’s into proteins

36. Insulin • Traditionally categorized by: • Strength • Onset and duration of action (PK) • Species source • Purity • Most important consideration now is PK • Most US patients on U-100 insulin • Most use biosynthetic “human” insulin, may see some porcine or bovine used • All US insulin is purified

37. Onset, Peak and Duration of Human Insulin Preps

38. Insulin Formulations • Insulin lispro and aspart made by altering insulin AA structure • NPH (neutral, protamine, Hagedorn) insulin made by adding protamine and zinc to neutral regular insulin • Lente and ultralente made by adding acetate buffers and zinc • Regular, lispro, aspart, and glargine are clear and colorless in vial • Glargine precipitates at physiologic pH

39. Insulin Considerations • Regardless of type, potency is the same • 1 unit lowers BG by 30-45 mg/dL in normal, healthy subjects • Regular insulin, Velosulin (R insulin with added buffers), Humalog, and probably Novolog can be used in insulin pumps • Insulin suspensions (intermediate and long-acting) must be administered subQ, not IV

40. Type 1 DiabetesInsulin • Exubera - dosing • Do not switch from SQ insulin based on units-to-dose • Based on weight – then titrate • 1 mg capsule = ~ 3 u SQ insulin • 3 mg capsule = ~8 u SQ insulin • 1mg + 1mg + 1mg ≠ 3 mg • Adjusting dose… • Change dose in 1 mg increments

41. Type 1 DiabetesInsulin • Contraindications – Exubera • Smokers or smoked within 6 months • Discontinue immediately if resume smoking • Lung disease – asthma, COPD • FEV1 < 70% predicted • ?? Bronchodilator use – can increase absorption • Monitoring – Exubera • Spirometry – baseline, then at 6 months, then yearly • If  20% decrease in FEV1, repeat; if still  20% decrease in FEV1  discontinue

42. Average Daily Insulin Requirements

43. Terms • Honeymoon Phase • Type 1 DM patients • Occurs soon after initial diagnosis • Insulin requirements low • Patient should still use insulin: • To minimize insulin antibody production • To lessen probability of insulin resistance

44. Terms • Split-Dose Therapy • Single daily injections not routinely used • Doses are divided based on: • Intensiveness of therapy • Type of insulin used for treatment • Regimens try to mimic activity of functioning pancreas

45. Insulin Adverse Events • Hypoglycemia • Weight gain • Insulin Resistance • Injection site effects

46. Exenatide • Incretin mimetic • Byetta – biosynthetic form of an incretin, GLP-1 (GLP = glucagon like peptide) • Mechanism of action • Mimics glucose dependent insulin secretion – first phase response • Enhances glucose dependent insulin secretion by pancreatic beta cells • Suppresses inappropriately elevated glucagon secretion during postprandial period • Slows gastric emptying • Administered via SC injection

47. Pramlintide Acetate • Symlin • Amylin mimetic • Co-located with insulin in secretory granules • Secreted with insulin in response to food intake • Slows gastric emptying • Suppresses inappropriate glucagon secretion • Centrally-mediated appetite modulation • Administered via SC injection

48. Sitagliptin • Januvia • DPP-4 Inhibitor (dipeptidyl peptidase-4) • Block the breakdown of incretin via inhibition of DPP-4 • Thus, produces similar effects to incretin mimetics

49. Questions?