1. Diabetes Crash Course:The Outpatient Setting Dr. Andrew Schmelz, PharmD Post-Doctoral Teaching Fellow Purdue University October 7, 2008 anschmel@purdue.edu

2. Objectives Upon completion of this crash course, clerkship students will be able to: • Differentiate characteristics of Type 1 and Type 2 diabetes mellitus • Describe the literature supporting intensive therapy for treating hyperglycemia • State goals of therapy for patients with DM • Organize antidiabetic agents into groups based on place in DM pharmacotherapy • Recommend an appropriate medication regimen for DM based on patient-specific parameters

3. Major Classifications • Type 1 Diabetes – results from β-cell destruction, usually leading to absolute insulin deficiency • Type 2 Diabetes – results from a progressive insulin secretory defect on the background of insulin resistance • Gestational Diabetes – diagnosed during pregnancy

4. Clinical Trials • DCCT: Type 1 patients • Improved glycemic control reduces the risk and slow the progression of microvascular disease • EDIC: Type 1 patients • Improved glycemic control protects against the occurrence of macrovascular disease • UKPDS: Type 2 patients • Strict glycemic control results in a reduction in risk of microvascular disease

5. Decrease in A1C • Secondary analysis revealed that a 1% decrease in A1C was associated with: • 35% reduction in microvascular endpoints • 18% reduction in MI • 17% reduction in all-cause mortality

6. Glycemic Goals • A1C is primary target for glycemic control • A1C goal for patients in general is 7% • A1C goal for the individual patient is as close to < 6% as possible without significant hypoglycemia

7. Antidiabetic Medications

8. Patient Case

9. Biguanides • Example: Metformin (Glucophage) • 500 mg daily or BID, Max: 2550 mg/day • Lowers A1c 1.5-2%  FIRST LINE AGENT • MOA: Decreases hepatic glucose production, increase response to insulin • Contraindications • SCr > 1.5 (males) or 1.4 (females) • Acute/chronic metabolic acidosis • HF requiring treatment

10. Biguanides (cont) • Adverse Effects • GI: Diarrhea, flatulence, nausea • Metallic taste • Lactic acidosis • Monitoring • Therapeutic: A1c, FPG • AE: SCr (therapy initiation and annually), BMP, intolerance • Bottom Line: Usually first choice for Type II patients unless contraindicated

11. Sulfonylureas • Examples: • Glipizide (Glucotrol) 5 mg daily before breakfast, Clinical max: 20 mg daily • Glyburide (DiaBeta, Micronase) • Glimepiride (Amaryl) • Lower A1c 1.5-2%  FIRST LINE AGENT • MOA: Increase insulin secretion • Contraindications: Hypersensitivity (sulfa)

12. Sulfonylureas (cont) • Adverse Effects • Hypoglycemia • Some weight gain • Allergic skin reactions / photosensitivity • Monitoring • Therapeutic: A1c, FBG • AE: FBG • Bottom Line: Also used near initiation of therapy

13. Thiazolidinediones • Examples: • Pioglitazone (Actos) 15 mg daily, Max 45 mg daily • Rosiglitazone (Avandia) • Lower A1c 1.0%  Alternative agent • MOA: inhibit PPAR-gamma (improves cellular response to insulin) • Contraindications: CHF (also macular edema, risk for MI)

14. TZDs (cont) • Adverse Effects • Hepatotoxicity (troglitazone pulled from market) • Exacerbation of CHF • Macular edema • Monitoring • Therapeutic: A1c, FBG • AEs: LFTs (baseline, periodically, d/c if >3 X ULN), CHF sxs, visual disturbances • Bottom Line: Use only if near A1c goal

15. Alpha-Glucosidase Inhibitors • Examples: • Acarbose (Precose) 25 mg 15-30 mins AC, Max 300 mg daily • Miglitol (Glyset) • Lower A1c < 1.0%  Special niche only • MOA: inhibit intestinal alpha-glucosidase • Contraindications: DKA, IBD, colonic ulceration, intestinal obstruction

16. AGIs (cont) • Adverse effects • GI: flatulence, diarrhea, abdominal pain/cramps • Rash • Increased LFTs • Monitoring • Therapeutic: A1c, FBGs, post-prandial glucose • AE: LFTs, s/sxs rash, intolerance • Bottom Line: Only for lowering PPG

17. Meglitinides • Examples: • Repaglinide (Prandin) 4 mg TID with meals, Max 12 mg TID • Nateglinide (Starlix) • Lower A1c 0.8-1%  Special niche only • MOA: Stimulate insulin secretion • Contraindications: Really, none

18. Meglitinides (cont) • Adverse Effects • Hypoglycemia (less than SUs) • Weight gain • Monitoring • Therapeutic: A1c, FBGs • AE: FBG • Bottom Line: Alternative for pts unable to take sulfonylurea

20. GLP-1 System Drugs • First example: • Exenatide (Byetta) 5 mcg SQ BID, Max 10 mcg BID • Lowers A1c 0.8-1%  Alternative agent • MOA: Synthetic GLP-1 • Contraindications: Really, none

21. GLP-1 System Drugs (cont) • Adverse Effects • Nausea (dose-dependant) • Hypoglycemia • Pancreatitis • Monitoring • Therapeutic: A1c, FBGs • AEs: FBGs • Bottom Line: New drug, place in therapy TBD

22. GLP-1 System Drugs (cont) • Second example: • Sitagliptin (Januvia) 100 mg daily (lower doses per renal function) • Lowers A1c 0.7-0.8  Alternative agent • MOA: inhibits DDP-IV • Contraindications: Really, none

23. GLP-1 System Drugs (cont) • Adverse Effects • Very little HA • Monitoring • Therapeutic: A1c, FBGs • Bottom Line: New drug, place in therapy TBD

24. Amylin Analogs • Example: • Pramlintide (Symlin) 60 mcg before meals, Max 120 mcg • Lowers A1c 0.5-0.6  Not very good, used in combination with insulin • MOA: Synthetic analog of amylin • Contraindications: Really, none

25. Amylin Analogs (cont) • Adverse effects • NV, anorexia (decrease over time, delay dose increase until nausea resolves) • Hypoglycemia • Monitoring • Therapeutic: A1c, FBGs • AEs: FBGs, sxs NV • Bottom Line: Utility? Only agent besides insulin for Type 1 patients

26. Comparison

27. Insulins • Rapid-acting Peak ~ 1 hour • Lispro (Humalog), Aspart (Novolog), Apidra (Glulysine) • Fast-acting Peak ~ 3 hours • Regular (Humulin R, Novolin R) • Intermediate-acting Peak ~ 8 hours • NPH (Humulin N, Novolin N) • Long-acting • Glargine (Lantus), Detemir (Levimir)

28. AS Case (cont) Lantus 34 units QHS and Humalog 6 units before meals