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 Differentiate characteristics of Type 1 and Type 2 diabetes mellitus Describe the literature supporting intensive therapy for treating hyperglycemia Describe the literature supporting intensive therapy for treating hyperglycemia State goals of therapy for patients with DM State goals of therapy for patients with DM Organize antidiabetic agents into groups based on place in DM pharmacotherapy Organize antidiabetic agents into groups based on place in DM pharmacotherapy Recommend an appropriate medication regimen for DM based on patient-specific parameters 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 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 Type 2 Diabetes – results from a progressive insulin secretory defect on the background of insulin resistance Gestational Diabetes – diagnosed during pregnancy Gestational Diabetes – diagnosed during pregnancy

4. Clinical Trials DCCT: Type 1 patients DCCT: Type 1 patients –Improved glycemic control reduces the risk and slow the progression of microvascular disease EDIC: Type 1 patients EDIC: Type 1 patients –Improved glycemic control protects against the occurrence of macrovascular disease UKPDS: Type 2 patients 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: 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 is primary target for glycemic control A1C goal for patients in general is 7% A1C goal for patients in general is 7% A1C goal for the individual patient is as close to < 6% as possible without significant hypoglycemia 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) Example: Metformin (Glucophage) –500 mg daily or BID, Max: 2550 mg/day Lowers A1c 1.5-2%  FIRST LINE AGENT Lowers A1c 1.5-2%  FIRST LINE AGENT MOA: Decreases hepatic glucose production, increase response to insulin MOA: Decreases hepatic glucose production, increase response to insulin Contraindications Contraindications –SCr > 1.5 (males) or 1.4 (females) –Acute/chronic metabolic acidosis –HF requiring treatment

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

11. Sulfonylureas Examples: 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 Lower A1c 1.5-2%  FIRST LINE AGENT MOA: Increase insulin secretion MOA: Increase insulin secretion Contraindications: Hypersensitivity (sulfa) Contraindications: Hypersensitivity (sulfa)

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

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

14. TZDs (cont) Adverse Effects Adverse Effects –Hepatotoxicity (troglitazone pulled from market) –Exacerbation of CHF –Macular edema Monitoring 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 Bottom Line: Use only if near A1c goal

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

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

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

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

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

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

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

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

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

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

26. Comparison Agent FBG ↓ (mg/dL) A1C ↓ Hypoglycemia Weight Effects Sulfonylureas50-601.5-2YesGain Metformin50-781.5-2No- α-glucosidase inhibitors 10-25<1.0No- Thiazolidinediones45-651.0NoGain Meglitinides30-500.8-1YesGain Exenatide10-250.8-1NoLoss Sitagliptin15-200.7-0.8No- Pramlintide10-200.5-0.6YesLoss Insulin↓↓>2.0YesGain

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

28. AS Case (cont) DateBreakfastLunchDinnerBedtime 2/03197298 2/0470178 2/05220276 2/0667145 2/07260259 2/0858121 2/09234267 2/1072132 Lantus 34 units QHS and Humalog 6 units before meals