1. Getting to Goal: Strategies for Diabetes Management Amy M. Egras, Pharm.D., BCPS JFMA Grand Rounds September 1, 2010

2. Objectives Discuss strategies to get patients with diabetes to their A1c goal. Discuss strategies to get patients with diabetes to their A1c goal. Discuss strategies to get patients with diabetes to their BP goal. Discuss strategies to get patients with diabetes to their BP goal. Discuss strategies to get patients with diabetes to their LDL goal. Discuss strategies to get patients with diabetes to their LDL goal.

3. Diabetes Goals HgA1c < 7% HgA1c < 7% 63% of patients are NOT at goal 63% of patients are NOT at goal BP goal of < 130/80 mmHg BP goal of < 130/80 mmHg 64.2% of patients are NOT at goal 64.2% of patients are NOT at goal LDL goal of < 100 mg/dL LDL goal of < 100 mg/dL 48.2% of patients are NOT at their cholesterol goal of < 200 mg/dL 48.2% of patients are NOT at their cholesterol goal of < 200 mg/dL HMO data: 71.2% of DM patients NOT at LDL goal HMO data: 71.2% of DM patients NOT at LDL goal FHS data: FHS data: 50 yo: 76.9% of patients NOT at LDL goal 50 yo: 76.9% of patients NOT at LDL goal 60 yo: 60% of patients NOT at LDL goal 60 yo: 60% of patients NOT at LDL goal JAMA. 2004;291:335-342. J Manag Care Pharm. 2007;13:652-663. Circulation. 2009;120:212-220.

4. Cardiovascular Risks ↑ 2-3 fold risk for CVD ↑ 2-3 fold risk for CVD Heart disease & stroke rates are 2-4 times higher Heart disease & stroke rates are 2-4 times higher 68% of diabetes-related deaths due to heart disease 68% of diabetes-related deaths due to heart disease 16% of diabetes-related deaths due to stroke 16% of diabetes-related deaths due to stroke Circulation. 2009;120:212-220. www.cdc.gov/diabetes/pubs/estimates07.htm

5. Goals & Prevention of CVD Glycemic control Glycemic control Long term follow-up suggests long-term reduction in macrovascular complications Long term follow-up suggests long-term reduction in macrovascular complications Blood pressure control Blood pressure control Reduces risk of CVD by 33-50% Reduces risk of CVD by 33-50% LDL cholesterol control LDL cholesterol control Reduce CVD complications 20-50% Reduce CVD complications 20-50% Diabetes Care. 2009;32:187-192. www.cdc.gov/diabetes/pubs/estimates07.htm

6. Glycemic Control http://www.freediabetestestsupplies.com/wp-content/uploads/diabetes-treatment-medications.jpg

7. Therapeutic Options Metformin Metformin Sulfonylureas Sulfonylureas TZDs TZDs Insulin Insulin DPP-4 inhibitors Glinides α- glucosidase inhibitors Incretin mimetics

8. Dipeptidyl Peptidase-4 Inhibitors Agents & dosing Agents & dosing Sitagliptin (Januvia ® ) 100 mg po daily Sitagliptin (Januvia ® ) 100 mg po daily Saxagliptin (Onglyza ® ) 2.5 – 5 mg po daily Saxagliptin (Onglyza ® ) 2.5 – 5 mg po daily Place in therapy Place in therapy Add on therapy for type 2 diabetes patients Add on therapy for type 2 diabetes patients ↓ A1C 0.7-1% ↓ A1C 0.7-1% Adverse effects: GI upset, headache, URI, peripheral edema (more common with saxagliptin), hypoglycemia (more common with saxagliptin and insulin secretagogues) Adverse effects: GI upset, headache, URI, peripheral edema (more common with saxagliptin), hypoglycemia (more common with saxagliptin and insulin secretagogues)

9. Glinides: Short-Acting Insulin Secretagogues Agents & dosing Agents & dosing Nateglinide (Starlix ® ) 60-120 mg with each meal Nateglinide (Starlix ® ) 60-120 mg with each meal Repaglinide (Prandin ® ) 0.5-2 mg with each meal Repaglinide (Prandin ® ) 0.5-2 mg with each meal Place in therapy: Place in therapy: Add on therapy for postprandial glucose control Add on therapy for postprandial glucose control ↓ A1C 0.5-1% ↓ A1C 0.5-1%

10. Glinides: Short-Acting Insulin Secretagogues Adverse effects: Hypoglycemia, weight gain Adverse effects: Hypoglycemia, weight gain Comments Comments Can be used in patients with renal insufficiency Can be used in patients with renal insufficiency Rapidly absorbed with a short duration of action Rapidly absorbed with a short duration of action If a meal is skipped, the medication should NOT be taken If a meal is skipped, the medication should NOT be taken Do NOT use in combination with a sulfonylureas Do NOT use in combination with a sulfonylureas

11. Alpha-glucosidase Inhibitors Agents & dosing Agents & dosing Acarbose (Precose ® ) 25-100 mg po TID with first bite of each meal Acarbose (Precose ® ) 25-100 mg po TID with first bite of each meal Miglitol (Glyset ® ) 25-200 mg po TID with first bite of each meal Miglitol (Glyset ® ) 25-200 mg po TID with first bite of each meal Place in therapy: Place in therapy: Add on therapy for postprandial glucose control Add on therapy for postprandial glucose control ↓ A1C 0.5-1% ↓ A1C 0.5-1% Adverse effects: Hypoglycemia, flatulence, abdominal discomfort, bloating, diarrhea, ↑ LFTs (rarely) Adverse effects: Hypoglycemia, flatulence, abdominal discomfort, bloating, diarrhea, ↑ LFTs (rarely)

12. Alpha-glucosidase Inhibitors Contraindicated in: Contraindicated in: Short bowel syndrome Short bowel syndrome Inflammatory bowel disease Inflammatory bowel disease Renal impairment (SCr > 2.0) Renal impairment (SCr > 2.0) Comments Comments Hypoglycemia must be treated with GLUCOSE, not sucrose Hypoglycemia must be treated with GLUCOSE, not sucrose If a meal is skipped, the medication should be skipped as well If a meal is skipped, the medication should be skipped as well

13. Incretin Mimetics Agent & dosing Agent & dosing Exenatide (Byetta ® ) 5-10 mcg SQ BID Exenatide (Byetta ® ) 5-10 mcg SQ BID Liraglutide (Victoza®) 1.2-1.8 mg SQ daily Liraglutide (Victoza®) 1.2-1.8 mg SQ daily Place in therapy Place in therapy Patients who are taking: Patients who are taking: Sulfonylurea Sulfonylurea Metformin Metformin Combination of sulfonylurea & metformin Combination of sulfonylurea & metformin ↓ A1C 0.5-1% ↓ A1C 0.5-1%

14. Incretin Mimetics Adverse effects: Nausea, vomiting, diarrhea, dyspepsia, hypoglycemia, weight loss, acute pancreatitis Adverse effects: Nausea, vomiting, diarrhea, dyspepsia, hypoglycemia, weight loss, acute pancreatitis Precautions Precautions Gastroparesis Gastroparesis ESRD or ClCr < 30 mL/min (exenatide only) ESRD or ClCr < 30 mL/min (exenatide only)

15. Incretin Mimetics Comments Comments Administer within 0-60 minutes before the morning and evening meals (exenatide) Administer within 0-60 minutes before the morning and evening meals (exenatide) Dose may be titrated Dose may be titrated Exenatide: increase to 10 mcg BID after one month of therapy Exenatide: increase to 10 mcg BID after one month of therapy Liraglutide: start with 0.6 mg for 1 week, then increase to 1.2 mg daily; if glycemic response is not optimal, may increase to 1.8 mg daily Liraglutide: start with 0.6 mg for 1 week, then increase to 1.2 mg daily; if glycemic response is not optimal, may increase to 1.8 mg daily May need to decrease dose of insulin secretagogue to reduce the risk of hypoglycemia May need to decrease dose of insulin secretagogue to reduce the risk of hypoglycemia

16. Incretin Mimetics Comments Comments Store in refrigerator Store in refrigerator Available in prefilled syringes Available in prefilled syringes Patient education for pen use and medication administration Patient education for pen use and medication administration Pen needles are NOT included Pen needles are NOT included

17. Achieving BP Goal http://todaysseniorsnetwork.com/Blood%20Pressure%20Measurement.jpg

18. Blood Pressure Goals Most patients will likely need at least 3 medications to get their BP to goal Most patients will likely need at least 3 medications to get their BP to goal 2005-2006 NHANES found 64% of patients with treated HTN achieved their BP goal 2005-2006 NHANES found 64% of patients with treated HTN achieved their BP goal NCHS Data Brief. 2008 Jan;(3):1-8.

19. Pharmacological Treatment Initial therapy should include: Initial therapy should include: ACE-inhibitor, OR ACE-inhibitor, OR ARB ARB If still not at goal, add a thiazide diuretic If still not at goal, add a thiazide diuretic CrCl > 30 mL/min CrCl > 30 mL/min Synergy with ACE-I or ARB Synergy with ACE-I or ARB Monitor: potassium, kidney function Monitor: potassium, kidney function Diabetes Care. 2010;33:Supplement 1.

20. Other Agents ß-blockers ß-blockers Benefit in those with CAD or HF Benefit in those with CAD or HF Monitor heart rate Monitor heart rate Calcium channel blockers Calcium channel blockers Non-dihydropyridines (verapamil, diltiazem) Non-dihydropyridines (verapamil, diltiazem) Kidney protective effects Kidney protective effects Caution: use with ß-blockers, monitor heart rate, constipation Caution: use with ß-blockers, monitor heart rate, constipation Dihydropyridines (amlodipine, nifedipine, felodipine) Dihydropyridines (amlodipine, nifedipine, felodipine) ACCOMPLISH trial showed decrease in CV events ACCOMPLISH trial showed decrease in CV events Caution: peripheral edema Caution: peripheral edema

21. Other Agents Clonidine Clonidine Anticholinergic side effects Anticholinergic side effects Rebound HTN with abrupt withdrawal Rebound HTN with abrupt withdrawal Use extreme caution with ß-blockers!! Use extreme caution with ß-blockers!! Aldosterone antagonists (spironolactone) Aldosterone antagonists (spironolactone) Beware of hyperkalemia especially if used with an ACE-I or ARB Beware of hyperkalemia especially if used with an ACE-I or ARB Gynecomastia; do not use in CrCl 2.5 mg/dL Gynecomastia; do not use in CrCl 2.5 mg/dL

22. Resistant Hypertension Definition: BP remains above goal with the concurrent use of 3 antihypertensive medications of different classes Definition: BP remains above goal with the concurrent use of 3 antihypertensive medications of different classes Medications at optimal doses Medications at optimal doses 1 medication is a diuretic 1 medication is a diuretic Consider an evaluation for secondary hypertension Consider an evaluation for secondary hypertension

23. Remember… Lifestyle modifications Lifestyle modifications Reduce sodium intake Reduce sodium intake Weight loss Weight loss Increase fruits, vegetables, and low-fat dairy Increase fruits, vegetables, and low-fat dairy Avoid excessive alcohol consumption Avoid excessive alcohol consumption Increase physical activity Increase physical activity Smoking cessation Smoking cessation Combination products Combination products

24. Achieving LDL Goal http://www.koupoukis.gr/wp-content/uploads/HLIC/calmainefoods.com//hdl-ldl.jpg

25. Statins Pts with CVD or > 40 yo with CVD risk factors should be started on a statin that lowers LDL 30-40% regardless of baseline LDL Pts with CVD or > 40 yo with CVD risk factors should be started on a statin that lowers LDL 30-40% regardless of baseline LDL StatinDose (mg/day) LDL-C reduction (%) Atorvastatin1039 Fluvastatin8035 Lovastatin4031 Pravastatin4034 Rosuvastatin5-1039-45 Simvastatin20-4035-41 Diabetes Care. 2010;33:Supplement 1.

26. Determine % LDL Reduction % reduction in LDL needed = (Current LDL- LDL goal)X 100 Current LDL Patient needs a 48% decrease in LDL % reduction in LDL needed = (191- 100) X 100 191

27. Potency of Statins Statin Approximate Equivalent Dose Percent Change from Baseline LDL Initial dosing Atorvastatin 10 mg Lovastatin 40 mg Pravastatin 40 mg Simvastatin 20 mg -31 to -38%For a 30-40% reduction in LDL-C Atorvastatin 20 mg Lovastatin 80 mg Rosuvastatin 5 mg Simvastatin 40 mg -45 to -48%For a 45-50% reduction in LDL-C Atorvastatin 40 mg Rosuvastatin 10 mg Simvastatin 80 mg -46 to -48%For a 50% reduction in LDL-C Atorvastatin 80 mg Rosuvastatin 20 mg -51 to -52%For > 50% reduction in LDL-C (but will likely need to add additional therapy) NOTE: Ratio of simvastatin to atorvastatin is 2:1; ratio of atorvastatin to rosuvastatin is 4:1; ratio of simvastatin to rosuvastatin is 8:1 Am J Cardiol. 1998;81(5):582-7. Am J Cardiol. 2003;92(2):152-60.

28. Adjusting Doses Recheck FLP in 6 weeks Recheck FLP in 6 weeks Not at goal? Not at goal? Double the dose: produces an additional 6% ↓ in LDL from baseline or an additional 10 mg/dL LDL drop Double the dose: produces an additional 6% ↓ in LDL from baseline or an additional 10 mg/dL LDL drop Switch to a more potent statin Switch to a more potent statin Add another agent Add another agent

29. Other Agents to Consider Bile acid sequestrants Bile acid sequestrants Ezetimibe Ezetimibe Fibrate Fibrate Niacin Niacin

30. Statin + BAS Products Products Cholestyramine (Questran) Cholestyramine (Questran ® ) Colestipol (Colestid) Colestipol (Colestid ® ) Colesevelam (WelChol) Colesevelam (WelChol ® ) Studies have shown an additional 7-20% reduction in LDL Studies have shown an additional 7-20% reduction in LDL J Fam Pract. 2006;55:70-2.

31. Statin + BAS For BAS: For BAS: Contraindications: GI obstruction, dysphagia, TG > 300 mg/dL Contraindications: GI obstruction, dysphagia, TG > 300 mg/dL SEs: Constipation, GI upset SEs: Constipation, GI upset Drug interactions Drug interactions Can directly bind other drugs and ↓ absorption Can directly bind other drugs and ↓ absorption Should be administered 1 hour before or 4-6 hours after other drugs Should be administered 1 hour before or 4-6 hours after other drugs Start low and go slow! Start low and go slow!

32. Statin + Ezetimibe Zetia Zetia ® Additional 12-21% decrease in LDL Additional 12-21% decrease in LDL Clinical pearls Clinical pearls Very well tolerated Very well tolerated Increase in hepatic transaminases Increase in hepatic transaminases J Fam Pract. 2006;55:70-2.

33. Statin + Fibrate Products Products Gemfibrozil (Lopid) Gemfibrozil (Lopid ® ) Fenofibrate (Tricor, Triglide, Lofibra, Antara) Fenofibrate (Tricor ®, Triglide ®, Lofibra ®, Antara ® ) Results in: Results in: 40% decrease in LDL 40% decrease in LDL > 50% decrease in triglycerides > 50% decrease in triglycerides 20% increase in HDL 20% increase in HDL J Fam Pract. 2006;55:70-2.

34. Statin + Fibrate Increased risk of myopathy in combination (greater with gemfibrozil) Increased risk of myopathy in combination (greater with gemfibrozil) For fibrates: For fibrates: Contraindications: Active liver disease, gallbladder disease, CrCl < 30 mL/min Contraindications: Active liver disease, gallbladder disease, CrCl < 30 mL/min SEs: GI upset, cholelithiasis, hepatotoxicity (rare), ↑ CPK SEs: GI upset, cholelithiasis, hepatotoxicity (rare), ↑ CPK

35. Statin + Niacin Products Products Immediate release (IR) Immediate release (IR) Sustained release (Slo-Niacin, Nicobid) Sustained release (Slo-Niacin ®, Nicobid ® ) Extended release (Niaspan) Extended release (Niaspan ® ) Results in: Results in: > 40% decrease in LDL > 40% decrease in LDL > 40% decrease in triglycerides > 40% decrease in triglycerides > 30% increase in HDL > 30% increase in HDL Clin Cardiol. 2003;26:112-8. Arch Intern Med. 2004;64:1121-7.

36. Statin + Niacin Increased risk of myopathy in combination Increased risk of myopathy in combination For niacin: For niacin: Contraindications: Active liver disease, active peptic ulcer disease, active gout Contraindications: Active liver disease, active peptic ulcer disease, active gout Caution: poorly controlled diabetes Caution: poorly controlled diabetes SEs: GI upset, flushing, itching, hepatotoxicity (highest with sustained release) SEs: GI upset, flushing, itching, hepatotoxicity (highest with sustained release) Dosing considerations Dosing considerations Take aspirin 325 mg before each dose Take aspirin 325 mg before each dose Take with food Take with food Start low and titrate up the dose slowly Start low and titrate up the dose slowly Avoid dosing with warm beverages Avoid dosing with warm beverages

37. Combination Products Ezetimibe with simvastatin (Vytorin ® ) Ezetimibe with simvastatin (Vytorin ® ) Extended-release niacin with simvastatin (Simcor ® ) Extended-release niacin with simvastatin (Simcor ® ) Extended-release niacin with lovastatin (Advicor ® ) Extended-release niacin with lovastatin (Advicor ® ) Atorvastatin with amlodipine (Caduet ® ) Atorvastatin with amlodipine (Caduet ® )

38. Remember… Lifestyle modifications Lifestyle modifications Decrease saturated fat, trans fat, and cholesterol Decrease saturated fat, trans fat, and cholesterol Increase omega-3-fatty acids, viscous fiber, and plant stanols/sterols Increase omega-3-fatty acids, viscous fiber, and plant stanols/sterols Weight loss Weight loss Increase physical activity Increase physical activity Smoking cessation Smoking cessation

39. Back to Basics http://diabetesindia.org/images/know_diabetes_ABC.jpg