1. Updates in Diabetes Management Kim Tartaglia, MD August 22, 2007

2. Objectives  Review medications used to achieve glycemic control  Review recent trials regarding diabetic medications  Provide general guidelines for managing diabetes  Review the management of specific patient profiles

3. Glycemic Control  Goal of ADA is HbA1C <7% For each 1% decrease in A1C, 25% reduction of microvascular events For each 1% decrease in A1C, 25% reduction of microvascular events  DCCT/EDIC Trials Decreased micro and macrovascular complications in DM1 w/ intensive therapy Decreased micro and macrovascular complications in DM1 w/ intensive therapy  UKPDS/Kumamoto Trials Decreased microvascular complications in DM2 with intensive therapy Decreased microvascular complications in DM2 with intensive therapy

4. Types of Insulin McEvoy GK, ed. Insulin human and insulin analogue. In: American Hospital Formulary Service. Bethesda, MD: American Society of Health-System Pharmacists; 2005: 2970-2980.

5. Inhaled Insulin  Brand Name: Exubera  Onset of Action: rapid acting  Considerations: contraindicated in smokers as absorption unpredictable  Monitoring: PFTs at outset and every 6 months  Meta-analysis in Annals of Int Med (2006) –Same number of patients reached target A1C –Slightly higher A1Cs –Slight higher patient satisfaction

6. Insulin Pump  Diabetes Care (2001) –Compared continuous insulin infusion (CSII) vs mutiple insulin injections (MDI) –No change in hypoglycemic evens or AIC –This contrasted trial w/ regular insulin that showed CSII had improved control –QOL was the same

7. Insulin Pump  Pump Basics Basal Basal Insulin:Carb ratio Insulin:Carb ratio Correction factor Correction factor

8. A word about DM1  Conventional vs Intensive Insulin therapy Intensive: >3 shots per day or insulin pump Intensive: >3 shots per day or insulin pump Drawback of intensive: Increased hypoglycemia, weight gain, and cost Drawback of intensive: Increased hypoglycemia, weight gain, and cost  Starting doses for new DM1 patients 0.2-0.4unit/kg/day, divided b/w basal and bolus 0.2-0.4unit/kg/day, divided b/w basal and bolus Most patients will require ~0.6unit/kg/day (more during puberty) Most patients will require ~0.6unit/kg/day (more during puberty)

9. Injectable Alternatives - Exenatide  Mechanism of Action –GLP-1 mimetic (synthetic form of extendin-4) –Triggers secretion of insulin, suppresses glucagon secretion, delays gastric emptying, improves satiety  Indication –DM2 who have failed oral therapy –Cannot by used with insulin; contraindicated in DM1  Dose –Starting: 5mcg BID; Target: 10mcg BID

10. Exenatide  Side effects –Nausea (44%), diarrhea/vomiting (13%), h/a  General considerations –Associated with significant weight loss (~5lb) –Less hypoglycemia than Lantus –If using w/ sulfonylurea, decrease dose –Give other meds at least 1hr before b/c of delayed gastric emptying

11. Injectable Alternatives- Pramlintide  Mechanism of Action –Analogue of human amylin (beta cells) –Inhibits release of insulin and delays gastric emptying  Can be used w/ DM1 or DM2  Must be used with insulin  Severe hypoglycemic episodes – 8% –Must decrease mealtime insulin 50% when starting Pramlintide

12. Pramlintide  Dose: Given TID (before major meals) –DM1: Start at 15mcg w/ goal of 60mcg –DM2: Start at 60mcg w/ target of 120mcg  Cannot be mixed w/ insulin (incompatible)  Side effects –nausea, h/a, vomiting  Assoc w/ ~3lb weight loss at highest dose  Safety not determined in kids

13. Oral agents - Secretagogues  Meglitinides – Repaglinide and Nateglinide  Mechanism of Action: Stimulate insulin secretion  Side effects: hypoglycemia, weight gain  General considerations –Nateglinide only decreases A1C 0.5-1%

14. Oral agents - Sulfonylureas  Glipizide, Glyburide, Glimepiride  Mechanism: Stimulates insulin secretion (glucose-dep when used chronically)  Side effects: hypoglycemia, weight gain  General considerations –Glyburide has highest hypoglycemia episodes and concern for ischemic heart dz (UGDP study) –Glipizide is generic; for XL, get full efficacy at 5-10mg daily (no benefit for going higher).

15. Glipizide Table 2. FPG and HbA1c in all patients at randomization and at final visit in the two studies Efficacy, Safety, and Dose-Response Characteristics of Glipizide Gastrointestinal Therapeutic System on Glycemic Control and Insulin Secretion in NIDDM: Results of two multicenter, randomized, placebo-controlled clinical trials. Diabetes Care 1997

16. Oral agents - Metformin  Mech of Action: decreases hepatic glucose production and ↓ insulin resistance  Side effects: abdominal pain, diarrhea, lactic acidosis  General considerations Should quickly titrate up to 1000mg BID Should quickly titrate up to 1000mg BID Decrease dose by half if CrCl=50-70 and do not use if CrCl 1.4) Decrease dose by half if CrCl=50-70 and do not use if CrCl 1.4) No role for extended release No role for extended release

17. Oral agents - TZDs  Rosiglitazone, Pioglitazone  Mech of Action: increased insulin senstivity in adipose, liver, muscle  Side effects: edema, CHF, weight gain  General considerations Contraindicated in CHF (can worsen) Contraindicated in CHF (can worsen) Recent NEJM: ↑ risk of MI and CV mortality in meta-analysis, another trial: ↑ risk of CHF Recent NEJM: ↑ risk of MI and CV mortality in meta-analysis, another trial: ↑ risk of CHF

18. Alpha-glucosidase inhibitors  Acarbose and Miglitol  Mech of Action: impairs enzymes to digest complex carbs, delaying their absorption  Side effects: flatulence, diarrhea  General considerations Most effective at ↓ post-prandial glucose (PPG) Most effective at ↓ post-prandial glucose (PPG) Only decreases A1C 0.5-1% Only decreases A1C 0.5-1%

19. Management of DM2  Physicians start pharmacotherapy late and do not titrate aggressively  Beta cell decline is the natural progression of DM2; therefore, you will have to step- up therapy  Most oral agents decrease A1c 1.5-2%; insulin will decrease A1C by >2%

20. Management of DM2  Rapidity of glycemic effect Insulin is most rapid (starts within minutes) Insulin is most rapid (starts within minutes) Secretagogues work within hours; full effect in 1-2 weeks Secretagogues work within hours; full effect in 1-2 weeks Metformin, AGIs take month for full efficacy (need to titrate weekly to decrease GI effects) Metformin, AGIs take month for full efficacy (need to titrate weekly to decrease GI effects) TZDs do not reach full effect until months after starting TZDs do not reach full effect until months after starting

21. DM2: Specific Considerations  48yo man found to have hyperglycemia on screening; A1C=8.4%. How do you treat? –Lifestyle only? –Monotherapy? With what? If A1C>8, consider SFU as has faster action and less side effects If A1C>8, consider SFU as has faster action and less side effects If A1C=7-8 or obese, consider metformin (no hypoglycemia, no weight gain) If A1C=7-8 or obese, consider metformin (no hypoglycemia, no weight gain) –Starting dose? Glipizide XL 2.5-5mg daily Glipizide XL 2.5-5mg daily Metformin 500mg QD-BID, titrate weekly Metformin 500mg QD-BID, titrate weekly

22. Management of DM2  Same patient, good control x2 years but on most recent check, A1C 7.8 persistently –What happened? –What do you do? Add second agent (metformin or SFU) Add second agent (metformin or SFU) Do not substitute Do not substitute

23. DM2 Management  51yo woman on maximum doses of metformin and glipizide, A1C=8.9% –What’s next? TZDs possibly if A1c<8% but given recent concerns would be hesitant TZDs possibly if A1c<8% but given recent concerns would be hesitant Start insulin: single injection of Lantus (glargine) while continuing oral therapy Start insulin: single injection of Lantus (glargine) while continuing oral therapy Start exenatide at 5mcg BID and titrate Start exenatide at 5mcg BID and titrate

24. DM2 Management  36yo obese woman w/ polyuria, polydipsia BG-338. A1C pending –What do you predict her A1C to be? A1C usually >10% in setting of overt symptoms A1C usually >10% in setting of overt symptoms –What is your first step in management? Insulin. Studies have shown glucose aggravates insulinopenia and insulin insenstivity. Insulin. Studies have shown glucose aggravates insulinopenia and insulin insenstivity. –Is she relegated to a life of insulin? No. Once she has improved control, oral therapy can be started No. Once she has improved control, oral therapy can be started

25. References  Diabetes Control and Complications Trial. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin- dependent diabetes mellitus. NEJM 1993; 329: 977.  Diabetes Control and Complications Trial. Intensive Diabetes Treatment and Cardiovascular disease in patients with type 1 diabetes. NEJM 2005; 353: 2643.  Ceglia L, et al. Meta-analysis: Efficacy and safety of inhaled insulin therapy in adults with diabetes mellitus. Ann Intern Med 2006; 145: 665-675.  Jones MC. Therapies for Diabetes. American Family Physician 2007; 75: 1831.  Mooradian AD, et al. Narrative Review: A Rational Approach to Starting Insulin Therapy. Ann Intern Med 2006; 145: 125-134.  Ohkubo Y, et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin dependent diabetes mellitus: a randomnzed prospective 6-year study. Diabetes Res Clin Pract 1995; 28: 103.  Ryan EA, et al. Diabetes Care 2004; 27: 1028.  Simonson DC, et al. Efficacy, Safety, and Dose-Response Characteristics of Glipizide Gastrointestinal Therapeutic System on Glycemic Control and Insulin Secretion in NIDDM: Results of two multicenter randomized,placebo- controlled clinical trials Diabetes Care 1997; 20: 597.

26. References  Prospective Diabetes Study UK Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes. Lancet 1998; 352: 837.  Prospective Diabetes Study UK Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes. Lancet 1998; 353: 854.  Riddle MC, et al. Glycemic Management of Type 2 Diabetes: An Emerging Stratey with Oral Agents, Insulins, and Combinations. Endocrin Metab Clin 2005; 34: 77.  Tsui E, et al. Intensive insulin therapy with insulin lispro. Diabetes Care 2001; 24: 1722.