Intensifying Insulin Therapy in Type 2 Diabetes: Strategies for Family Medicine Amy Aronovitz, MD Endocrinologist, Northshore University HealthSystem Chicago, IL David Trachtenbarg, MD Medical Director, Diabetes Care Center, Methodist Medical Center Clinical Professor, University of Illinois College of Medicine at Peoria, Peoria, IL

The evidence-based recommendations in this presentation are from the American Diabetes Association. Source: Standards of Medical Care in Diabetes—2010. Diabetes Care 2010;33(Suppl 1):S11-S61. Website: 1/S11.full.pdf+html Strength of Evidence is indicated following each recommendation. For a description of evidence levels, see Evidence-based Recommendations on the resources page. Evidence-based Recommendations

Case 1: Initiating Premeal Insulin Module 1

Beta Cell Function and Insulin Resistance in Type 2 Diabetes Hermans MP. Diabetes Vasc Dis Res 2007;4(suppl 2):S7-S11. Insulin resistance β-cell function Percentage

Normal Insulin Secretion Bergenstal R. Endocr Pract 2000;6:93-7. Time (hours) Dinner Lunch Breakfast Serum insulin (mU/L)

Uses of Insulin Basal –Long-acting insulin –Keeps blood glucose stable when patient doesn’t eat Meal bolus –Rapid-acting insulin –Covers carbohydrates in meals Correction scale –Brings glucose to target if high

Basal Insulin Replacement Profiles Plasma insulin levels (µU/mL) NPH (12–20 hours) Detemir (16–20 hours) Glargine (20–24 hours) Goldstein BJ, et al. Textbook of Type 2 Diabetes. London: Informa; 2003: Plank J, et al. Diabetes Care 2005;28: Time (hours)

Bolus Insulin Replacement Profiles Plasma insulin levels (µU/mL) Regular (6–10 hours) Aspart, lispro, glulisine (4–6 hours) Goldstein BJ, et al. Textbook of Type 2 Diabetes. London: Informa; 2003: Plank J, et al. Diabetes Care 2005;28: Time (hours)

Basal/Bolus Treatment Regimen Leahy J, et al. Insulin Therapy. New York, NY: Marcel Dekker; 2002: Nathan DM. N Engl J Med 2002;347: Breakfast LunchDinner Time (hours) Insulin action

Basal/Bolus Treatment Regimen Leahy J, et al. Insulin Therapy. New York, NY: Marcel Dekker; 2002: Nathan DM. N Engl J Med 2002;347: Breakfast LunchDinner Time (hours) Insulin action Glargine or detemir

Basal/Bolus Treatment Regimen Leahy J, et al. Insulin Therapy. New York, NY: Marcel Dekker; 2002: Nathan DM. N Engl J Med 2002;347: Breakfast LunchDinner Time (hours) Insulin action Glargine or detemir Aspart, lispro, or glulisine

Recommended Blood Glucose Goals * A1C: <7% Preprandial: 70 mg/dL-130 mg/dL 2-hour postprandial: <140 mg/dL-180 mg/dL Bedtime: Individualized to patient American Diabetes Association. Checking your blood glucose. Available at: your-blood-glucose.html. Accessed January 6, *No predisposition for hypoglycemia.

Case 1: Profile 45-year-old woman with 15-year history of T2DM Also has HTN and hyperlipidemia BMI: 39 Current regimen –Metformin: 1,000 mg bid –Repaglinide: 4 mg per meal –Sitagliptin: 100 mg qd –Glargine: 48 U at night Concerned because of high A1C (8.5%) over past 6 months despite compliance with therapy

Polling Question Results (N=100) When starting a basal/bolus insulin regimen, what is the primary concern voiced by patients in your practice? Hassle and intrusiveness of injections36% Hassle, pain and need for frequent glucose monitoring15% Indication disease is worsening15% Weight gain7% Fear of hypoglycemia7%

Polling Question Results (N=100) What clinical scenario do you find most challenging to manage? Managing the patient with labile BG readings29% Explaining carb counting27% Transitioning patient on multiple oral medications and basal insulin to a basal/bolus regimen 25% Making insulin dosing adjustments based on BG readings 6%

Case 1: BG Log FastingAC LunchAC DinnerBedtime Thursday Friday Saturday Sunday AC = before. BS Value (mg/dL)

Initiating Insulin: Rules of Thumb Weight-based calculation: 0.4 U/kg –Titrate slowly; most patients will need 0.7 U/kg-1.0 U/kg Split dose: 50% basal, 50% bolus Bolus dosing options –Dose divided by 3; take meal size into consideration –If patient is resistant to multiple injections, one shot with largest meal may be an option

Case 1: New Regimen New regimen –Continue metformin, 1,000 mg bid –Discontinue sitagliptin and repaglinide –Decrease glargine to 21 U q 24 hours –Add aspart, 7 U before meals Patient to keep blood glucose log, testing before each meal and at bedtime, and return in 2 weeks

Case 1: Follow-up Visits

FastingAC LunchAC DinnerBedtime Monday Tuesday Wednesday Regimen Metformin: 1,000 mg bid Glargine: 21 U q 24 hours Aspart: 7 U AC meals Visit 2: BG Log AC = before.

Change in Regimen New regimen: –Metformin: 1,000 mg bid –Glargine: 21 U q 24 hours –Aspart: 9 U before breakfast 7 U before lunch 7 U before dinner

Visit 3: BG on Bolus/Basal Regimen FastingAC LunchAC DinnerBedtime Thursday (at 4 pm BG 49) 200 Friday Saturday Regimen Metformin: 1,000 mg bid Glargine: 21 U at bedtime Aspart: 9 U AC breakfast, 7 U AC lunch, 7 U AC dinner AC = before.

Change in Regimen Metformin: 1,000 mg bid Glargine: 18 U q 24 hours Aspart: –9 U before breakfast –7 U before lunch –9 U before dinner

Visit 4: BG on Bolus/Basal Regimen FastingAC LunchAC DinnerBedtime Sunday Monday Tuesday Regimen Metformin: 1,000 mg bid Glargine: 18 U at bedtime Aspart: 9 U AC breakfast, 7 U AC lunch, 9 U AC dinner AC = before.

Change in Regimen Metformin: 1,000 mg bid Glargine: 18 U q 24 hours Aspart: –9 U before breakfast –5 U before lunch –9 U before dinner

Module 1: Summary Points Due to progressive decline in beta cell function, most patients with type 2 diabetes will require basal/bolus insulin to maintain optimal glucose control. A blood glucose log is an important tool and can help guide adjustments in treatment. Frequent follow-up is necessary when initiating bolus insulin to fine-tune the regimen.

Self-Monitoring of Blood Glucose (SMBG) Recommendation #1: SMBG should be carried out three or more times daily for patients using multiple insulin injections or insulin pump therapy. (A) To achieve postprandial glucose targets, postprandial SMBG may be appropriate. (E) When prescribing SMBG, ensure that patients receive initial instruction in, and routine follow-up evaluation of, SMBG technique and using data to adjust therapy. (E) Evidence-based Recommendation ADA. Standards of Medical Care in Diabetes—2010. Diabetes Care 2010;33(Suppl 1):S11-S61.

Glycemic Goal Recommendation #2: Lowering A1C to below or around 7% has been shown to reduce microvascular and neuropathic complications of type 1 and type 2 diabetes. Therefore, for microvascular disease prevention, the A1C goal for nonpregnant adults in general is 7%. (A) Less-stringent A1C goals than the general goal of <7% may be appropriate for patients with a history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, and extensive comorbid conditions, and those with longstanding diabetes in whom the general goal is difficult to attain despite diabetes self-management education, appropriate glucose monitoring, and effective doses of multiple glucose-lowering agents, including insulin. (C) Evidence-based Recommendation ADA. Standards of Medical Care in Diabetes—2010. Diabetes Care 2010;33(Suppl 1):S11-S61.

Initiating Premeal Insulin: Video Vignette Module 2

Sample Meal and Correction Scale Blood SugarBreakfastLunchDinner Bedtime or Not Eating LowHighSub-Q Ins Below 70 Eat, check blood glucose every 15 minutes until above 100 mg/dl then give amount on line above

Insulin Pumps OmniPod Paradigm Revel Ping

Module 2: Summary Points It’s essential that patients receive instruction on how to administer mealtime insulin when they start a basal/bolus regimen. Also need to address treatment of hypoglycemia. It’s also a good time to review need for consistency in timing and content of meals, and the importance of SMBG.

Module 2: Summary Points (cont) Education can help address patient concerns and barriers to compliance. Future visits can be geared toward more advanced topics such as carb counting, glycemic index, exercise and insulin pumps.

Diabetes Self-Management Education Recommendation #3: People with diabetes should receive diabetes self- management education according to national standards when their diabetes is diagnosed, and as needed thereafter. (B) Evidence-based Recommendation ADA. Standards of Medical Care in Diabetes—2010. Diabetes Care 2010;33(Suppl 1):S11-S61.

Medical Nutrition Therapy Recommendation #4: Individuals with diabetes should receive individualized medical nutrition therapy (MNT) as needed to achieve treatment goals, preferably provided by a registered dietitian familiar with components of diabetes MNT. (A) Evidence-based Recommendation ADA. Standards of Medical Care in Diabetes—2010. Diabetes Care 2010;33(Suppl 1):S11-S61.

Hypoglycemia Recommendation #5: Glucose (15 g-20 g) is the preferred treatment for the conscious individual with hypoglycemia, although any form of carbohydrate that contains glucose may be used. If, after 15 minutes, SMBG shows continued hypoglycemia, treatment should be repeated. (E) Evidence-based Recommendation ADA. Standards of Medical Care in Diabetes—2010. Diabetes Care 2010;33(Suppl 1):S11-S61.

Troubleshooting Common Challenges With Basal/Bolus Regimens Module 3

Case 2: High A1C on Fixed-Dose Insulin

62-year-old man with 25-year history of T2DM Complicated by nephropathy, neuropathy, HTN and hyperlipidemia On insulin for 10 years: 70/30 55 U in morning and 45 U in evening Previous physician told him this regimen would allow him to avoid insulin injections at work Case 2: Profile

On further questioning, patient reports: –Erratic work schedule; often misses lunch break –Several hypoglycemic episodes in early afternoon, so frequently omits dose with breakfast –Eats dinner at variable times; thought he was supposed to take 70/30 at bedtime, not dinner Last A1C was 9.4% Case 2: Profile (cont)

BID “Split-Mix” Premixed Insulin NPH Breakfast Lunch DinnerBedtime Regular Insulin effect Morning Afternoon Evening Night NPH

Pitfalls of Premixed Insulin Does not mimic normal physiology Risk of inadequate insulin titration Requires consistency in meals and snacks Higher risk of hypoglycemia

Basal/Bolus Prescription Patient receiving total of 100 U 80% of 100 U is 80 U 80 U divided in half is 40 U 40 U divided for three meals, largest dose at dinner: -12 U before breakfast -12 U before lunch -16 U before dinner

Case 3: Use of Correction Scale

68-year-old man with 20-year history of T2DM Complicated by CAD (CABG), HTN and hyperlipidemia Reports starting detemir 6 months ago due to rising A1C –Dose titrated to 30 U qhs Recently started lispro correction scale: –1 U/50 mg/dL above 150 mg/dL at meals and bedtime –Takes no insulin if BG <150 mg/dL BG readings now during the day Case 3: Profile

FastingAC LunchAC DinnerBedtime Thursday Friday Saturday Sunday Case 3: BG Log AC = before.

Review: Uses of Insulin Basal Remains stable if not eating Meal bolus Returns to baseline 4 hours after meal with known carbohydrate Correction scale Returns to target at 4 hours after correction

Approaches to Initiate Correction Scale 1 U-2 U per 50 mg/dL above 150 mg/dL OR “1500 rule” –Correction factor: 1500 / total daily insulin dose –1 U of insulin will lower glucose by correction factor –Similar to “1800 rule” for T1DM

Case 3: Change in Regimen Detemir: 24 U qhs Lispro: 8 U before each meal –Correction scale 1 U/ 30 mg/dL above 140 mg/dL Calculation of Correction Scale Total daily insulin dose = 48 U Correction factor = 1500/48 = Every 1 U of insulin should lower BG by mg/dL

Sample Correction Scale Blood SugarBreakfastLunchDinnerBedtime LowSub-Q Ins 70 to to to to to to to to to to >379 give 16 units and call if does not improve

Case 4: Morning Hyperglycemia

Case 4: Profile 55-year-old man with history of uncontrolled T2DM, obesity, HTN and hypothyroidism Concerned about elevated BG on waking On basal/bolus insulin regimen for past 5 years: –Glargine; 60 U at bedtime –Glulisine; 10 U before meals, plus correction scale 1 U/25 mg/dL above 150 mg/dL

FastingAC LunchAC DinnerBedtime Thursday n/a Friday n/a Saturday n/a Sunday n/a Case 4: BG Log AC = before.

Morning Hyperglycemia: Potential Causes Unsatisfactory glulisine dose with dinner Dawn phenomenon –Diurnal variation in counter-regulatory hormone levels stimulating insulin resistance Somogyi effect –Body’s reaction to overnight hypoglycemia Short term: Glucagon/epinephrine Long term: Cortisol/growth hormone

Investigating Morning Hyperglycemia What can you do to help identify problem? –Check blood sugar at bedtime and between 2-3 a.m. –Continuous glucose monitoring

Interpreting High Morning BG CauseBedtime2-3 a.m.Fasting Insufficient dinner doseHigh Somogyi effectNormalLowHigh Dawn phenomenonNormal High

Initially, the patient reported BG readings in the mid- 300s before bedtime. Once the dose of glulisine with dinner was increased, the morning hyperglycemia resolved. Case 4: Summary

Module 3: Summary Points Fixed-dose regimens require consistent mealtimes and carbohydrate content. Basal/bolus regimens offer patients greater flexibility. Blood glucose patterns are the key to determining the cause of morning hyperglycemia. Preventing high blood glucose is better than treating it once it happens.