Insulin Initiation and Intensification Neil Skolnik, M.D. Associate Director Family Medicine Residency Program Abington Memorial Hospital Professor of Family and Community Medicine Temple University School of Medicine Disclosure Dr. Neil Skolnik has an financial relationship or interest with a commercial entity that may have a direct interest in the subject matter of this session. Dr. Skolnik sits as part of a consultant or advisory board partnership, a Speaker s Bureaus, and receives research grants or supports. Dr. Skolnik has a relationship with AstraZeneca, Sanofi, Lilly, Teva, and Amgen. No conflict of interest exists. Objectives Review the place of Insulin in current guidelines Review initiation of insulin management Describe methods for intensifying insulin management in patients with type 2 diabetes in a clinical setting Describe new alternatives for intensification of therapy for patients who do not reach goal with the use of basal insulin 1
When starting Insulin in patients with Type 2 DM, the recommended way to initiate insulin is: A. Start with long acting insulin at a dose of 0.4 0.5 mg/kg/d, have patient call with blood sugars for dose adjustment B. Start with long acting insulin at a dose of 10 u, if fasting Glu > 130, have patient increase Insulin by 2 u every 3 days. Follow up in office in 2 4 weeks C. Start with long acting insulin at a dose of 0.3 mg/kg/d, along with pre meal short acting insulin Consider stopping titration of basal insulin and adding additional therapy when: A. After 3 6 months of titration, A1c is greater than goal B. Fasting Glucose at target or low, and A1c greater than goal C. Daily insulin dose exceeds 0.5 u/kg/d. D. Numbers 1 and 2 above E. All of the above Case Study Question 55 year old male, weight 255 lbs with Type 2 Diabetes and hypertension is on Metformin 850 mg bid and Insulin Glargine 60 u daily daily. His A1c is 8.2 and his fasting A.M. blood sugars have been ranging from 90 110. 2
Of the following choices, which would be the best recommendation: A. Accept the A1c of 8.2 B. Increase Insulin Glargine slowly over the next month to 70 80 u to try to decrease his A1c C. Add an SGLT 2 inhibitor D. Add a GLP 1 Agonist Case 55 year old male with Type 2 Diabetes and hypertension. Meds: Metformin 850 mg bid; Glipizide 10 mg daily A1c 6.9 Case One year Later 55 y.o. Type 2 Diabetes,hypertension. Gained 10 pounds over the past year Meds: Metformin 850 mg bid; Glipizide 10 mg A1c 8.2 What Next? Lots of choices TZD, DPP4, GLP 1, SGLT2, Insulin Physician chose Sitagliptin 100mg daily 3
Case 6 m later 55 y.o. Type 2 Diabetes,hypertension. Meds: Metformin 850 mg bid; Glipizide 10 mg A1c 8.2; Sitagliptin 100mg A1c 8.0 What next? Why Basal Insulin In Type 2 Diabetes? Role of Basal Insulin in Type 2 Diabetes: Beta-cell function declines as Type 2 diabetes progresses 100 75 Diagnosis Beta-cell decline exceeds 50% by time of diagnosis IGT Beta-cell 50 function (%) Postprandial 25 Hyperglycemia Type 2 Diabetes Insulin initiation 0 12 8 4 0 4 8 12 Years from diagnosis Lebovitz H. Diabetes Rev 1999;7:139-153. 4
Insulin in Type 2 Diabetes Many type 2 patients will require insulin if they live long enough -5 years or more post diagnosis -A1C >8 to 9% -Function of many non-insulin meds based on presence of native insulin production by the pancreas ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 3. ANTI HYPERGLYCEMIC THERAPY Therapeutic options: Insulin Rapid (Lispro, Aspart, Glulisine) Insulin level Short (Regular) Intermediate (NPH) Long (Detemir) Long (Glargine) Hours 0 2 4 6 8 10 12 14 16 18 20 22 24 Hours after injection Basal Insulin in Type 2 Diabetes Glargine (Lantus),Detemir (Levemir), Glargine U-300 (Toujeo), Degludec (approved in Europe, not FDA approved in US) (NPH) Good, potent add-on for improved A1C Second line agent for some patients A1C >8 to 9, diabetes duration longer than 5 years 5
Practical Insulin Management: Starting Insulin Starting Insulin Start long acting insulin Starting Dose: 10 u or 0.1-0.2 u/kg If fasting Glu > 130, increase Insulin by 2 u every 3 days. Can increase insulin by 4 u every 3 days if fasting Glu > 180 If hypoglycemia, or Fasting Glu < 70, decrease insulin by 4 u, or 10% of dose if, whichever is greater A1C < 7, continue regimen A1C 7 Diabetes Care, August 2006;29(8):1963 Diabetes Care, Dec 2008;31:1-11 What to do with Oral Meds when Starting Insulin Metformin may continue metformin less weight gain than with insulin alone SU do not improve A1c or decrease weight gain or hypoglycemia when used with insulin. Usually reasonable to stop, once insulin is started. May continue initially and then stop. TZD reduce dose or stop to avoid edema and weight gain, though may help in using less insulin in some patients. Incretin Mimetics May be helpful with insulin in decreasing weight gain and decreasing insulin dose. Increased cost. 6
When to Look Up After 3 6 months of titration, A1c greater than goal Fasting Glucose at target or low, and A1c greater than goal this is an indication of post prandial glucose excursion Overnight hypoglycemia The need for prandial insulin becomes more likely as the daily insulin dose exceeds 0.5u/kg/d. Moving Toward Multiple Daily Injections (MDI) As type 2 patients take larger doses of basal insulin, temptation is to split basal dose and give BID Alternative next steps : Can do basal + 1 bolus (rapid acting) Can do basal + GLP-1 Adding Bolus Insulin for Meals in Type 2 Diabetes Rapid Acting Insulin Lispro (Humalog) Aspart (Novalog) Glulisine (Apidra) Why might bolus insulin be important in some Type 2 patients? 7
Fasting and Postprandial Glycemic Excursions as a Function of A1C 80 Postprandial hyperglycemia Fasting hyperglycemia Contribution (%) 60 40 20 0 1 (<7.3) Monnier L et al. Diabetes Care. 2003;26:881-885. 2 (7.3 8.4) 3 (8.5 9.2) A1C (%) Quintiles 4 (9.3 10.2) 5 (>10.2) Insulin Post Prandial Blood Sugar vs. Fasting Blood Sugar Basal long acting insulin best addresses fasting blood sugar Bolus rapid acting insulin addresses post prandial blood sugar 3 Ways to Intensify Insulin In Type 2 Diabetes Simple: 90/10: 2 injections 1 basal, 1 bolus (w/biggest meal) Advanced: Non-Carb Counting 1 basal, 3 boluses estimated dosing based on meal size Sophisticated: Carb-counting 1 basal, 3 boluses (+ maybe snack boluses) calculated on carb intake + premeal blood glucose value 8
Initiate of Basal-Bolus Therapy 90/10 rule (90% basal, 10% bolus) for 2 injection regimen (or just start with 4 u bolus) Start with largest meal of the day If A1c <8%, consider decrease basal by same number of units adding to pre-meal insulin Edelman S. Diabetes Care August 2014;37:1 9 Harris SB. Diabetes Care March 2014;37:1 7 Inzucchi S. Diabetes Care 2015;38:140 149 Titrating 90/10 Rule Targeting 2 hour post meal blood glucose (after bolus rapid acting) to <130 consistently Increase by 1 u daily if post-prandial blood glucose is over target AUTONOMY: The First Randomized Trial Comparing Two Patient Driven Approaches to Initiate and Titrate Prandial Insulin Lispro in Type 2 Diabetes Two independent, multinational, parallel, open label studies, identical in design 18 85 years old Type 2 DM (study A: N = 528; study B: N = 578), On basal insulin plus oral antidiabetic drugs for 3 months HbA1c 7.0% to 12.0% Edelman S. Diabetes Care August 2014;37:2132 2140 9
Optimized on insulin glargine, then randomized to one of two self titration algorithm groups adjusting lispro either: every day (Q1D) or every 3 days (Q3D) 24 weeks. Q1D algorithm: self titrated daily based on premeal glucose from the previous day; for example, when adjusting the prebreakfast dose, subjects used their prelunch reading from the day before Premeal target glucose: 85 114 mg/dl. If target not achieved, increase dose 1 unit/day until target is reached. Edelman S. Diabetes Care August 2014;37:2132 2140 If blood glucose 56 84 mg/dl, the dose was decreased by 1 unit, if < 56 mg/dl, the dose was decreased by 2 units. Edelman S. Diabetes Care August 2014;37:2132 2140 10
Q3D algorithm: self titrated every 3 days based on the median blood glucose readings from the 3 days before Used average of pre meal blood glucoses Edelman S. Diabetes Care August 2014;37:2132 2140 Blood Glucose (mg/dl) Adjust Insulin <56 Decrease 4u 56 84 Decrease 2u 85 114 No change 115 144 Increase 2u >145 Increase 4 u Edelman S. Diabetes Care August 2014;37:2132 2140 Results Both algorithms had significant and equivalent reductions in HbA1c from baseline (study A: Q3D 0.96%, Q1D 1.00% ) The incidence and rate of hypoglycemia were similar for Q3D and Q1D in both studies. Edelman S. Diabetes Care August 2014;37:2132 2140 11
Take Home Point Many Methods to Increase to Multi dose Insulin Clinical Inertia in People With Type 2 Diabetes Retrospective cohort study based on 81,573 people with type 2 diabetes in the U.K. Median time from above HbA1c cutoff to intensification of Therapy Diabetes Care 36:3411 3417, 2013 Time to Intensification of Therapy Baseline Regimen A1c>7.0 A1c>7.5 A1c>8.0 One Oral Agent 2.9 years 1.9 years 1.6 years Two Oral Agents 7.2 years 7.2 years 6.9 years Time to Insulin (base one, two or three oral agents) 7.1 years 6.1 years 6.0 years Diabetes Care 36:3411 3417, 2013 12
Take home Point : When to Look Up After 3 6 months of titration, A1c greater than goal Fasting Glucose at target or low, and A1c greater than goal this is an indication of post prandial glucose excursion Overnight hypoglycemia The need for prandial insulin becomes more likely as the daily insulin dose exceeds 0.5u/kg/d. Building On Basal Bolus 2 Dose Daily Regimens Continue to add on smaller doses of bolus rapid acting (i.e., 2 to 5 units) to other meals (+snacks) with similar titration targeting 2 hour post meal blood glucose <180 Appropriate changes in basal long acting insulin dose as measured by FBS Ideally will be working toward 30-50% total daily dose of insulin as bolus rapid acting Summary Insulin Management http://commons.wikimedia.org/wiki/file:galapagos_tortoise_(5213306875).jpg 13
GLP 1 Agonists as add on to Basal Insulin Basal Insulin best addresses fasting blood glucose GLP 1 best addresses post prandial GLP 1 Agonists Generic Name Brand Name Dosing Exenatide Byetta Twice Daily Liraglutide Victoza Daily Exenatide Weekly Bydureon Weekly Albiglutide Tanzeum Weekly Dulaglutide Trulicity Weekly Comparison of Adding Albiglutide Vs. Thrice Daily Prandial Insulin Lispro for Type 2 DM Not Adequately Controlled on Basal Insulin Patients taking basal insulin (with or without oral agents) with HbA1c 7 10.5% (53 91 mmol/mol) entered a glargine standardization period, followed by randomization to albiglutide, 30 mg weekly (n = 282), subsequently uptitrated to 50 mg, if necessary, or thrice daily prandial lispro (n = 281) titrated while continuing metformin and/or pioglitazone. Diabetes Care August 2014 37:2317-2325 14
Results Change over time in mean HbA1c (A), mean FPG (B), and weight (C). Diabetes Care August 2014 37:2317-2325 Diabetes Care August 2014 37:2317-2325 Adverse Events Adverse Event Albiglutide Lispro Severe Hypoglycemia 0 2 Symptomatic Hypoglycemia 16% 30% Nausea 11% 1% Vomiting 7% 1% Injection Site Reactions 10% %5 Diabetes Care August 2014 37:2317-2325 15
Exenatide v Bolus Insulin 30 week randomized trial with 12 weeks prior insulin optimization, 627 patients with insufficient postoptimization glycated hemoglobin A1c (HbA1c) Randomized to exenatide (10 20 mg/day) or thrice daily mealtime lispro titrated both added to insulin glargine (mean 61 units/day at randomization) and metformin (mean 2,000 mg/day). Diabetes Care October 2014 37:10 2763-2773 Results: Change A1c, Fasting Glucose, and Weight Diabetes Care October 2014;37:10 2763-2773 Diabetes Care October 2014;37:10 2763-2773 16
Adverse Events GI AEs nausea, vomiting, diarrhea more common for exenatide 47% vs. Lispo 13% Hypoglycemia was greater with lispro: minor (41% Lispro vs. 30% for exenatide) confirmed nonnocturnal hypoglycemia (34% Lispro vs. 15% for exenatide) Major hypoglycemic episode Two exenatide and seven lispro recipients had at least one major hypo Diabetes Care October 2014;37:10 2763-2773 Hypoglycemia http://care.diabetesjournals.org/content/suppl/2014/07/09/d c14-0876.dc1/dc140876supplementarydata.pdf Diabetes Care October 2014;37:10 2763-2773 GLP 1 Agonists and Basal Insulin GLP 1 agonist and basal insulin combination treatment can enable achievement.robust glycaemic control with no increased hypoglycaemia or weight gain. Glucagon like peptide 1 receptor agonist and basal insulin combination treatment for the management of type 2 diabetes: a systematic review and meta analysis. Lancet Volume 384, No. 9961, p2228 2234, 20 December 2014. 17
Everything You Need to Know In two Slides ADA/EASD Type 2 Medication Algorithm Inzucchi S. Diabetes Care 2015;38:140 149 Inzucchi S. Diabetes Care 2015;38:140 149 18
Insulin Management Inzucchi S. Diabetes Care 2015;38:140 149 Summary Review the place of Insulin in current guidelines Review initiation of insulin management Describe methods for intensifying insulin management in patients with type 2 diabetes in a clinical setting Describe new alternatives for intensification of therapy for patients who do not reach goal with the use of basal insulin 19
When starting Insulin in patients with Type 2 DM, the recommended way to initiate insulin is: A. Start with long acting insulin at a dose of 0.4 0.5 mg/kg/d, have patient call with blood sugars for dose adjustment B. Start with long acting insulin at a dose of 10 u, if fasting Glu > 130, have patient increase Insulin by 2 u every 3 days. Follow up in office in 2 4 weeks C. Start with long acting insulin at a dose of 0.3 mg/kg/d, along with pre meal short acting insulin Consider stopping titration of basal insulin and adding additional therapy when: A. After 3 6 months of titration, A1c is greater than goal B. Fasting Glucose at target or low, and A1c greater than goal C. Daily insulin dose exceeds 0.5 u/kg/d. D. Numbers 1 and 2 above E. All of the above Case Study Question 55 year old male, weight 255 lbs with Type 2 Diabetes and hypertension is on Metformin 850 mg bid and Insulin Glargine 60 u daily daily. His A1c is 8.2 and his fasting A.M. blood sugars have been ranging from 90 110. 20
Of the following choices, which would be the best recommendation: A. Accept the A1c of 8.2 B. Increase Insulin Glargine slowly over the next month to 70 80 u to try to decrease his A1c C. Add an SGLT 2 inhibitor D. Add a GLP 1 Agonist 21