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 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 and hypertension is on 850 mg bid and 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; 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

Diagnosis Beta-cell decline exceeds 50% 75 by time of diagnosis

IGT Insulin Beta-cell 50 initiation function (%) Postprandial 25 Hyperglycemia Type 2 Diabetes

0

12 84 04 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)

Short (Regular) level

Intermediate (NPH) Insulin 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 , or Fasting A1C < 7, Glu < 70, decrease insulin continue by 4 u, or 10% of dose if, whichever is greater 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. • 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

60

40

20 Contribution (%)

0 1 2 3 4 5 (<7.3) (7.3–8.4) (8.5–9.2) (9.3–10.2) (>10.2)

Monnier L et al. Diabetes Care. 2003;26:881-885. A1C (%) Quintiles

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 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 7.1 years 6.1 years 6.0 years three oral agents)

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 Byetta Twice Daily Victoza Daily Exenatide Weekly Bydureon Weekly Tanzeum Weekly 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 .

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 02

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 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‐ , 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 Diabetes Care October c14-0876.DC1/DC140876SupplementaryData.pdf 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.” – ‐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