1. INCORPORATING NEW DIABETES TREATMENTS Rx for Therapeutic Inertia Part 2 – Using Insulin
Elliot Sternthal, MD, FACP, FACE
Clinical Director of Endocrinology
VA Boston Healthcare System
Assistant Professor of Medicine
Boston University School of Medicine

4. Clinical Inertia: Failure to Advance Therapy When Required
Percentage of subjects advancing when A1C >8%
At insulin initiation, the average patient had:
100
5 years with A1C >8%
10 years with A1C >7% 80
66.6% 60
44.6%
% of Subjects
35.3% 40
18.6% 20
Diet
Sulfonylurea
Metformin
Combination
Brown JB, Nichols GA, Perry A. Diabetes Care. 2004;27:

6. When To Start Insulin in T2DM
When combination oral/injectable agents become inadequate
Unacceptable side effects of oral/injectable agents
Patient wants more flexibility
Special circumstances (i.e. steroid use, infection, pregnancy)
Patients with hepatic or renal disease,
Patients with CAD, TG
CAD=coronary artery disease; T2DM=type 2 diabetes mellitus; TG=triglycerides.
Holman et al. NEJM. 2009; 361: ; Lebovitz HE. Diabetes Rev ;7(3):

7. Profiles: Human Insulin and Analogues
Plasma insulin levels
Hours
NPH
Glargine
Regular
Aspart, Lispro, Glulisine
Detemir 2 4 6 8 10 12 16 18 20 22 24 14

8. Insulin Therapy in Type 2 Diabetes Current Strategies
Basal insulin therapy
Long-acting insulin analog once daily
Intermediate-acting NPH at bedtime
Prandial Human or Analog insulin
Once daily at largest meal
Twice daily (breakfast and dinner)
Three times daily (with each meal)
Intensive insulin therapy
Basal + rapid-acting analog insulin
Twice daily at meals
Premixed Human or Analog insulin
Once or twice daily
Insulin pump therapy .

9. If the Earliest Defect in T2DM is Postprandial Hyperglycemia, Why Start with Basal insulin?
Ease of use
Lower hypoglycemia risk
Basal hyperglycemia (from liver) contributes to postprandial hyperglycemia
Allows beta-cell “rest” between meals and overnight
Correction of “glucotoxicity” improves insulin and incretin hormone action
Allows consideration of several options for prandial control:
Incretin-based therapy (DPP-4 inhibitor, GLP-1 receptor agonist)
Insulin secretagogues (sulfonylurea, meglitinide)
Alpha-glucosidase inhibitors
Prandial insulin (rapid-acting analogs, Regular)
insulin therapy. Please advise
Key message: Data demonstrate that the progressive decline in beta-cell function may
be improved if patients with diabetes are treated early in the disease.
It is important to understand the need to preserve beta-cell function when thinking about
effective early treatment of type 2 diabetes. The use of short course insulin therapy has been
evaluated to “rest” the beta cells, with the thought that overworked beta cells will be able to
improve overall function with short-term relief of high metabolic demand. The effects of a 2-week
course of intensive insulin treatment by continuous subcutaneous insulin infusion (CSII) on
glycemic control and beta-cell function was evaluated in 138 patients with newly diagnosed
diabetes who had severe fasting hyperglycemia (>200 mg/dL; >11.1 mmol/L). After 2 weeks of
CSII, insulin was stopped and patients were maintained on diet and physical activity alone.
The graph on the left shows estimates of beta-cell function measured using the Homeostasis
Model Assessment (HOMA-B) before and after CSII. Note the significant increase in beta-cell
function from 36.1 to (P<.001) after the 2-week beta-cell “rest” period.
The graph on the right shows the percentage of patients in diabetes remission (defined as near
euglycemia on diet alone) at 3, 6, 12, and 24 months after cessation of CSII. Nearly 60% of
patients in remission at 3 months were still in remission at 24 months. These data demonstrate
that decreased beta-cell function may be improved if patients are treated early in the disease.
Reference
Li Y, Xu W, Liao Z, et al. Induction of long-term glycemic control in newly diagnosed type 2
diabetic patients is associated with improvement of beta-cell function. Diabetes Care.
2004;27:
For the intensification choices use the AACE algorithm
For 1-5 attached is possible solution
T2DM= type 2 diabetes; PP = post prandial; GLP-1=glucagon-like peptide-1; DPP-4=dipeptidyl peptidase-4.
Garber AJ, et al. Endocr Pract. 2013;19: ; Holman et al. NEJM. 2009; 361: ; Li Y, et al.Diabetes Care. 2004;27: ; Shepherd J et al. Diabetes Care. 2006;29:

10. Combining Basal Insulin and Oral Medications
Insulin as monotherapy can lead to weight gain with high doses typically needed in type 2 diabetes
Combining oral medications and insulin reduces insulin requirement and weight gain
Basal insulin may decrease glucotoxicity, enhancing efficacy of oral agents (Starling’s curve of the beta cell)
Studies show greater reduction of A1c when adding basal insulin to oral agent vs insulin monotherapy (bid premix)
Transition to insulin may be easier when adding single basal dose to oral medications

11. When is Rapid-acting Insulin Required?
When basal insulin has controlled fasting BG but postprandial BG is still high
If A1c is still above target after starting basal insulin
Adapted from “Insulin Therapy and Your Practice:Strategies for Improving
Patient Outcomes”, Jack L. Leahy, MD. American Diabetes Association, Inc. 2004

12. Stepped Insulin Therapy – Basal Plus Concept
Basal Plus 2 prandial for largest glucose excursions
Basal—Bolus Basal + 3x prandial
Basal Plus 1 prandial for largest glucose excursion
Basal insulin once daily (optimized)
OHA mono- or combination therapy
Diet and exercise
A1C uncontrolled, FBG on target PPBG >160 mg/dL
A1C uncontrolled
Time
Raccah D, et al. Diabet Metab Res Rev. 2007;23:

13. Basal-Bolus Insulin Treatment With Insulin Analogues
Lispro, glulisine, or aspart
U/mL
100 B L D
Glargine 80 60 40
Normal pattern 20
0600
0800
1800
1200
2400
Time of day
B=breakfast; L=lunch; D=dinner

14. Premixed (Biphasic) Human or Analog Insulin
Initiation
Divide basal dose in half and administer before breakfast and supper; subsequent titration may be required
Titrate: Add 1 to 2 units to prebreakfast or presupper dose to reach blood glucose targets, continue to increase daily until targets are met
Premixed insulin may be appropriate
When basal/bolus cannot be used
and
For those with regular lifestyles, who eat similar amounts at similar times each day
Those who wish only 2 injections/day
Garber AJ, et al. Endocr Pract. 2013;19:

15. Conclusions Start with a simple regimen of once-daily Basal Insulin
Continue oral antihyperglycemic and hypoglycemic agents
Give enough insulin to meet individual patient’s needs
Use a treatment algorithm that involves the patient
Up-titrate the dose based on the FBG
Aim for AGGRESSIVE FBG = 90 to 130 mg/dl
If A1C remains high when FBG is in the target range start Prandial Insulin (or other agent)
Start prandial insulin before problematic meals (SMBG)
Adjust for impaired renal function
If feasible, use carbohydrate counting, premeal correction doses and pattern management
Prandial control most important in lowering A1c < 7%
Alternative options are to add a DPP-4 inhibitor or a GLP-1 RA
Premix analog insulin
May be appropriate for stable diet/activity

16. Clinical Cases Insulin Continuum

17. Case 1 59 yo Caucasian woman Type 2 DM x 15 years
Metformin 1000 mg BID + glipizide 10 mg BID + GLP-1 RA
Recent HbA1c = 8.9%
Weight = 85 kg
SMBG: FBG = ; 2 hr PC =
GFR = 40mL/min

18. Case 1-Clinical Issues
FPG > PC BG: increased HGO > reduced peripheral glucose uptake
PC BGs reflect prandial control of SU, metformin and GLP-1 RA
Not candidate for SGLT2 inhibitor b/o reduced GFR
Adding basal insulin will control increased HGO
Initial Dose: 10 units or 0.2 u/kg daily (same for NPH)
Timing: same time every day, dose at bedtime preferable (easier to titrate)
Monitor BG:
Titrate basal insulin based on FPG or 3 AM BGs, not presupper BG which often reflects lack of prandial insulin at lunch. Titration according to presupper BG risks nocturnal hypoglycemia.
How to initiate pharmacotherapy given his medication contraindications due to comorbidities

19. Case 1-Clinical Issues Increase based on FBG
Goal FBG is
Titrate weekly until at goal
Increase Glargine based on average of preceding 2 days FBGs
Increase 2u
Increase 4u
Increase 6u
> 180 Increase 8u
Decrease Glargine by 2 units if
FBG < 80 mg/dL 3 days in a row or > 3x a week OR
Decrease Glargine by 4 units or 10% if
Hypoglycemia or FBG < 70 mg/dl

20. Case 1-Clinical Issues Alternative quick basal titration:
Increase by 2 units every 3 days
Continue until FBG  130 mg/dl

21. Case 2 Same patient 59 yo Caucasian woman
Metformin 1000 mg BID + glipizide 10 mg BID + GLP-1 RA + basal insulin 36 units QHS
Prednisone 20 mg QD started for PMR
Recent HbA1c = 8.3% > 3 months
SMBG: FBG = ; 2 hr PC breakfast = ; 2 hr PC supper =

22. Case 2-Clinical Issues FPG = at target PC supper BG is highest
Candidate for basal plus: HbA1c not at goal after 3 mo. basal therapy → add bolus (prandial) insulin with largest meal
4 units rapid-acting insulin analog QD with largest meal/ meal with greatest glucose excursion
alternatively 0.1unit/kg
stop that meal SU
monitor 2 hour pp BG & titrate bolus dose (2 units every 3 days)
2-hour postprandial goal is mg/dl (<140 AACE)
Follow-up at 3 months
4 units rapid-acting insulin analog QD with largest meal/ monitor 2 hour pp BG & titrate bolus dose (2 units every 3 days)

23. Case 2 –Clinical Issues Alternative Prandial Insulin Titration
Postprandial BG x 3 consecutive days (mg/dl)
Adjust rapid-acting dose (U/injection)
≥180 +3 +2 +1
Maintain dose
80-100 -1
60-80 -2
<60 -4

24. Case 3 76 yo AA man Type 2 DM x 16 years
Regular lifestyle and meal schedule/content-supper largest
Exercises in afternoons after lunch, 5/7 d
Metformin 1000 mg BID + glipizide 10 mg BID + DPP-4 inhib
Recent HbA1c = 8.7%; C-peptide = 0.73; Cr = 1.32
Weight gain x 5yrs since retired; wt = 90 kg
SMBG: FBG = ; 2 hr PC =
Reluctant to do multiple injections

25. Case 3-Clinical issues Β-cell exhaustion
Lifestyle→Candidate for 70/30 BID premix insulin
Initial insulin requirement: 0.4 units/kg = 36 units/d
Because of afternoon exercise and large PM meal→split insulin: AM-40% & PM -60% = 14 units QAM & 22 units QPM
Targets: AC/fasting = ; 2 hr PC =
SMBG: AC = ; 2 hr pc breakfast =
2 hr pc supper = →↑AM dose by 10-20%
D/C BID SU because receiving BID prandial insulin

26. Case 4 Same patient 76 yo AA man
Metformin 1000 mg BID + DPP-4 inhib + BID 70/30 premix = 22 units QAM & 28 units QPM (50 units/d)
SMBG: AC brk = , 2 hr PC supper =
HbA1c = 8.6%

27. Case 4-Clinical Issues
Problem: ↑PM premix to address ↑FBG limited by risk of hypoglycemia after supper
> insulin resistance in liver than muscle→↑nocturnal HGO
Pt wiling to do 3-4 injections /d to improve control
Convert BID premix to basal-bolus program
Converting from NPH component to glargine
determine TDD of NPH in premix
ex: 50 u premix 70/30 QD = NPH 35 units/d
glargine dose = 80% TDD NPH (0.8 x 35)= 28 units QHS
titrate glargine to target FBG < 130 mg/dl

28. Case 4-Clinical Issues
Converting from regular/rapid-acting analog component of premix to rapid-acting analog AC TID
determine TDD of regular/rapid-acting analog content of premix
ex: 50 u premix 70/30 QD = regular/analog 15 units /d
Prandial analog insulin/meal = TDD regular or analog/ 3 = 15 units /3 = 5 units rapid-acting analog AC TID
monitor BG and titrate bolus (prandial) per algorithm

29. TAKE AWAY MESSAGE: AVOID THERAPEUTIC INERTIA THANK YOU FOR PARTICIPATING IN THIS PROGRAM

30. Appendix Slides

31. Concentrated Insulins
Approved
Conc
Volume
Supplied
#units
Admin.
Features
Glargine
U-300
February 2015 3X
1/3
Prefilled Pen
450 QD
More compact sc depot with
smaller surface area;
“Flatter” insulin
Lispro
U-200
May 2015 2X
1/2
600
AC TID
Bioequiv. to Lispro
U-100;
Similar time to max. conc.
Regular
U-500
1952 (Beef)
1997 (Human) 5X
1/5
Vial (20 mL)
10,000
AC BID-TID
Prefilled pen in
develop.

32. Newest insulin in US: Insulin Degludec (Tresiba)
Approved September 2015
Basal insulin-flat activity x 24 hrs; duration = 42 hrs
Glutamic acid + C16 fatty acid attached to B29→sc depot
Dosed once daily at any time of day (min. 8 hrs between consecutive injections)
Available as U-100 (300 u) & U-200 (600 u) prefilled pens
Available as 70/30 (Ryzodeg): U-100 degludec (70%) + aspart (30%)

33. Inhaled Human Insulin Approved July 2014
Dry powder, human regular insulin
Adsorbed onto technosphere microparticles
Dissolves immediately when inhaled
Ultra-rapid acting: peak concentration at minutes, back to baseline at 180 minutes
Bioavailability: 21-30% of subcut. dose
Mealtime glycemic control
Need to use with basal insulin in type 1 DM

34. Inhaled Human Insulin Supplied: 4 or 8 unit cartridges
Dosing: Insulin naïve: 4 units AC
Using sc prandial insulin: Conversion
subcut (units) inhaled (units)

35. Inhaled Human Insulin Adverse Effects/Contraindications
Hypoglycemia: similar or lower than sc insulin
Decreased FEV1: small, occurs w/i first 3 months, potentially reversible with discontinuation
Lung cancer: 2 cases in clinical trials-both heavy smokers
Not recommended in smokers or recent stoppers
Contraindicated in COPD, asthma
REMS: baseline , 6 mo. and annual spirometry
5 year monitoring to assess risk of lung cancer, change in PFTs