1. The Optimisation and Intensification of Insulin Therapy in Type 2 Diabetes
Speaker name and affiliation
UKDBT01539 September 2013
Prescribing information is available on the last slide.

2. Intensification of insulin therapy
When current regimen is failing to achieve goals of therapy

3. Agenda and learning points
The reality of intensification
Regimen change – the evidence
Basal plus and basal bolus – the practicalities of adding mealtime insulin
BD mixtures
Next steps

4. What does intensification mean?
Type 2 diabetes is characterised by the progressive loss of beta cell function in addition to certain levels of insulin resistance. Most people with Type 2 diabetes will need larger doses of insulin as compared to those with Type 1 diabetes, so understanding how to optimise the dose and intensify insulin therapy is vital if good glycaemic control is to be achieved.
This is a keypad question slide for delegates to respond to and to stimulate discussion at the start of this session.

5. Intensification with insulin
It becomes necessary when HbA1c goals / targets are not met despite optimum pharmacological interventions and lifestyle measures
When compliance is not an issue.
Note
Managing sub-optimal diabetes control is not all about changing treatment
The most important aspect is identifying the reason for poor control first, assessment should be thorough as:
Changing treatment alone may not improve control

6. The patient’s perspective
Insulin intensification usually means an increase in:
Number of injections
Frequency of blood glucose monitoring
Risk of hypoglycaemia particularly when blood glucose levels are getting closer to normal
Weight, majority of patients gain weight as glycaemic control improves
Pay more attention to meeting dietary and lifestyle requirements

7. Insulin therapy in diabetes
From the patient perspective, key messages are:
Ensure the patient is aware there are many options for insulin intensification
Self blood glucose monitoring is recommended in line with dose titration and ‘hypo’ awareness
Patient must understand dose ‘titration’ – i.e. change in dose to match changes in daily glucose, meals, activity….
Patient needs to understand the practicality of ‘hypos’ – i.e. prevention, recognition and treatment
Weight gain is a potential side effect – but can be managed
Understanding key management e.g sick day care , driving restrictions

8. Typical initial insulin regimens
Intermediate acting insulin often given nocte
Humulin® I (isophane human insulin (prb))
Insulatard® (isophane insulin)
Insuman® Basal (isophane insulin)
Long acting analogue insulin
Lantus® (insulin glargine)
Levemir® (insulin detemir)
Tresiba® (insulin degludec)
BD Mixtures
Analogue :
Humalog™ Mix25™ (25% insulin lispro (rDNA) injection. 75%insulin lispro protamine suspension)
Humalog™ Mix50™ (50% insulin lispro (rDNA) injection. 50%insulin lispro protamine suspension)
NovoMix30® (biphasic insulin aspart)
Human:
Humulin® M3 (human insulin(prb) 30%soluble insulin 70%isophane insulin)
Insuman® Comb 25 (biphasic isophane insulin)
Speaker to acknowledge the first two bullet points show the typical initial insulin regimens BUT worth introducing BD mixtures as discussion to follow.
Insultard®, Levermir® and Tresiba® and NovoMix 30® are registered trademarks of Novo Nordisk Ltd
Insuman® Lantus® and Insuman® Comb 25 are registered trademarks of Sanofi Aventis

9. Intensifying insulin regimens: Options to consider
Quick reference guide to NICE Guidelines:
(CG87: May 2009)
Monitor those using basal insulin regimens (NPH or a long-acting analogue [insulin detemir, insulin glargine]) for need for short-acting insulin before meals or pre-mixed insulin
Monitor those using pre-mixed insulin once or twice daily for need for further injection of short-acting insulin before meals or change to mealtime plus basal regimen
NICE Type 2 diabetes CG87. London: NICE; May 2009; n/a: 1-431

10. Treating-To-Target in Type 2 Diabetes (4-T Study)
Three-year UK/Ireland study in 708 people with type 2 diabetes
First Phase – Year 1
One-year head-to-head comparison of efficacy of three different analogue insulins, when used as add-on therapy with dual oral antidiabetic therapy
Second Phase – Years 2 & 3
Evaluation over 2 more years of the need for more-complex insulin regimens, and the overall efficacy of three different randomized insulin treatment strategies

11. 4-T study: 3 year efficacy of complex insulin regimens in Type 2 diabetes
HbA1c (1year)
% 6.5 or under
Weight gain (kg)
Hypoglycaemia
Biphasic
7.1%
31.9 %
5.7 kg
3.0
Pre-prandial
6.8%
44.8%
6.4 kg
5.7
Basal
6.9%
43.2%
3.6 kg
1.7
*Grade 2 or 3, median rates per patient per year
Holman RR et al N Engl J Med :

12. 4-T study: 3 year efficacy of complex insulin regimens in Type 2 diabetes
Demographics
No difference between 3 groups
Age , Duration of diabetes, BMI,
HbA1c, Concomitant OHA’s
Results
No statistically difference in median HbA1c between groups
Differences in proportions reaching target level
Hypos lowest in basal group
Weight gain highest in prandial group
> 65% of patients who required intensification using a second insulin:
67.7% for biphasic
73.6% for prandial
81.6% for basal
Holman RR et al N Engl J Med :

13. Intensifying insulin regimens
Which regimen?
There is no one ‘right’ choice, and one regimen is not necessarily forever. If it is unsuitable it should be changed
Who decides?
Your role is to explain the options and present all the pros and cons. The final decision must be made by the person themselves
Royal College of Nursing. Starting insulin treatment in adults with Type 2 diabetes 2006; NA: 1-28

14. Intensifying insulin therapy from basal
How do HCPs determine/define insulin “failure” ?
HbA1c unacceptable despite good fasting glucose control
Persistent hyperglycaemia during the day
Problematic day or night-time hypoglycaemia
Probable change required if large individual injection dose (e.g. >80 units) is escalating and still not approaching FPG target
Increasingly patients with type 2 diabetes are being commenced on basal insulin

15. Common options for intensifying basal insulin regimens
Switch to twice-daily premixed insulin
Add once-daily prandial insulin with the largest meal (basal-plus)
Additional prandial injections can be added
Add three times daily prandial insulin with meals (basal-bolus)
Intensify with an additional injection
Adapted from Barnett A et al (2008) Int J Clin Pract 62: 1647–53

16. Insulin regimens for type 2 diabetes compared
Frequent blood glucose monitoring
To follow on from the previous slide, this graphic aims to illustrate some of the pros and cons of the different options for intensification from a basal insulin regimen in type 2 diabetes.

17. What next if not achieving goals of therapy on basal insulin alone?
Insidious transfer to basal bolus or Basal + + +
Initiation as above is within HCP skill range
*Basal + indicates an insulin regimen of basal insulin, plus 1 bolus injection

18. What does basal bolus mean for the patient with Type 2 diabetes
4 – 5 injections per day
Choice of short/rapid acting insulin
Choice of long acting insulin
Choice of pen devices
Flexibility to adjust timing and dose of insulin
Increased frequency of blood glucose monitoring
Consider how many Type 2 patients either want to do this or could develop the skills to manage a complex regime

19. Matching insulin activity profiles to diet
Options and Outcomes

20. Insulin activity profile of Basal +++
Long Acting insulin
Insulin activity
Aim of Long acting insulin is to manage glucose levels between meals
Aim of Rapid acting insulin is to manage the glucose from the meals.
Rapid-Acting insulin
These diagrams are theoretical representations based on known pharmacological profiles, e.g. see Heise T et al (1998) Diabetes Care 21:

21. Carbohydrate awareness and Basal +++ in Type 2
Insulin activity
Long Acting insulin
Rapid-Acting insulin
Time
This patient is eating similar amounts of carbohydrate at each meal ( ~ 50grams) and is giving the same amount of rapid acting insulin at meals
Check BG levels 2 hours after meal
Eat similar amounts of carbohydrate at each meal
Inject same amount of rapid acting insulin at meals
Aim of Long acting insulin is to manage glucose levels between meals
Aim of Rapid acting insulin is to manage the glucose from the meals.
These diagrams are theoretical representations based on known pharmacological profiles, e.g. see Heise T et al (1998) Diabetes Care 21:

22. Challenges of Basal+++ in Type 2 diabetes
Because of insulin resistance, insulin sensitivity is poor
Self management of basal bolus / Basal+++
Carbohydrate counting or awareness
Correction doses are rarely taught to patients with Type 2 diabetes
Increasing insulin doses due to insulin resistance
Weight gain
Self titration/adjustment poor in many patients
Question
What makes Basal+++ successful in Type 2 diabetes?

23. Varying dose of rapid-acting insulin in Basal +++
Long Acting insulin
Rapid-Acting insulin
Insulin activity
This patient is eating DIFFERENT amounts of carbohydrate at each meal and is VARYING THE DOSE of rapid acting insulin at meals
Time
These diagrams are theoretical representations based on known pharmacological profiles, e.g. see Heise T et al (1998) Diabetes Care 21:

24. Adding pre-meal insulin to basal
Patients who fail to reach treatment goals despite maximum oral therapy and basal insulin could require the addition of pre-meal short or rapid acting insulin in order to improve postprandial control.
Start with the addition of one injection of pre-meal insulin with the biggest meal, largest carbohydrate intake
Titrate on a meal by meal basis to achieve postprandial blood glucose goal
Initially 10% of the patient’s basal insulin dose should be replaced by the pre -meal insulin
These are general guidelines and management should be individualised for specific patients.
Hirsch IB et al Clinical Diabetes ;2:78-86

25. Factors to consider before implementing a basal plus approach
Is the patient willing and able to take 4 – 5 injections a day?
Will the patient be able to develop an understanding of carbohydrate content of meals?
Will the patient be able to adjust their insulin dose based on the above?
If not
Hirsch IB et al Clinical Diabetes ;2:78-86

26. What next if not achieving goals of therapy on basal insulin alone?
Is a BD mixture more appropriate?

27. Transferring patients from a once-daily basal insulin to a BD mixture
Assess patients suitability for fixed mixture
Do they eat regular meals ?
Do they miss meals ever ?
Is the timing of meals similar each day
Use structured blood glucose monitoring and diet assessment (discovery sheets) to determine above and how current basal insulin dose should be split when initiated

28. Discovery sheets
Used for up to 7 days to facilitate a structured blood glucose monitoring approach
Patients are asked to record pre and post prandial blood glucose results, alongside food eaten
Helps determine pre prandial blood glucose control & post prandial response to carbohydrate intake
Engages and facilitates patients making the connection between blood glucose monitoring results and food eaten
Engages patients in identifying possible solutions.
Facilitates HCP with the patient to decide next best insulin solution.

29. Discovery sheets

30. Transferring patients from a once-daily basal insulin to a BD mixture
Caution should be taken when transferring from one insulin to another
When transferring to either a 30/70 or 25/75 premixed insulin
The total daily dose of basal insulin can be split by different ratios
50% of the total basal dose given pre breakfast
50% of the total basal dose given pre evening meal Or
70% of the total basal dose pre breakfast
30% of the total basal dose pre evening meal
Initial targets for fasting and pre-evening meal glucose levels (5-7 mmol/l)
Use fasting glucose to titrate evening dose and pre-evening meal to titrate am dose
Use patients bgm diary and food diary (or discovery sheet) to determine how best to spilt insulin dose
Hirsch IB et al Clinical Diabetes ;2:78-86
AccessMedicine Harrison's Online. Chapter 344: Diabetes Mellitus 2011; N/A: 1-12

31. Practicalities of changing from basal insulin to pre mixed insulin
Having decided on how the pre mixed insulin is to be split between pre breakfast and evening meal
(eg 50% am /50% pm or 70% am /30% pm)
Day 1
First dose of pre mixed insulin is given with evening meal
Basal insulin stopped
Day 2
First dose of morning pre mixed insulin is given
Followed by second dose of pre mixed insulin with evening meal

32. Challenges of BD mixtures in Type 2
Perceptions, seen as:
More complex to initiate and titrate than a basal insulin
Depending on individual lifestyle, may be seen as inflexible compared with Basal+++
Planned snacking required for some patients
May cause more weight gain and more hypoglycaemia than basal regimens
Basal bolus seen by some as the gold standard insulin therapy
Raskin P et al. Diabetes Care, :

33. Advantages of premixed insulin analogues
Rapid acting insulin analogues exhibit earlier and higher peak metabolic activity and shorter duration of action than human insulin
Both basal and rapid-acting prandial insulin are provided in every injection and are effective and simple for patients to use
Can be injected up to 3x daily and can effectively control postprandial hyperglycaemia
Potentially improve postprandial glycaemic excursions throughout a 24hr period
Rosenstock J, et al. Diabetes Care 2008; 31:20-25

34. Activity profile of premixed insulin analogues
For a 75/25 premixed insulin analogue this is how units break down
Rapid-Acting insulin
Long Acting insulin
Reiterating the essential point that BD mix has long and short acting components. Size of meal is important.
Long-acting insulin component manages glucose levels between meals
Rapid-acting insulin component manages glucose load from the meals.
These diagrams are theoretical representations based on known pharmacological profiles, e.g. see HeiseT et al (1998) Diabetes Care 21:

35. Activity profile of premixed insulin analogues
Rapid-Acting insulin
Long Acting insulin
Aim of Long acting insulin is to manage glucose levels between meals
Aim of Rapid acting insulin is to manage the glucose from the meals.
These diagrams are theoretical representations based on known pharmacological profiles, e.g. see HeiseT et al (1998) Diabetes Care 21:

36. Eating under the curve!
Patients need to be taught how to eat under the curve
Patients taking mixtures need to be aware they need to eat similar amounts of carbohydrate. Post prandial blood glucose monitoring will help the patient determine carbohydrate portion size to match insulin profile

37. How do you determine/define BD premixed insulin “failure”
HbA1c unacceptable
Persistent hyperglycaemia (either pre-injection or post-prandial are high-risk times)
Problematic day or night-time hypoglycaemia (pre lunch and pre/post bed are high-risk times)
Variable hypoglycaemia and hyperglycaemia because of lack of flexibility in twice-daily regimen
How do Health care professionals decide pre-mixed insulin isn't working ??

38. What next if not achieving goals of therapy on BD mixture?
Options:
Add in prandial insulin lunchtime
Basal bolus
TDS Mix
Combination of different mixtures
The next intensification option will be determined by blood glucose profiles and patients food diary
If a patient is failing to achieve control on bd mixed insulin, what are the next options? These may include
prandial insulin at lunchtime which would require a new pen device and an additional insulin.
When choosing a Tds mix either the same mix or a new mix, this means the patient would only use one pen device, unlike basal bolus.

39. Intensifying insulin therapy
Summary
Changing insulin regimen alone may not improve control
Assess factors influencing poor control
Intensifying insulin therapy typically means increasing the number of injections per day
Consider the patients physical and cognitive ability to take on a more complex insulin regimen
Ensure patients are involved in their treatment – providing appropriate education so enabling them to make informed choices about the potential options when intensifying their insulin therapy

40. UKDBT01539 September 2013