1. Insulin Initiation for Type 2 diabetes in General Practice
Nicole McGrath
2013

2. Does the patient need insulin?
Not achieving target HbA1c mmol/mol
1. Doing as much as possible re diet and exercise
Gym membership deals
Advice on food: types and amount
Bariatric Surgery; Optifast
Willingness to change?
2. Taking maximum doses of oral medication
Metformin can be continued until eGFR<30ml/min
Gliclazide 320mg/day; Glipizide 30mg/day
Pioglitazone for young, obese
Don’t forget Acarbose
Drug adherence? Checking with patient and with dispensing

3. 4. Is the target HbA1c realistic for the patient:
3. Is the patient actually primarily insulin deficient (rather than insulin resistant):
Suboptimal HbA1c and slim with weight loss
BMI <= 25;
Overweight patient with duration of diabetes > 10 years; previously good glycaemic control on oral agents
4. Is the target HbA1c realistic for the patient:
Frail, elderly, mentally ill: trigger HbA1c for commencement of insulin may be higher (e.g. HbA1c> 65 mmol/mol)

4. Diagnosis of type 2 diabetes
Type 2 diabetes is a progressive disease that requires progressive treatment
ß-cell function and insulin secretion progressively decline in type 2 diabetes
Diagnosis of type 2 diabetes

5. Is insulin going to be effective?
1. How much is the patient prepared to do?
Testing regularly: need to know the blood glucose (BG) profile to work out the best insulin regime
Learning how to self-inject
Learning how to adjust the doses
2. How much are you and your nurse prepared to do?
Teaching how to inject
Supervising titration of dose in a timely manner
Giving advice on dose adjustment for meal content, exercise if on multidose regime

6. Education Required Lifestyle advice; BG monitoring Use of insulin pens
Injection technique
Insulin action, timing of injections, storage
Disposal of sharps
Hypo management, prevention
Sick day management

7. How many injections per day?
How many is the patient prepared to do?
How high is the HbA1c? Are the oral agents providing any benefit?
Likely if HbA1c is between 55 and 75 mmol/mol:
Once daily insulin added on to oral agents indicated
HbA1c > 75: oral agents failing and full switch to insulin may be best.

8. Insulin therapy. Pre mix – useful for Regular lifestyles
Eat similar amounts of Carbohydrate
Insulin depleted – slim
Combination with OHA – 1injection start.
BD Stop Actos / OHA
Basal bolus - Most useful for –
Type 1 diabetes
Erratic lifestyle / eating patterns
Need flexibility – shifts, sports
Optimal control needed.
Keep Metformin – Type 2 also. TYPE 1 OBESE
Basal only will lower HbA1c by 1.8% in clinical trials for up to 28 weeks
Patient with HbA1c of 8.5% - good starting point

9. Once daily basal insulin
Glargine (Lantus) vs. Isophane (Protophane/Humulin NPH)
NZ Guideline Group (NZGG): Isophane
Commonly used: Glargine
Isophane: cheaper, long and safe track record, hours of action
Protophane: Novo pen; Humulin NPH: Luxura pen
i.e. no real difference between the two brands but specific pen needs to be given

10. Basal Insulin: provides background insulin but does not cover meals
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Isophane
Glargine
Schematic action profiles, theoretical representation of insulin injected once a day - results may vary from patient to patient.

11. Once daily Isophane insulin (Protophane or Humulin NPH): Indications
Night dose: Good for patients whose blood sugars climb overnight but have even control during the day due to oral agents:
Continue oral agents and prescribe Isophane insulin at 8-9pm
Morning dose: Elderly patients often do not need much diabetes treatment overnight (reduced hepatic gluconeogenesis) and also useful for those on Prednisone mane
Fasting BG 4-6 but climb during the day
Continue oral agents and prescribe Isophane insulin at 8-9am

12. What are the pros and cons of the Novopen vs. the Luxura?
slightly bigger numbers
its mechanism makes counting the clicks (for the  sight impaired ) a little easier.
need to pull the end out first before dialing up
Luxura (Huma Pen)
heavier
mechanism feels a little looser - possibly easier to make mistakes
you just dial.

13. Isophane insulin: Starting Dose
NZGG suggest 10 units starting dose
Insulin requirement relates to body weight
If patient > 50kg, expect the dose will need to climb
If patient overweight (BMI > 30) or HbA1c > 65 mmol/mol, suggest start at a higher dose, e.g. 0.2 units/kg body weight/day
e.g. 100kg patient will likely need at least 20 units

14. Glargine (Lantus) insulin
Only funded long-acting insulin analogue (Levemir not funded)
Concerns about potential cancer risk have been disputed
24 hour action for approximately 70-80% patients
Constant insulin profile with no peak action
can be given at any time of the day so long as the same time each day
More sensitive to heat than other insulins

15. Glargine (Lantus) Insulin
Given either with disposable pen (Solostar Pen) or in penfill used in ClikSTAR Pen
If prescribe Solostar, no need to provide pen and no need for patient to refill pen, but more waste
Solostar Pen ready filled and dispensed at pharmacy
ClikSTAR pen: satisfactory but not as robust as NovoPen/Luxura pen:
Large numbers, easy to see

16. Once daily Glargine (Lantus): Indications
24 hour basal insulin needed: BG high in the morning and climb over the day
HbA1c > 65 despite maximum oral agents
An introduction to insulin for those who really need full insulin cover but reluctant/unwilling; more coverage than Isophane
No need to time Glargine insulin injection with meals
Still need to cover postprandial hyperglycaemia with something (oral agents or insulin)

17. ...resulting in undesired mealtime glucose excursions
The problem with type 2 diabetes The mealtime insulin secretory response is blunted…
A normal insulin response following a meal is two-phased. Insulin is rapidly released by beta-cells into the portal circulation within minutes of glucose arrival in the bloodstream. This insulin spike lasts about 10 minutes giving rise to what is known as first-phase insulin release. This is followed by a second-phase release, which lasts for 1–2 hours and gradually falls back to normal levels.
In type 2 diabetes, this first-phase insulin release is lost and the second phase is blunted resulting in postprandial hyperglycaemia.
Although both phases of insulin release are needed, the first-phase insulin release is essential to overall glucose control.
Reference:
Polonsky KS et al. New Engl J Med 1988; 318:1231–39.
...resulting in undesired mealtime glucose excursions

18. Both fasting & mealtime glucose contribute to HbA1c
Clinical evidence suggests that reducing PPG excursions is as important, or perhaps more important than fasting blood glucose (FBG), for achieving HbA1c goals

19. Oral hpoglycaemic agents (OHA) and basal insulin
Tempting to stop all OHA and just have one injection per day
Will achieve better control than no treatment
Can result in worse control if patient was taking oral medication as prescribed
Metformin useful agent to continue in most patients
Reduces insulin resistance
Treats post-prandial hyperglycaemia
No hypoglycaemia due to Metformin itself
Continue at same dose

20. Suphonylureas and basal insulin
NZGG:
Once daily Isophane: continue Sulphonylurea
Twice daily Isophane: discontinue Sulphonylurea
If control just above target HbA1c, then this may work
But Isophane will not cover post-prandial hyperglycaemia:
If HbA1c > 65, continue Sulphonylurea
Once daily Glargine: similar to twice daily Isophane

21. Some typical treatment regimens: OHA and basal insulin
Metformin 850mg tds, Gliclazide 160mg bd, Protophane 15 units nocte
Metformin 1gm tds, Humulin N 12 units bd
Gliclazide 80mg tds, Glargine 30 units daily (renal pt)

22. Other OHA Pioglitazone: usually discontinued at insulin commencement
Increased risk of fluid retention
But…. In young overweight patient maybe continued to help minimise the insulin dose
Acarbose: can be continued if useful

23. Are OHA adding anything?
If HbA1c > 75 mmol/mol and pt taking the OHA at maximum doses, then probably not
If 2-hour post-prandial BG > 10, then probably not
Will depend on pre-prandial BG
Will need insulin to cover meals……unless patient can reduce carbohydrates / meal size

24. Insulin Mealtime Cover
Rapid-acting insulin Onset approx 10 minutes after injection. Duration of action around 1–3 hours. Rapid-acting insulin should be given immediately before a meal (or can be given soon after meals) Brand names: Humalog, NovoRapid, Apidra Short-acting insulin Onset approx 30 minutes after injection. Duration of action around 3-6 hours. Short-acting insulin should be given minutes before a meal Brand names: Humulin R, Actrapid
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25. Short acting insulin Actrapid and Humulin R not routinely used
Can be useful to try and cover both breakfast and lunch or extended evening food intake
E.g. children who do not want to inject at school
Adults who eat most of their food in the evening but over an extended period (probably better in a pre-mixed formulation)

26. Rapid acting Insulins Novorapid vs Humalog vs Apidra
No significant difference between them
Novorapid: Novo pen; slightly longer tail of action, up to 4-5 hours
Humalog: Luxura pen; action 3-4 hours
Apidra: disposable solostar pen; action 3-4 hrs

27. Basal bolus insulin regimes
Basal insulin (Isophane or Glargine) taken once or twice daily
Bolus insulin (Novorapid, Humalog or Apidra) with meals
Standard regimen for type 1 diabetes
Becoming popular with insulin requiring type 2 pts
Most flexible insulin regimen
But… does require multiple insulin injections per day
Plus education about adjusting bolus insulin doses for variable meals

28. Basal bolus regimens
Usual: Rapid acting insulin tds + Glargine mane or nocte
Examples of variations:
Glargine once daily + Apidra with main evening meal+ Metformin tds (can give Glargine and Apidra at same time)
Good for pt who eats large evening meal, snacks during day
Humulin N mane + Humalog with breakfast and lunch + Metformin tds
Pt on Prednisone 10mg mane for PMR
Can become somewhat complicated!

29. Pre-mixed Insulins
Avoid complicated regimens in patients who need more than basal insulin + OHA
Cover background insulin requirements + meal cover
Two injections per day timed with breakfast and evening meals
Have to eat at these times
Good opportunity to stress importance of regular meals
Usually continue Metformin but discontinue sulphonylurea, other OHA

30. Pre-mixed Insulins: Covering meals and giving basal cover
A mixture of either rapid or short-acting and intermediate-acting insulin which act just like two injections of the separate components taken at the same time
Useful for many type 2 patients with tablet failure requiring insulin
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31. Pre-mixed Insulins: Short acting insulin + isophane
Penmix 30: 30% Actrapid, 70% Protophane
Penmix 50: 50% Actrapid, 70% Protophane
Humulin 30/70: 30% Humulin R, 70% Humulin N
Ideally injected 20 mins before meal
Actrapid/Humulin R longer duration of action
cover breakfast and lunch
but can linger and potentiate hypoglycaemia overnight
Most patients use Penmix 30 or Humulin 30
Penmix 50 useful for big eaters

32. Pre-mixed Insulins: Rapid acting insulin + isophane
Humalog Mix 25: 25% Humalog, 75% Humulin N
Novomix 30: 30% Novorapid, 70% Protophane
Humalog Mix 50: 50% Humalog, 50% Humulin N
Cover breakfast and dinner well, but not lunch
Inject when meal served or just after
Most patients use Humalog Mix 25 or Novomix 30:
Not much difference
Novomix 30: disposable pen
Humalog Mix 50 can be useful to cover large evening meal

33. Pre-mixed Insulins Pros
cover overnight hyperglycaemia and address postprandial excursions
Humalog Mix/ Novomix:
Inject at meal-time
Less likelihood pre-prandial hypoglycaemia
Penmix/Humulin Mix
Improved cover lunch and late night snack
Cons
injections must be given at meal times; work best if regular time for breakfast and evening meal
difficult to adjust dose if:
large variation in carbohdrate component of meal
sudden increase in physical activity
Humalog/Novo Mix
Not good lunch cover
Penmix/Humulin Mix
Inject 20 mins before meal

34. Insulin prescription How to get around expected increase of dose?
Need to also prescribe insulin pen needles
We recommend 5mm needle length to ensure subcutaneous administration (rather than intramuscular) for most people
How to get around expected increase of dose?
Prescribe higher dose but instruct patient to start with lower dose? May cause confusion
Write on script that dose may be increased and repeats needed early
Write another script if supplies run out early

35. Adjusting insulin doses
The patient should be instructed in adjusting their own insulin – checking with the practice weekly.
2-4 unit adjustment every 3-4 days until target blood glucose is reached.
Targets: Pre breakfast target <7.0mmol/L
2 hour post meal target <10.0mmol/L
Pre-dinner target 6.0–7.0mmol/L
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36. Insulin Dosage Adjustments – Pre-mixed insulin Regime (on HealthPoint)

37. Insulin Dosage Adjustments – Basal Bolus Regime (on HealthPoint)
Blood Glucose Levels (mmols/litre)
Less than 4 or hypo
4-8
8-15
15 or higher
Blood testing times
Before breakfast
Reduce
cloudy night time insulin by 2 units
Good
Control
Increase
cloudy night time insulin by 4 units.
Before lunch
breakfast insulin by 2 units
breakfast insulin by 4 units
Before evening meal
lunch insulin by 2 units
Lunch insulin by 2 units
lunch insulin by 4 units
Before bed
evening insulin by 2 units
evening insulin by 4 units

38. Increasing Insulin Doses: Isophane nocte
Pre breakfast (fasting) BG
Usually >8 mmol/L and never less than 4:
Increase dose by 4–6 units
Usually 6–8 mmol/L and never less than 4:
Increase dose by 2–4 units
Once receiving >20 units daily + 3 consecutive pre breakfast (fasting) BG results higher than agreed BG target AND BG never less than 4 mmol/L
Insulin dose can be increased by 10–20% of total daily dose

39. Twice daily Isophane (= Glargine)
Pre evening meal BG
Usually >8 mmol/L and never less than 4
Increase pre breakfast insulin dose by 4–5 units
Usually 7–8 mmol/L and never less than 4
Increase pre breakfast insulin dose by 2–4 units
Once receiving >20 units daily
3 consecutive BG results (either pre breakfast or pre evening meal) higher than agreed BG target AND BG never less than 4 mmol/L
Appropriate insulin dose can be increased by 10–20% of total daily dose

40. Post-prandial testing
Check 2 hours after meal: target BG < 10
If on OHA, maximise
If still not meeting target, make sure basal insulin dose is correct (pre-meal BG < 7)
If basal insulin correct then need to add rapid acting insulin or
Change to Premixed insulin regime

41. Not testing (or not very much)!
Difficult to manage accurately
Most patients will check fasting BG
At least can adjust basal insulin (unless pt eats overnight)
Alternate times of testing so once or twice daily test can give maximum information; certain days of the week
Sometimes pre-prandial, sometimes post-prandial
Evening meal usually largest so 2 hours after dinner
Regular HbA1c (2-3 monthly)

42. HbA1c remains suboptimal
Is basal insulin enough?
Is the dose correct: fasting BG < 7
Some obese patients require large doses of insulin
Basal insulin 0.5 units/kg body weight/day
What about post-prandial hyperglycaemia?
It always comes back to the food!
If basal dose correct and on maximum OHA
Change to Pre-mixed insulin / basal bolus

43. Changing Insulin Regimens
Options if HbA1c suboptimal on basal insulin:
If not on sulphonylurea: add it on and maximise
If on once daily Isophane, change to bd or Glargine
If on maximum orals: change to Pre-mixed bd insulin
Stop sulphonylurea, give same insulin dose as basal
Isophane 24 units bd: Penmix units bd
Or, continue with basal insulin, stop sulphonylurea and add rapid acting insulin
Usually need same total daily dose as basal insulin
Glargine 30 units daily: Novorapid 10 units tds

44. When to refer to Secondary services
This will depend on your teams’ experience:
Current situation (from my viewpoint):
Some practices independently start patients on insulin
Refer when issues with hypoglycaemia impact on improved control.
Or not achieving any improvement in HbA1c
Sometimes patients will self-refer
Other practices refer everyone who is on OHAs with suboptimal HbA1c
Appropriate if skill base and time not there

45. Secondary Services
Expectation for the future (from Ministry of Health):
Insulin for type 2 diabetes patients will be initiated by all GPs
Mostly basal insulin + OHA, or pre-mixed insulin bd
May mean more patients are started on insulin early (appropriately)
Remember basal insulin only will not be sufficient for a number of patients and long-term adjustment is required
We are interested to see young type 2 pts < 25 yrs to provide intensive input

46. Summary Checklist for commencement of insulin
Maximised lifestyle changes, OHA
Patient willing; skill base in practice
Decision on insulin regime depends on
BG profile ideally
HbA1c
Patient preference
Familiarity of your team with regimen and follow-up required