Practical Guidance on the Use of Premix Insulin

Analogs in Initiating, Intensifying, or Switching

Insulin Regimens in Type 2 Diabetes
Ted Wu, Bryan Betty, Michelle Downie, Manish Khanolkar, Gary Kilov, Brandon Orr-Walker, Gordon Senator and
Greg Fulcher

Ted Wu et al. Diabetes Ther. 2015 Jun 24.DOI 10.1007/s13300-015-0116-0

 Introduction
• Premix insulin analogs are well established as a treatment for T2D

• However there is a lack of practical guidance on:

• Choosing an initial regimen
• Switching to a premix regimen from a complex basal-bolus regimen

• The objectives of this independent expert panel was to formulate guidance on:
• Initiating therapy with premix insulin analogs
• Recognizing when patients need intensification
• Switching from basal–bolus to premix insulin analog therapy when
appropriate

T2D, Type 2 diabetes; GPs, general practitioners;

Ted Wu et al. Diabetes Ther. 2015 Jun 24.DOI 10.1007/s13300-015-0116-0
 Evidence Base for Premix Insulin Analogs:
Initiation of Insulin: Premix Insulin analogs Vs. Basal Analogs

• Systematic reviews1,2,3,4 of the available evidence suggest that treatment with

premix insulin analogs compared with basal insulin results in:
• Better overall glycaemic control with premix insulins
• Slightly greater risk of Hypoglycaemia and weight gain with premix insulins

• Factors not addressed in clinical trials may influence outcomes

• Complexity of regimen
• Need for titration

1. Llag et al. Clin Ther. 2007;29:1254–70.; 2. Qayyum et al. Ann Intern Med. 2008;149:549–59.; 3. Lasserson D et al. Diabetologia. 2009;52:1990–2000.;4. Vaag at al.
Eur J Endocrinol. 2012;166:159–70
Ted Wu et al. Diabetes Ther. 2015 Jun 24.DOI 10.1007/s13300-015-0116-0
 Evidence Base for Premix Insulin Analogs
Intensification of Insulin: Premix Insulin Analogs vs. Basal-Plus or
Basal–Bolus Regimens

Evidence Key results (Premix Vs. Basal Bolus)

Higher chance of reaching HbA1c goal with no difference in the

Meta-analysis1
incidence of hypoglycaemia or weight gain with Basal Bolus regimen

PARADIGM2 No difference in efficacy and safety outcomes

Evidence Key results (Premix Vs. Basal Plus)

More patients reach HbA1c targets with premix insulin with higher
GALAPAGOS3
rates of overall and nocturnal hypoglycaemia

LAnScape4 Fewer episodes of nocturnal hypoglycaemia with premix insulin

1. Giugliano et al. Diabetes Care. 2011;34:510–7; 2. Bowering K et al. Diabet Med. 2012;29:e263–72; 3. Aschner P et al. Diabetes. 2013;62(Suppl 1):A241–2;
4. Vora J et al. Diabetes. 2013;62(Suppl 1A):LB13
Ted Wu et al. Diabetes Ther. 2015 Jun 24.DOI 10.1007/s13300-015-0116-0
 Evidence Base for Premix Insulin Analogs
Switching from Basal–Bolus to Premix Therapy

• Basal–bolus insulin regimen--->premix insulin: Relatively uncommon scenario

• Patients who may need to switch:

• Unable or unwilling to cope with the complexity of a basal–bolus regimen
• Commencing treatment with a basal-bolus therapy in hospital who may no longer
need an intensive regimen following discharge

• A1chieve1: Switch from a Glargine/NPH based basal-bolus regimen to BIAsp

30 BID
• Improvement in effectiveness and safety outcomes- May be attributed to better
treatment adherence due to simpler regimen with BIAsp 30

• No available guidelines except Turkish guidelines

1. Dieuzeide G et al. PrimCare Diabetes. 2014;8:111–7
Ted Wu et al. Diabetes Ther. 2015 Jun 24.DOI 10.1007/s13300-015-0116-0
 Conclusions from the Available Evidence*

• A better HbA1c reduction was accompanied by a higher rate of hypoglycemia,

and both arms* were accompanied by weight gain

• No single insulin or regimen was best on all endpoints

• While the differences may have reached statistical significance, they were
often of limited clinical relevance

• It is important to choose a regimen to which patients are likely to adhere

*Results from the trials in both initiation and intensification with premix vs. basal based regimens
Ted Wu et al. Diabetes Ther. 2015 Jun 24.DOI 10.1007/s13300-015-0116-0
 Recommendations: Considerations at Initiation
Patient factors to consider when deciding whether to use premix insulin analog or basal insulin
for initiation

Favours premix Considerations Favours basal

What is the postprandial

>3 mmol/L (>54mg/dL) <1 mmol/L (<18mg/dL)
increment?
Is the patient likely to manage
No basal-bolus therapy when Yes
intensification is needed ?
Is there a large carbohydrate
Yes No
intake at one or two meals
Is the patient’s lifestyle
Yes predictable (e.g. eating pattern, No
working hours )?

Patient’s ability to cope with intensification should influence the choice of initiation regimen

Ted Wu et al. Diabetes Ther. 2015 Jun 24.DOI 10.1007/s13300-015-0116-0

 Recommendations: Considerations for Future
Intensification
Factors that will determine whether future intensification should be with basal–bolus or premix
insulin analog therapy

Favours premix Considerations Favours basal-bolus

Patient preference regarding Comfortable with more frequent

Prefers fewer injections
number of injections injections

Patient preference regarding self- Comfortable with more frequent

Prefers less frequent monitoring
monitoring of blood glucose monitoring
Patient ability to inject (e.g.
Poor cognitive ability, manual dexterity, Good
need for carer)

Ted Wu et al. Diabetes Ther. 2015 Jun 24.DOI 10.1007/s13300-015-0116-0

 Dosing/Titration Guidelines for Initiating Insulin
with Premix Insulin Analogs OD*
• When choosing an insulin dose, and for dose titration focus on
safety and convenience

• Initiate with premix insulin analog OD, immediately before or soon

after the start of the meal with the highest prandial load (usually Lowest premeal blood Adjustment for
the evening meal) glucose level the next dose

≥7.0 mmol/L (≥126

• Initiate with a dose of 10–12 units and titrate mg/dL)
+2 units

4.1–6.9 mmol/L (73–

• Increase by 2 units once or twice a week until the patient reaches 124 mg/dL)
0 units
target+ or experiences hypoglycaemia. Dose titration can be halted ≤4.0 mmol/L (≤72
when self-monitored blood glucose levels consistently fall within the -2 units
mg/dL)
target

• If blood glucose <4mmol/L (<72mg/dL) or hypoglycaemia occurs,

down-titrate by 2 units. If hypoglycaemia persists, the patient
should review with their doctor or nurse

* Based on consensus; + [aim for <7 mmol/L (<126 mg/dL), but no values <4 mmol/L (<72 mg/dL) based on the lowest premeal glucose level]
Ted Wu et al. Diabetes Ther. 2015 Jun 24.DOI 10.1007/s13300-015-0116-0
 Use of Other Glucose-Lowering Drugs*

• All combination use is subject to local registration rules

• Metformin should always be continued unless it is poorly tolerated or contraindicated

• Consider maintaining SU’s with once-daily premix insulin. However, they

should not be given at the same time of day as the premix insulin dose. Discontinue
SU’s once patients intensify to twice-daily premix insulin

• DPP4-I / SGLT2I / AGI’s can be continued together with insulin

• TZD’s: combining these agents with insulin may exacerbate edema

• GLP-1 RA may be insulin sparing and can be used

• Consider lowering the dose of the non-insulin drug, other than metformin, at insulin
initiation

*Based on consensus
SU’s, Sulfonylureas; DPP4-I, Dipeptidyl peptidase-4 inhibitors; SGLT2I : Sodium glucose co-transporter- inhibitors; AGI’s, alpha-glucosidase inhibitors; GLP-1 RA Glucagon-
like peptide-1 agonists ; TZD’s ,Thiazolidinediones
Ted Wu et al. Diabetes Ther. 2015 Jun 24.DOI 10.1007/s13300-015-0116-0
 Intensifying Insulin Therapy to Premix Insulin Analogs
BID in Primary Care: Practical Guidance on Switching

Practical guidance for switching from basal insulin [once

daily (OD) or twice daily(BID)], or from premix insulin When to intensify?
analog OD, to premix insulin analog BID*
• HbA1c level above the
• From basal: 1:1 total dose switch to premix insulin analog. individualized target for 3-6
Split the dose 50/50 breakfast and dinner months**

• From premix insulin analog OD: split the OD dose 50/50 • If 2-h postprandial blood
breakfast and dinner glucose values are above 10
mmol/L or a difference of > 3
• Administer premix insulin analog immediately before or soon mmol/L
after the start of a meal
• Maximum dose of 40-50 units is
• Titrate the dose preferably once or twice a week reached on premix insulin
analog OD
• Adjust the evening meal dose first, followed by the breakfast
dose

* Based on consensus and modified from Unnikrishnan AG et al. Int J Clin Pract. 2009;63:1571–7; ** Without any obvious reversible reason
Ted Wu et al. Diabetes Ther. 2015 Jun 24.DOI 10.1007/s13300-015-0116-0
 Intensifying Insulin Therapy to Premix Insulin Analogs
BID in Primary Care: Practical Guidance for Switching*

Basal insulin OD or BID

HbA1c 7-8% HbA1c >8%

(53-64mmol/mol) (>64mmol/mol)

FPG>7 mmol/L FPG 4-7 mmol/L

(>126mg/dL) (73-126mg/dL)

Titrate basal insulin to

achieve FPG<7 mmol/L Switch to premix insulin analogue BID
(<126mg/dL)

Algorithm for switching from basal insulin therapy OD or BID to BID premix insulin analog
*Modified from Unnikrishnan AG et al. Int J Clin Pract. 2009;63:1571–7

Ted Wu et al. Diabetes Ther. 2015 Jun 24.DOI 10.1007/s13300-015-0116-0

 Intensifying Premix Insulin Therapy from OD to BID

Premix insulin OD (evening meal)a

FPG 4-7 mmol/L FPG >7 mmol/L

(73-126 mg/dL) (>126 mg/dL)

Titrate premix insulin OD to

HbA1c > 7 % achieve FPG <7 mmol/L
(>53 mmol/mol) (<126 mg/dL)

If significant hypoglycemia occurs

during titration

Add another injectionb

(i.e. intensify to premix insulin analog BID)

Algorithm for intensifying premix insulin analog therapy from OD to BID*

*Modified from Unnikrishnan AG et al. Int J Clin Pract. 2009;63:1571–7; a. The evening meal is given as an example. Breakfast injections may also be suitable, in which
case the pre-evening meal blood glucose should be monitored; b. Split the OD dose 50/50 breakfast and dinner. BID twice daily, FPG fasting plasma glucose, OD once daily
Ted Wu et al. Diabetes Ther. 2015 Jun 24.DOI 10.1007/s13300-015-0116-0
 Titration Algorithm for Switching from Basal–Bolus to
Premix Insulin Analog*

• General guidance: as always, titration must be tailored to the

individual patient
Switch:
• These guidelines do not override clinical judgment and
knowledge
• Patient is unwilling or unable
• Reduce total daily dose of all insulin by 20–30% to use basal-bolus therapy

• Then split this value 50/50 to give you the starting dose of • HbA1c above target
premix insulin analog at breakfast and evening meal consistently on a basal-bolus
• Unusual meal patterns may lead you to reconsider the initial regimen
dose ratio
• Patients discharged from
• Titrate the dose preferably once or twice a week hospital on a basal bolus
regimen if appropriate
• Adjust the evening meal dose first, followed by the breakfast
dose

• Safety is key: go slowly

* Based on consensus
Ted Wu et al. Diabetes Ther. 2015 Jun 24.DOI 10.1007/s13300-015-0116-0