How to intensify basal insulin with

Premix and Basal Bolus approach

Djoko Wahono Soetmadji

 Presentation title Date 3

Outlines
• Diagnosis and Classification of Diabetes
• Natural history of type 2 diabetes
• Starting insulin after oral agents failure
• Insulin intensification – rationale
• What are treatment options for intensifying?
• Intensifying from basal insulin to premixed
insulin analogues
• Intensifying from basal insulin to bolus insulin analogues
• Summary
Diagnosis and Classification of Dibetes
 Slide no 5

Diabetes Mellitus
Established Diagnosis Poliuria BG (mg/dL)
Polidipsi  Casual  200
 BW  Fasting  126
Lethargi 2 h PP  200

Define Etiology

Type 1 Type 1½ Type 2

Obese Nonobese
 Type 1 Type 2
Clinical Features
Age at onset Usually < 30 Usually > 40
Onset Acute Insidious
Weight Non obese Obese
Spontaneous ketosis Common Rare
Chronic complication (++) (++)

Epidemiology
Prevalence 0,5% 2%
Sex Male prepdominancece Female predominance
 Type 1 Type 2
Insulin (C-petide) level ↓↓ / (-) ↓/N/

Genetics
Concordance in twins 40% 70 – 90%
HLA asoociation (+) (DR3/DR4) (-)

Pathology
Islet cell mass Severely reduced Moderately reduced
Insulitis at onset Present ?

Immunology
Associated with other endocrinopathy Frequent Frequent
Anti-islet ell immunity
• Humoral 60 – 80% at onset 5 – 20%
 Cell mediatedl 35 – 50% at onset < 5%
 8

Type 2 Diabetes

• Type 2 Diabetes is a complex and progressive disease, requiring

timely treatment escalation

• Guidelines interpret existing evidence in order to help

all physicians

• The increase in the number of available therapies has increased

treatment options

• Guidelines should be revised as new evidence accrues

• Guidelines do not replace clinical judgement in the individual patient

Nathan DM, et al. Diabetes Care 2009;32 193-203.

Different Characteristics of Patient

Outpatient ClinicDiabetes and Endocrinology, Dr. Saiful

Anwar Hospital, Malang
 Clinical Subtypes of Type 1 Diabetes
• Slowly progressive Type 1 (SP type 1) diabetes (Diabetes
Care 16: 780 – 788, 1993)
1. ICA and/or GAD ab (+)
2. Non-insulin dependent at onset
3. Non-insulin requiring period more than 13 months
after the onset or diagnosis
• Regular
• Fulminant Type 1 diabetes ( N Eng J Med 342: 301, 2000)
1. Ketosis/ketoasidosis within a week after the onset of
hyperglycemic symptoms
2. Serum C-peptide < 0.3 ng/ml (fasting) and
< 0.5 ng/ml (after meal or iv. Glucagon)
3. AIC < 5.5% on first visit
Type 1½ diabetes

Italy : population-based : 22.3% overall, n = 130, age 30–54,

all new diabetes BMI <25; Bruno G :Diabetes Care 22:50–
55, 1999)
Malang, Indonesia : hospital base (BMI < 25, age 15 –
72) 22,2%, (Arsana & Soeatmadji, PERKENI, 2000)
Holland : population sample (all known diabetes) : 3.5%, n =
2,350, age 50–74 (Ruige JB : Diabetes Care 20:1108–
1110, 1997)
U.K. : 10% overall, 34% 25–34 years of age, 7% 55–65 years
of age, n = 3,672 non-insulin requiring diabetes
Type 1½ Diabetes (Latent Autoimmune Diabetes in
Slide no 12

Adult, Slowly Progression Type 1 Diabetes)

Diabetes Care Publish Ahead of Pr©in t, published online April 10, 2014
 Slide no 13

Management of Type 2 Diabetes

• Lifestyle modification
- Healthy diet
- Regular exercise Individualised
• Pharmacological Treatment Patient-centred care
- Oral hypoglycaemic agent Patient education
- GLP-1 agonist
- Insulin
Natural History of Type 2 Diabetes

Lifestyle modification
OHA ± Insulin

Years from diagnosis

Type 2 Diabetes is a complex and progressive disease requiring timely treatment escalation
 16

Type 2 diabetes is a progressive disease

Progression of Type 2 Diabetes

Insulin resistance

Hepatic glucose production

Insulin level

Beta-cell function

4–7 years Postprandial

glucose

Fasting plasma
glucose

Development of Microvascular Complications

Development of Macrovascular Complications

Impaired Glucose Tolerance Diabetes

Diabetes Diagnosis

Conceptual representation adapted from Ramlo-Halsted BA, Edelman SV. Prim Care 1999;26(4):771–789. © 1999 Elsevier
Paradigm of Therapy of Type 2 Diabetes

• Aggressive Treatment – Driven by individual target

(AIC < 6.5%, <7%)
• Early Combination, Including with Insulin
- Oral + oral
- Oral + insulin
- GLP-1 + Insulin
• Aggressive Insulin Treatment
Summary of glycemic recommendations for non-
pregnant adults with diabetes
• Glycaemic Target
- A1C is the primary target <7.0%*
- Preprandial glucose 80–130 mg/dl (3.9–7.2 mmol/l)
- Peak postprandial <180 mg/dl (10.0 mmol/l)
• Key concepts in setting glycemic goals:
- Goals should be individualized based on:
- duration of diabetes
- age/life expectancy
- comorbid conditions
- known CVD or advanced microvascular complications
- hypoglycemia unawareness
- individual patient considerations
• More or less stringent glycemic goals may be appropriate for individual patients
• Postprandial glucose may be targeted if A1C goals are not met despite reaching
preprandial glucose goals
 Slide no 19

Drug Treatment
Obese

Standard-release
If metformin is
Metformin
contraindicated or not
tolerated

Use Insulin but Repaglinide DPP-4 inhibitor or

not to soon Pioglitazone or
Sulfonylurea
 Slide no 20

Drug Treatment
Non-obese

Sulfonylurea
If SU is
contraindicated or not
tolerated

Start Insulin Metformin

and not to late DPP-4 inhibitor or
Pioglitazone
 Slide no 21

Individualised Care
Tailored to the needs and circumstances
• Personal preferences
• Comorbidities
• Risks from polypharmacy
• Ability to benefit from long-term interventions because
of reduced life expectancy
 Slide no 22

Timely treatment escalation

Think about whether to stop any medicines that are not effective
How do we define insulin intensification?

INITIATE Starting insulin therapy

Dose titration to ensure that the patient receives

OPTIMISE the maximum benefit from the prescribed
treatment

Modification of the insulin regimen

INTENSIFY (e.g. adding to or changing the therapy in order
to maintain glycaemic control)
Optimisation and intensification

function (%)
Beta-cell

Type 2
diabetes

Treatment optimisation and intensification

The progressive nature of type 2 diabetes and the associated gradual
reduction in beta-cell function necessitate constant optimisation and
intensification of the treatment regimen

OADs, oral antidiabetic drugs; UKPDS, UK Prospective Diabetes Study

Adapted from Lebovitz. Diabetes Rev 1999;7:139–53 (data are from the UKPDS population: UKPDS 16. Diabetes 1995;44:1249–58); Wright et al.
Diabetes Care 2002;25:330–6
The Physiological Requirement for Insulin
DWS 2011

Pancreatic output :
basal  prandial

• Basal insulin : the amount of insulin necessary to prevent fasting

gluconeogenesis (fasting hyperglycemia) and ketogenesis

• Prandial insulin : the amaount of insulin necessary to cover meals

without development of posprandial hyperglycemia
 Slide no 30

Type of Insulins
• Basal Insulin
• Prandrial Insulin
• Mixed Insulin (Basal + Prandrial)

Principle of Treatment
Mimicking physiological endogenous insulin secretion
 DWS 2011

Insulin and Glucose Pattern in Type 2

Diabetes: Basal vs Meal-time

Riddle MC. Diabetes Care 1990;13:676-686

 DWS 2011

Insulin and Glucose Patterns in Type 2 Diabetes:

Basal vs Mealtime

Basal Hyperglycemia Mealtime Hyperglycemia

Plasma glucose (mg/dL)

250

200

Type 2 diabetes
150

100
Normal
50

0 0600 1200 1800 2400 0600

Time of day

Riddle MC. Diabetes Care. 1990. 13:676-686; Riddle MC. Practical Cardiology
 Initiation and intensification in T2D:
summary of international guidelines
Guideline Initiation Intensification
ADA/EASD 2015 position • Basal • Add GLP-1RA
statement update1 • Basal-plus then basal−bolus
• Premix BID then basal−bolus
AACE2 • Basal • Add GLP-1RA or prandial insulin
• (Premix among other options)
IDF3 • Basal OD • Basal-plus or basal−bolus
• Premix OD/BID
Diabetes Australia4 • Basal OD • Basal-plus or basal−bolus
Premix OD • Premix BID or TID
Canadian Diabetes • Basal OD • Basal-plus or basal−bolus
Association5 • Premix OD/BID • Premix BID or TID
NICE6 • Basal OD/BID • Basal-plus or basal−bolus
• Premix OD/BID Premix
AACE, American Association of Clinical Endocrinologists; ADA, American Diabetes Association; BID, twice daily; EASD, European Association for the Study of
Diabetes; GLP-1RA, glucagon-like peptide-1 receptor agonist; IDF, International Diabetes Federation; NICE, UK National Institute for Health and Care Excellence;
OD, once daily; TID, three times daily; T2D, type 2 diabetes
1. Inzucchi et al. Diabetes Care 2015;38:140−9; 2. 6. Garber et al. Endocr Pract 2015;21:438–47 3.IDF Clinical Guidelines Task Force. Global Guideline for Type
2 Diabetes, 2012. www.idf.org/sites/default/files/IDF-Guideline-for-Type-2-Diabetes.pdf; 4. General practice management of type 2 diabetes, 2014–15.
Melbourne: The Royal Australian College of General Practitioners and Diabetes Australia. 2014. https://www.diabetesaustralia.com.au/best-practice-guidelines; 5.
Harper et al. Can J Diabetes 2013;37(Suppl. 1):S61–8 (Appendix 3); 6. NICE. The management of type 2 diabetes. NICE Clinical Guideline 87 (modified December
2014). www.nice.org.uk/guidance/cg87/chapter/1-recommendations#/glucose-control-insulin-therapy;
 Treatment Strategies Insulins

• Basal insulin: targets FPG > PPG

• Benefit: Only 1-2 injections per day

• Drawback: Patients may require prandial insulin to reach HbA1c targets

• Prandial (mealtime) insulin: targets PPG > FPG

• Benefit: Most physiologic; best at targeting PPG

• Drawback: Most injections; requires addition of basal insulin to target FPG

• Premixed insulin: targets both FPG and PPG

• Benefit: Fewer injections than prandial

• Drawback: Unable to adjust components separately

Lasserson DS, et al. Diabetologia. 2009;52(10):1990-2000.

Algoritme Pengelolaan DM Tipe 2 di Indonesia KONSENSUS PERKENI 2015
Modifikasi pola hidup sehat

HbA1c < 7.5% HbA1c ≥ 7.5% HbA1c ≥ 9.0%

Gejala (-) Gejala (+)
Monoterapi* dengan salah Kombinasi 2 obat* dengan Kombinasi 2 obat
satu obat di bawah ini mekanisme kerja yang berbeda
Insulin ± obat jenis lain
Kombinasi 3 obat
• Metformin • Agonis GLP-1
• Agonis GLP-1 Kombinasi 3 obat
• Agonis GLP-1 • Penghambat DPP-IV

Metformin atau obat lini pertama yang lain

Metformin atau obat lini pertama yang lain +
• Penghambat DPP-IV
• Penghambat DPP-IV • Tiazolidindion
• Tiazolidindion
• Penghambat Glukosidase • Penghambat SGLT-2

Obat lini kedua +

• Penghambat SGLT-2
Alfa • Insulin Basal
• Insulin Basal
• Penghambat SGLT-2** • SU/Glinid
• Kolsevelam**
Mulai atau intensifikasi

+
• Tiazolidindion • Kolsevelam**
• Bromokriptin-QR
• Sulfonilurea • Bromokriptin-QR
• Penghambat
Insulin
• Glinid • Penghambat
Glukosidase Alfa
Glukosidase Alfa
Keterangan
*Obat yang terdaftar, pemilihan dan
Jika HbAc1 > 6.4%
Jika belum memenuhi sasaran dalam penggunaannya disarankan mempertimbangkan
dalam 3 bulan tambahan Jika belum memenuhi sasaran
3 bulan, mulai terapi insulin atau faktor keuntungan, kerugian biaya, dan ketersediaan
obat ke 2 (kombinasi 2 dalam 3 bulan, masuk ke
intensifikasi terapi insulin sesuai tabel 11
obat) kombinasi 3 obat
** Kolsevelam belum tersedia di Indonesia
Bromokriptin QR umumnya digunakan pada terapi
tumor hipofisis
Konsensus Pengelolaan dan Pencegahan Diabetes Melitus Tipe 2 di Indonesia. 2015.
 Selecting an insulin T2D1,2

Guidelines state
• “One may commence insulin therapy with basal insulin, which has
a slightly lower risk of nocturnal hypoglycaemia, especially if the
FBG is consistently above target”

However,
• “Premixed insulin may be simpler for a patient in whom both
fasting and postprandial glucose are constantly elevated”

1. General practice management of type 2 diabetes: 2014–2015. Melbourne: The Royal Australian College of General Practitioners and Diabetes Australia, 2014;
2. Phillips. Aust Fam Physician 2006;35:975–8
 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

 Initiation and intensification: ADA/EASD
No. of
Basal insulin
injections (usually with metformin ± other noninsulin agent)
Complexity
Start: 10 U/day or 0.1–0.2 U/kg/day
1 Adjust: 10–15% or 2–4 U once-twice weekly to reach FBG Low
target
For hypo: determine & address cause;  dose by 4 U or 10–
STEP-Wise 20% If not controlled after FBG target is reached (or if dose
study >0.5 U/kg/day), treat PPG excursions with mealtime
insulin
(consider initial GLP-1RA trial)

Add 1 rapid insulin injection* before largest meal Change to premixed insulin* twice daily
Start: 4 U, 0.1 U/kg or 10% basal dose. If HbA1c <8%, Start: divide current basal dose into 2/3 AM, 1/3 PM or 1/2
consider  basal by same amount AM, 1/2 PM
2 Adjust:  dose by 1–2 U or 10–15% once to twice Adjust:  dose by 1–2 U or 10–15% once to twice weekly Mod
weekly until SMBG target reached until SMBG target reached
For hypo: determine and address cause;  For hypo: determine & address cause;  corresponding
corresponding dose by 2–4 U or 10–20% dose by 2–4 U or FullStep
10–20% study
Add ≥2 rapid insulin* injections before meals (“basal-bolus”)
Start: 4 U, 0.1 U/kg or 10% basal dose/meal. If HbA1c <8%, consider  basal
If not by same amount If not
controlled, Adjust:  dose by 1–2 U/10–15% once to twice weekly until SMBG target controlled,
consider reached consider
basal–bolus For hypo: determine & address cause;  corresponding dose by 2–4 U or 10– basal–bolus
20%
3+ High
Flexibility: More flexible Less flexible
*Regular human insulin and human NPH-regular premixed formulations prandial (70/30) are less costly alternatives to rapid-acting and premixed insulin
analogues, but their pharmacodynamic profiles make them suboptimal for coverage of post glucose excursions. ADA, American Diabetes Association; EASD,
European Association for the Study of Diabetes; FBG, fasting blood glucose; GLP-1RA, glucagon-like peptide-1 receptor agonist; HbA1c, glycated haemoglobin;
PPG, postprandial glucose; SMBG, self-monitoring of blood glucose
Inzucchi et al. Diabetes Care 2015;38:140–9.
ADA/EASD Position on Sequential Insulin
Strategy in Type 2 Diabetes
Non-Insulin
Number of Regimen
Regimes Injections Complexity

Basal Insulin Only

Usually with OAD 1 Low

Basal Insulin + 1 mealtime Pre-mixed Insulin twice-

2 Mod.
rapid-acting injection daily

Basal Insulin + >2 mealtime +3 High

rapid-acting injection

More Flexible Less Flexible Flexibility

Less Convenient More Convenient Convenience*

Inzucci SE, et al. Diabetologia. 2012. * Gumprecht et al. Intensification to to biphasic insulin aspart
30/70. Int J Clin Pract 2009
 No. of
Initiation and intensification: ADA/EASD
Basal insulin
injections (usually with metformin ± other noninsulin agent)
Complexity
Start: 10 U/day or 0.1–0.2 U/kg/day
1 Adjust: 10–15% or 2–4 U once-twice weekly to reach FBG Low
target
For hypo: determine & address cause;  dose by 4 U or 10–
STEP-Wise 20% If not controlled after FBG target is reached (or if dose
study >0.5 U/kg/day), treat PPG excursions with mealtime
insulin
(consider initial GLP-1RA trial)

Add 1 rapid insulin injection* before largest meal Change to premixed insulin* twice daily
Start: 4 U, 0.1 U/kg or 10% basal dose. If HbA1c <8%, Start: divide current basal dose into 2/3 AM, 1/3 PM or 1/2
consider  basal by same amount AM, 1/2 PM
2 Adjust:  dose by 1–2 U or 10–15% once to twice Mod
Adjust:  dose by 1–2 U or 10–15% once to twice weekly
weekly until SMBG target reached until SMBG target reached
For hypo: determine and address cause;  For hypo: determine & address cause;  corresponding
corresponding dose by 2–4 U or 10–20% dose by 2–4 U or FullStep
10–20% study
Add ≥2 rapid insulin* injections before meals (“basal-bolus”)
Start: 4 U, 0.1 U/kg or 10% basal dose/meal. If HbA1c <8%, consider  basal
If not by same amount If not
controlled, Adjust:  dose by 1–2 U/10–15% once to twice weekly until SMBG target controlled,
consider reached consider
basal–bolus For hypo: determine & address cause;  corresponding dose by 2–4 U or 10– basal–bolus
20%
3+ High
Flexibility: More flexible Less flexible
*Regular human insulin and human NPH-regular premixed formulations prandial (70/30) are less costly alternatives to rapid-acting and premixed insulin
analogues, but their pharmacodynamic profiles make them suboptimal for coverage of post glucose excursions. ADA, American Diabetes Association; EASD,
European Association for the Study of Diabetes; FBG, fasting blood glucose; GLP-1RA, glucagon-like peptide-1 receptor agonist; HbA1c, glycated haemoglobin;
PPG, postprandial glucose; SMBG, self-monitoring of blood glucose
Inzucchi et al. Diabetes Care 2015;38:140–9.
Premixed vs Basal Bolus
 Presentation title Date

Premixed insulin Therapy

• Premixed insulin is simple and • Less flexible (fixed dose

convenient for the patient due combination)
to one device can cover both • Difficult to adjust the dose
fasting and prandial glucose
• Less injection compare to
basal bolus
 Presentation title Date

Basal Bolus Therapy

• Physiologic (Ideal insulin • Less convenient for patient

therapy for patients) due to 4 times injection per
• More flexible (easy to titrate day
the dose)
Conclusion

• Because of the progessiveness of diabetes, Insulin regimen and dosage needs

to be monitored and intensified

• NovoMix® is option for the intensification, provide simple and convenience for
the patients

• Basal bolus therapy is an ideal treatment option since provide optimal A1C
control, but has a limitation with 4 times injection daily.
Thank You
Natural History of Type 2 Diabetes

Lifestyle modification
OHO ± Insulin Insulin

Years from diagnosis

Type 2 Diabetes is a complex and progressive disease requiring timely treatment escalation
 60

Type 2 diabetes is a progressive disease

Progression of Type 2 Diabetes

Insulin resistance

Hepatic glucose production

Insulin level

Beta-cell function

4–7 years Postprandial

glucose

Fasting plasma
glucose

Development of Microvascular Complications

Development of Macrovascular Complications

Impaired Glucose Tolerance Diabetes

Diabetes Diagnosis

Conceptual representation adapted from Ramlo-Halsted BA, Edelman SV. Prim Care 1999;26(4):771–789. © 1999 Elsevier