Initiation insulin concept from

OAD uncontrolled in T2DM

Patiens
 Multiple defects contribute to the
Pathophysiology of T2DM : Egregious eleven

Schwartz SS et al. Diabetes Care 2016;39:179–186

 Algorithm of type 2 diabetes management
in Indonesia (Perkeni, 2019)
GOAL THERAPY : HbA1c <7% (Individualised)

HEALTHY LIFESTYLE MODIFICATION

Entry HbA1c Entry HbA1c Entry HbA1c
<7.5% >7.5%-9% >9%

MONOTHERAPY SYMPTOMS
DUAL THERAPY
Metformin (combination of 2 drugs NO YES
GLP-1 RA with different
mechanism)
If not at DUAL INSULIN
DPP-4i GLP-1 RA
goal in 3 TRIPLE THERAPY THERAPY ±
months,
Metformin or other first line drug

AG-i (combination of 3 drugs with Other

proceed
DPP-4i different mechanism) OR Agents
to DUAL
SGLT-2i THERAP If not at
Y TZD goal in 3 GLP-1 RA TRIPLE
Metformin or other first line drug

TZD months, THERAPY

SGLT-2i proceed to
DPP-4i
TRIPLE If not at
SU/GN
Second line drugs

THERAPY
Basal goal in 3
(combinatio TZD
Insulin n of 3 months,
proceed
drugs)
SGLT-2i ADD OR INTENSIFY
SU/GN to ADD
OR INSULIN
Basal Insulin INTENSIF
AG-i
Y Insulin
SU/GN Therapy

AG-i
 T2DM is a progressive disease

Lifestyle + OADs
β-cell function (%)

Basal insulin + OADs

Titrate dose to reach/maintain glycaemic targets

Basal and 1–3 injections of bolus or premix

Initiate
Intensify for mealtime insulin coverage

Optimise

Intensify

Treatment optimisation and intensification

OAD, oral antidiabetic drug

Schematic diagram adapted from Kahn. Diabetologia 2003;46:3–19

Inzucchi et al. Diabetologia 2012;55:1577–96
 Diabetes in Indonesia
DiabCare 2008
1832 subjects
Mean HbA1c 8,16%

IDMPS 2006-2007
674 subjects
Mean HbA1c 8,27%
HbA1c <7% : 34%

DiabCare 1998
1932 subjects
Mean HbA1c 8,1%
 J Diabetes Investig 2017; 8: 346–353

• Insulin was prescribed for just 20% of the patients during a 1-year follow-up
period, and less than half (44.5%) of the patients who were taking two OHAs
started insulin after 6 years.
• Patient-related factors for delay in insulin initiation included older age, shorter
duration of diabetes and lower HbA1c.
• Physician-related factors included age (~50 to <60 years), sex (women) and
number (<1000) of patients consulted per month.
• Patient refusal (33.6%) and physicians’ concerns of patient non-compliance
(26.5%) were the major physician-reported reasons for delaying insulin therapy.
 Initiation of basal insulin is often
delayed in Asia
• FINE Asia study 1

• T2DM patients were poorly controlled, with a diabetes

duration of 9.3 years and an HbA1c level of 9.8% at basal
insulin initiation in the FINE Asia study
• CREDIT study 2

• T2DM patients were also poorly controlled, with a

diabetes duration of 9 years and an HbA1c level of 9.2% at
insulin initiation in the CREDIT study
1. Tsai ST, et al. J Diabetes 2011;3:208–16;
2. Balkau B, et al. Diabetes Res Clin Pract 2015; 108:432–40;
3. Inzucchi SE, et al. Diabetes Care 2015;38:140–9.
CREDIT, Cardiovascular Risk Evaluation in people with Type 2 Diabetes on Insulin Therapy;
FINE, First Basal Insulin Evaluation; T2DM, type 2 diabetes mellitus
Initiation of basal insulin is often delayed
in Asia

• International guidelines recommend considering

initiation of basal insulin soon after the failure of
monotherapy;3 despite this, evidence suggests that
The average
insulin initiation time tooften
in Asia is initiation
delayed of insulin is
≥ 9 years1,2

3. Inzucchi SE, et al. Diabetes Care 2015;38:140–9.

 Early intervention with basal insulin maintains glycemic
control in the long term
Clinical inertia
OAD OAD
OAD monotherapy OAD OAD + multiple daily
Diet
Intervention! monotherapy uptitration combination + basal insulin insulin injections
Intervention!
10 Basal insulin

9 Intervention!
HbA1c (%)

Intervention!
8
Intervention!

Duration of diabetes (years)

OAD, oral antidiabetic drug; Del Prato S, et al. Int J Clin Pract 2005;59:1345–55.
 ADA/EASD position statement 2015

ADA/EASD  HbA1c (<7%) is not achieved

“within 3 months of monotherapy with
metformin + lifestyle modif.  consider
“two-drug combination”
Among the different options for dual therapy
with metformin, the guidelines state that
basal insulin is of the “highest efficacy”

ADA, American Diabetes Association; Inzucchi SE, et al. Diabetes Care 2015;38:140–9.
EASD, European Association for the Study of Diabetes
 Insulin glargine is an extensively
studied basal insulin used for diabetes
treatment
Indication: Insulin glargine (Lantus) is a long-
acting insulin analog to improve glycemic control
in T1DM and in adults T2DM.
Insulin glargine can be administered at any time
of the day but should be administered once a
day at the same time every day1
Insulin glargine offers flexible dose adjustments to
meet individual patients’ needs2,3
1. Sanofi. LANTUS® (Insulin Glargine) Prescribing Information. USA, 2015;
2. Strange P. J Diabetes Sci Technol 2007;1;540–8;
T2DM, type 2 diabetes mellitus 3. Barnett A. Clin Ther 2007;29:987–99.
 Outcomes from treat-to-target
studies with basal insulin (insulin
glargine)
• HbA1c<7% can often be attained1–3
• Basal insulin is well tolerated
• Nocturnal hypoglycemia is reduced1
• Rates of daytime hypoglycemia are low1
• Severe hypoglycemia is infrequent1,4
• Treatment with basal insulin before HbA1c reaches
>8% increases the chance of achieving glycemic
control1,2 1. Riddle MC, et al. Diabetes Care 2003;26:3080–6;
2. Banerji MA, et al. Postgrad Med 2014;126:111–25;
3. Gerstein HC, et al. Diabet Med 2006;23:736–42;
4. Yki-Järvinen H, et al. Diabetes Care 2007;30:1364–9.
Insulin Basal: Initiation
 Why does Insulin basal?
Most insulin is
initiated when
HbA1c >8.5%

100

% contribution to HbA1c
PPG
30% FPG
80 45% 40%
50%
70%
60

40
70%
55% 60%
50%
20
30%
0
8.5–9.2 9.3–10.2<7.3 7.3–8.4 >10.2
HbA1c range (%)
Adapted from Monnier et al. Diabetes Care 2003;26:881–5.

400
20
300 T2DM

Plasma glucose
Plasma glucose

15

(mmol/l)
(mg/dl)

200 Hyperglycaemia due to an increase in fasting glucose

10

100 5
Normal
Meal Meal Meal
0 0
6 10 14 18 22 2 6
Time of day (hours)

Comparison of 24-hour glucose levels in control subjects versus patients with diabetes (p<0.001).
Adapted from Polonsky K, et al. N Engl J Med 1988;318:1231―1239.
Copyright © 2007 Massachusetts Medical Society. All rights reserved.
ADA, 2019 AACE/ACE, 2018
 A1c Attained After Initiating Titrated
Insulin Glargine
Baseline Study end
9.5
9.0 8.7 8.8 8.7
8.6 8.6
8.5
∆ -1.6 ∆ -1.6 ∆ -1.7 ∆ -2.0 ∆ -1.7
A1c (%)

8.0
7.5
7.0 7.0 7.0 6.8 7.0
7.0
6.5
6.0
5.5
T-T-T1 INSIGHT2 APOLLO3 INITIATE4 Observational5
n = 367 n = 206 n = 174 n = 58 n = 11,511

Typically ~50% of people attain <7%.

1. Riddle MC, et al. Diabetes Care 2003;26:3080-3086.
2.
3.
Gerstein HC, et al. Diabetes Med 2006;23:736-742.
Bretzel RG, et al. Lancet 2008;371:10731084.
Similar results are obtained
4. Yki-Järvinen H, et al. Diabetes Care 2007;30:1364-1369. with insulin detemir.
5. Schreiber SA, Haak T. Diabetes Obes Metab 2007;9:31-38.
 Baseline A1c Predicts Attainment of 7%
A1c After Initiation of Glargine
2193 people with type 2 diabetes after 24 weeks of systematically
titrated glargine added to 1 or 2 oral agents.

Percentage of patients attaining A1c <7%

80 75
70
60 56
% of ppts

50
40 34
30
20
10
0
<8 8 - 8.4 8.5 - 8.9 9 - 9.4 ≥9.5

75% attain target A1c when baseline <8.0%.

Riddle MC, et al. Diab Obes Metab 2013;15:819-825.
 ORIGIN: insulin provides long-term near-normal
glycemic control

HbA1c, %
Patients on insulin glargine
ORIGIN study 7.0 achieved
• Investigated patients with IGT, IFG or and maintained low HbA1c
early T2DM at high CV risk†
6.5 6.5 6.5
• N=12,537 6.5 6.4 6.4 6.4
6.3
• Randomized to insulin glargine (with a 6.4 6.2
6.3
target FPG ≤95 mg/dL [5.3 mmol/L]) vs 6.2 6.2
standard care 6.0 6.1
6.0 6.0
• Median follow-up of 6.2 years 5.9
Gla
Standard care
5.5
0 1 2 3 4 5 6 7
Years
• When used to target normal FPG levels for more than 6 years, insulin glargine had a neutral
effect on the primary CV endpoints and cancers vs standard care*
• Rates of severe hypoglycemia were 1.00 versus 0.31 per 100 person-years
• Median weight increased by 1.6 kg in the insulin glargine group and fell by 0.5 kg in the
standard-care group
CV, cardiovascular; FPG, fasting plasma glucose; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; ORIGIN, Outcome Reduction with an Initial Glargine
Intervention; T2DM, type 2 diabetes mellitus
* Coprimary outcomes were nonfatal myocardial infarction, nonfatal stroke, or death from CV causes, and these events plus revascularization or hospitalization for heart
failure
†
The enrolled population in ORIGIN is broader than the population indicated for Lantus®
ORIGIN Investigators. N Engl J Med. 2012;367:319–28.
 Conclusion
• The decision to start the T2DM patient on insulin is usually
precipitated by worsening symptoms of hyperglycaemia and a
persistently elevated HbA1c level despite maximal or near
maximal doses of oral glucose lowering agents and / or GLP-1
receptor agonist.
• Treating diabetes with insulin means trying to mimic normal
physiology.
• Insulin treatment must be evaluated because the current study
shows that there is a delay in insulin initiation in people with
type 2 diabetes.
• Starting insulin therapy with basal insulin will achieve optimal
FPG and reduction the HbA1c.