Initiation and intensification basal

Initiation and intensification basal

insulin therapy with prandial insulin
insulin therapy with prandial insulin

dr. Lalu Buly Fatrahady Utama Sp.PD

Speaker name

MAT-ID-2001073 – V 1.0 (01/2021)

MAT-ID-2001073 – V 1.0 (01/2021)
Case: 48-year-old Asian female
History of present illness
Known T2DM for 7 years
Complained of poor glycemic control, with
- HbA1C ~9–10% over the past year
- FPG ~180–230 mg/dL

Antidiabetic medications included:

- Glimepiride 4 mg/day
- Metformin 2000 mg/day

She had tried pioglitazone but discontinued it owing to excessive

weight gain and edema
Case: 48-year-old Asian female
Relevant past medical history, comorbidities
Hypertension and dyslipidemia for 3 years
Medication:
- Losartan
- Amlodipine
- Simvastatin

Found to have overt proteinuria for 1 year

Estimated glomerular filtration rate: 68 mL/min/1.73 m2

Family history:
Both parents had diabetes
 Case: 52-year-old Asian female
• Current findings
– BMI: 24 kg/m2 (BB 70 kg, TB 170cm)
– BP: 130/85 mmHg
– Fundi:
• Moderate, non-proliferative diabetic retinopathy
– Extremities:
• Decreased pinprick sensation over both feet
• Normal Ankle Brachial Index (ABI)

• Current laboratory results

– HbA1c: 10.4 %
– FPG: 230 mg/dL
– LDL-C: 84 mg/dL
 Question 1
• How would you manage this patient?

1. Increase dose of glimepiride

2. Add DPP-4 inhibitors

3. Add SGLT2 inhibitors

4. Begin insulin therapy

Answer Option 4
 Non-insulin anti-hyperglycemic agents for T2DM

HbA1C Hypo- Weight Dosing

Class glycemia Change (times/day) Other Safety Issues
Reduction

Metformin 1.5 No Neutral 2 GI, lactic acidosis

Sulfonylureas 1.5 Yes Gain 1 Secondary failure

Thiazolidinediones 0.5–1.4 No Gain 1 Edema, CHF, fractures

GLP-1 Receptor Agonists ~1.5 No Loss 1 GI, pancreatitis, ?MTC

DPP-4 inhibitors 0.6–0.8 No Neutral 1 Pancreatitis

SGLT-2 inhibitors 0.8-1.0 No Loss 1 GTI, DKA, AKI

Adapted from: Nathan DM, et al. Diabetes Care. 2007; 30(3):753–9. Nathan DM, et al. Diabetes Care. 2006; 29(8):1963–72. Nathan DM, et al.
Diabetes Care. 2009; 32(1):193–203. ADA. Diabetes Care. 2008; 31:S12–S54; Inzucchi SE Diabetes Care 2015;38:140–149.
Early T2D: OAD

Established T2D: OAD + Basal

Late T2D: Basal + Bolus

 Addressing Patient-Related Concerns Regarding Insulin
Patient concern about insulin
It means that I have failed to follow
diet
It means that I am really sick
It will restrict my lifestyle
I will gain weight
I could never give myself an injection
Discussion point
Your pancreas is failing, not you
Insulin is simply replacing what is
missing
We can tailor your insulin regimen to
fit into your life
We can use pens to make it more
convenient
If you start it early and continue to
work on your diet, you can take
insulin without weight gain
The needles are very small
Let's give you your first injection in
the office
 PEN SOLOSTAR

Available at https://www.lantus.com/get-to-know-the-lantus-solostar-pen, access on 5 Dec 2020

Physiologic Insulin Secretion
 Case continued…
• Patient was initiated with insulin glargine and
was able to further up-titrate the dose to 30
U/d without experiencing hypoglycemia
• Her FBG level at this stage was 144 mg/dL and
HbA1c = 8.1%
 Question 3
• What is the most appropriate next step of management?

1. Further up-titrate the dose of insulin glargine to reach a

target of FBG ~ 100 mg/dL

2. Continue the current dose of insulin

3. Add a prandial insulin before main meal

4. Add DPP-4 inhibitor

Answer Option 1
 Insulin glargine trials: Effective dose titration consistently
Baseline
reduces HbA1c to target Study endpoint
10

9.5
9 8.85 8.80 8.80 8.82
8.61 8.70 8.60

8
HbA1c (%)

7.18
7 7.14 7.15 7.14
6.96 7.00 6.80 6.96

Treat-To- LANMET2 APOLLO3 LAPTOP4 Triple INITIATE6 40097 INSIGHT8

Target1 Therapy5
n=367 n=61 n=204 n=177 n=104 n=58 n=624 n=206

1. Riddle M, et al. Diabetes Care 2003; 26:3080−6; 2. Yki-Järvinen H, et al. Diabetologia 2006; 49:442−51; 3. Bretzel RG, et al. Lancet 2008; 371:1073; 4. Janka H, et al.
Diabetes Care 2005; 28:254−9; 5. Rosenstock J, et al. Diabetes Care 2006; 29:554−9; 6. Yki-Jarvinen H, et al. Diabetes Care 2007; 30:1364–69; 7. Standl E. et al. Horm
Metab Res 2006; 38: 172–7; 8. Gerstein H, et al. Diabetic Medicine 2006; 23: 736–42.
 Insulin dosages using the treat-to-target method with insulin glargine
Units/day Units/kg/day 0.80
80
70 0.62
0.70
59
60 0.60
0.51
50 47.2 0.48 0.50
Units/day 0.41 42.38
Units/kg/day
40 38.1 0.40
30 0.30
20 0.20
10 0.10

T-T-T1 INSIGHT2 APOLLO3 INITIATE4

n=367 n=206 n=204 n=121

Mean daily requirement: 0.4 to 0.6 units/kg

1. Riddle M, et al. Diabetes Care 2003; 26:3080; 2. Gerstein HC, et al. Diabetes Med 2006; 23:736; 3. Bretzel
RG, et al. Lancet 2008; 371:1073. 4. Yki-Järvinen H, et al. Diabetes Care 2007; 30:1364.
 Dose optimization/ TITRATION in guidelines
Up-titration
• ADA 20201: increase dose by 2 U every 3 days to reach FPG target without
hypoglycemia
• IDF 20122:
• Self-titration regimen: insulin dose increases of 2 U every 3 days
• Physician led: biweekly or more frequent contact with a health-care professional
• AACE/ACE 20203:
• Fixed regimen: increase total daily dose of basal insulin by 2 U every 2–3 days
• Adjustable regimen
• Titrate insulin every 2–3 days according to:
• FBG>180 mg/dL: increase total daily dose by 20%
• FBG 140–180 mg/dL: increase total daily dose by 10%
• FBG 110–139 mg/dL: increase dose by 1 U
Down-titration: hypoglycemia
• ADA 20201: lower dose by 10-20%
• AACE/ACE 20203:
• BG<70 mg/dL: decrease total daily dose by 10–20%
• BG<40 mg/dL: decrease total daily dose by 20–40%

AACE, American Association of Clinical Endocrinologists; ACE, American College of Endocrinology; ADA, American Diabetes Association; BG, blood glucose EASD, European
Association for the Study of Diabetes; FBG, fasting blood glucose
1 American Diabetes Association. Diabetes Care 2020;43(Suppl. 1):S98–S110 | https://doi.org/10.2337/dc20-S009; 2. International Diabetes
Federation. Global Guideline for Type 2 Diabetes. 2012; Available at: http://www.idf.org/sites/default/files/IDF-Guideline-for-Type-2-Diabetes.pdf
(accessed October 2015); 3. Garber AJ, et al. Endocr Pract. 2020;26(No. 1): 107-139.
 Up-titration of insulin dose and effect on FPG in the
Treat-to-Target Trial

Insulin dose (U/day) Fasting plasma glucose (mg/dl)

50 43 44
41
206 39
40 36
37
33 200
31 Insulin dosage
30 28
175
25
21
153
20 16
142 150
135 135 FPG
10
128 125
10 121
118 117 116

0 100
0 2 4 6 8 10 12 14 16 18
Weeks
Mean insulin dose 0.45 u/kg

Riddle MC, et al. Diabetes Care 2003; 26:3080–86.

 • Insulin glargine therapy is well tolerated during up-titration and maintenance
PG-cut-off
(mg/dL): <70 <56 <70 <56 <36 <70 <56 <70 <56 <36 <70 <56 <70 <56 <36

7.0
6.0
Episodes per patient-year

5.0
4.1
3.9
4.0 3.6

3.0
2.0
1.4 1.3
1.1
1.0 0.5
0.7 0.6
0.2 0.3 0.3
0.0 0.0 0.0
0.0
Overall Nocturnal Severe Overall Nocturnal Severe Overall Nocturnal Severe

0–12 weeks1 12–24 weeks1 0–24 weeks2

(titration) (maintenance) (n=2837)
PG, plasma glucose

1. Owens DR, et al. Diabetes Res Clin Pract 2014; 106:264–74

2. DeVries H, et al. Endocrinol 2014; 10:23–30.

Rates of hypoglycemia with insulin glargine during titration and maintenance period
 Case continued…

After discussion with the patient, the insulin glargine dose was
further up titrated. The final insullin dose was 38 U/day, which
kept her fasting glucose level at around 110 mg/dL and HbA1c
7.2 g/dL

She did not experience hypoglycemia and satisfied with the

regimen

However after approximately 8 months after treatment, her

HbA1c gradually increased and this was despite following a strict
diet with regular exercises

Her fasting glucose level was still approximately 130 mg/dL

Early T2D: OAD
Established T2D: OAD + Basal

Late T2D: Basal + Bolus

 Question 4

• What is the most appropriate next step of management for

this patient?

1. Further up-titrate the dose of insulin glargine to reach a target

of FBG 70-100 mg/dL

2. Switch to a premixed insulin regimen

3. Add a prandial insulin before the main meal

4. Add a prandial insulin before each meal

Answer Option 3
PERKENI 2019 : approach to starting and adjusting insulin in type 2 diabetes
 Insulin glargine + insulin glulisine vs. premixed insulin in T2D: Improved
glycemic control (All-to-Target study)

• 588 insulin-naive T2D patients (baseline HbA1c 9.4 ± 1.6%) randomized to once-daily glargine + 0–1 glulisine (G+1,
n=194), glargine + 0–3 glulisine (G+3, n=194) or twice-daily premixed protamine-aspart/aspart (PM-2, n=194) for 60
weeks
HbA1c change over 60 weeks Proportion reaching HbA1c <7% over 60 weeks
Baseline 60 weeks
p=0.0309
*
p=0.025

10 9.3 9.4 50 49
*
9.4 45
9
39

Percentage with
8 7.2 7.1 40
7

HbA1c <7%
HbA1c (%)

7
6 30
5
4 20
3
2 10
1
0 0
Premixed Glargine + Glargine + Premixed Glargine + Glargine +
insulin 0–1 glulisine 0–3 glulisine insulin 0–1 glulisine 0–3 glulisine

Basal insulin plus a single prandial injection was as effective in improving glycemic control as premixed insulin. A greater
proportion of patients reached HbA 1c<7% with basal insulin plus a single prandial injection than premixed insulin.

*Absolute mean difference in HbA 1c change with G+1 and PM-2 = -0.34 (95% CI -0.82 to +0.15,
p=0.0359), non-inferiority confirmed.

Adapted from Riddle MC, et al. Diabetes Obes Metab. 2014; 16:396-402.
 ALL TO TARGET: Symptomatic hypoglycemia
* P < 0.05 vs. Premixed
15
Event-rates per person-yr

BG < 70 mg/dl BG < 50 mg/dl

10
* *
5

* *
0
Premixed Basal + Basal +
1 shot 0-3 shot

Basal + prandial Insulin had significantly less

hypoglycemia compared to premixed
Adapted from Riddle MC, et al. Diabetes Obes Metab. 2014; 16:396-402.
Insulin Glulisine has unique molecule structure and zinc-free formula. The unique molecular structure of
insulin Glulisine provides faster absorption and onset of action, plus stability without the need for zinc
 Insulin Glulisine has a faster onset of action vs.
insulin aspart in healthy volunteers
• Randomized, double-blind, cross-over, euglycemic clamp study comparing the PK/PD
profile of insulin glulisine vs. insulin aspart in 12 healthy volunteers

Variable Insulin glulisine Insulin aspart P-value

Mean (SD) or
median (range) - in AUC-GIR0–30 min (mg/kg) 30 (26) 16 (18) 0.0421
case of time GIRmax-t10% (min) 9 (2-23) 17 (3-20) 0.0146
parameters -
metabolic effects INSmax-t10% (min) 3 (0-15) 12 (1-15) 0.0005

AUC-GIR0-30 min = Area under the glucose infusion rate curve from 0 to 30 min after drug administration
GIRmax-t10% (min) = Time to 10% of the maximum glucose infusion rate
INSmax-t10% (min) = Time to 10% of the maximum observed insulin concentration

Insulin glulisine had a significantly higher early metabolic effect, an earlier

onset of action and a faster absorption compared with insulin aspart

Arnolds S, et al. Exp Clin Endocrinol Diabetes 2010;118:662-4.

 Flexibility Usage of Glulisine : postprandial vs prepandial
administration
multicenter, randomized, open-label trial conducted in USA, 345 patients, for a 52-week treatment period

premeal arm: insulin glulisine 3x/day ,0–15 min before 3 main meals + insulin glargine once daily ±metformin
postmeal arm: insulin glulisine 3x/day, 20 min after the start of ameal +insulin glargine once daily, ±metformin.

Postprandial glulisine administration provided similar glycaemic control and was non-inferior to preprandial
administration showing dosing flexibility and the feasibility of such approach when clinically indicated.
Ratner R, et al. Diabetes Obes Metab. 2011;13(12):1142-1148.
 Summary

• Basal insulin regimens are a simple and effective strategy for

glycemic control in T2DM patients who fail to control their diabetes
using oral agents
• Basal Insulin dose should be up-titrated to achieve a fasting
glucose target of  100 mg/dL
• If target fasting glucose has been reached but HbA1c is still above
target, a prandial insulin should be added
• Glargine and Glulisine are effective to improve glycemic control
• Healthcare professionals should evaluate patients who are planning
to fast and ensure that they understand the importance of glucose
monitoring throughout the fast and how to prevent hypoglycemia