When SU and MF fails….

Basal is Better

Dr . Joe George
MD,DNB,DM (Endocrinology)
Consultant Endocrinologist
 Aim

To Show

Why basal insulin is the best option

in OAD failure

15 minutes
Why other options are inferior
What the current guidelines say?
Principles in selecting anti hyperglycemic agent.

1. Efficacy in lowering blood glucose

2. Non glycemic effects in preventing long term complications

3.Safety profile & tolerability

4.Ease of use

5. Cost of therapy
ADA/ EASD consensus statement

Diagnosis Step 2 Step 3

Well validated Intensify insulin

core therapy if already on
- Add SU basal.
Lifestyle - Basal Insulin
+
Metformin Less validated Add a third
therapy agent to current
- Pioglitazone treatment like
- GLP1 basal insulin
Initiation and adjustment of insulin regimens.

Start with NPH HS or

Glargine /Detimir
HS/morning

Uptitrate to control fasting

and adjust OHA

If FPG controlled & PPG elevated despite

titration, shift to multiple insulin regime
What about Indian Guideline ?
Why premix in India?

Cost of therapy

Ease of Use
Principles in selecting anti hyperglycemic agent.

1. Efficacy in lowering blood glucose

2. Non glycemic effects in preventing long term complications

3.Safety profile & tolerability

4.Ease of use

5.Expense
When SU and MF fails….

Dose of OHA Level of glycemia

When SU and MF fails…. Dose of OHA

Generic Name Recommended daily Optimum dose

dosage (Max)

Glimiperide 8 mg 4 mg

Glipizide (ER) 20 mg 10 mg

Glibenclamide 20 mg 10 mg

Repaglanide 16 mg 12 mg
When SU and MF fails…. Level of glycemia

ADA/EASD Guideline Indian Insulin Guideline

 Up-titrate if target glycemia not  Start insulin when

achieved
 FPG : 90-130
 PPG: <180  FPG> 150 mg/dl
 HbA1c: <7%  PPG > 200 mg/dl
 HbA1c: >8.5 %
 Natural History of T2DM

Obesity IGT* Diabetes Uncontrolled

Hyperglycemia
Post-Meal
Plasma Glucose
Glucose
Fasting Glucose
120 (mg/dL)

Relative
-Cell Insulin Resistance
Function
100 (%)
Insulin Secretion

-20 -10 0 10 20 30
Years of Diabetes
*IGT = impaired glucose
tolerance.
Adapted from International Diabetes Center (IDC), Minneapolis, Minnesota.
 Aim

To Show

Why basal insulin is the best option

in OAD failure

15 minutes
Why other options are inferior
Why not Glitazone?
 Troglitazone timeline

Officer removed
from FDA panel Liver failure
noticed
Troglitazone
study in NEJM FDA officer
points out Troglitazone
“breakthrough” Withdrawn
liver injury, approved
(fastest from UK, ADA
heart
Glitazones approval in 60 says unwarranted
problem in
identified years)
Applied for trials
approval

Apr Nov Jun Oct Nov Jan May Dec

82 94 96 96 96 97 97 97
 Troglitazone timeline
Article series Data shows
in LA times risk of liver
against drug. failure
Wins pulitzer 1200 times
NEJM prize
Endo society Rozi and Pio
publish pre Troglitazo endorses approved by
approval ne arm of continued FDA
data DPP
showing use of
stopped troglitazone
liver injury Mar
2000

Mar Jun Dec Mar Mar May

98 98 98 99 99 99

Troglitazone
withdrawn
 Roziglitazone timeline

Concern on CV GSK website

shows that drug FDA adds black
safety raised.
increases box warning
Forced to sign
agreement with ischemic events
Drug estimated to
GSK have caused
Meta analysis mortality of 1 lakh
FDA approve Report suggests of CV outcome in US
Rozy CCF with Rozi published Sep
10

May July Jan Sep May Oct

99 99 01 05 07 07

Withdrawn
by EU, US
restrict use
Pioglitazone timeline

• Fluid retention
• CHF
• Weight gain
• Bone fractures
• Bladder cancer
Key genes activated via stimulation of the PPAR – γ

↑↑Lipoprotein lipaseβ - cells)

GLUT - 2 (islet
↑ Fatty acid transporter
↓ 11 β - hydroxysteroid
protein (FATP/CD36)
dehydrogenase - 1
 ↑ Adipocyte fatty acid binding
 ↓ Resistin, ↓ RBP 4
protein (aP2)
↑↑Acyl
Adiponectin ( ↑ leptin ?)
- CoA synthetase
↑↓Malic
TNFenzyme
- α , ↓ IL - 6
↑↓Glycerol
CRP and some
kinase (inproinfl
ammatory?)cytokines, ↓ NF κ
adipocytes
 ↑BPEPCK (adipocytes), ↑
perilipin
↓ PAI - 1, ↓ MMP - 9
↑↑GLUT
UCP- -41(by
(?)derepression),
 Incretin therapy in Diabetes
GLP-1 concentration with GLP-1 analogue & DPP-4 inhibitor

GLP-1 levels after 7 days’ liraglutide GLP-1 levels after 28 days’ vildagliptin
6 µg/kg OD* (n=13) 100 mg BD (n=9)

120 120
Liraglutide dose
GLP-1 (pmol/L)

90 90

DPP-4 inhibitor
60 60 (vildagliptin)
dose

30 30

0 0
8 12 16 20 24 8 12 16 20 24
Time (h) Time (h)
*GLP-1 levels for liraglutide calculated as 1.5% free liraglutide

Degn et al. Diabetes 2004;53:1187–94. Mari et al. J Clin Endocrinol Metab 2005;90:4888–94
 Incretin
Insulin and glucagon therapy
dynamics in Diabetes
in response to meals in normal
subjects and Type 2 diabetes
20.0 Meal
Normal subects n=11;
18.3
Type 2 diabetes n=12
16.6
Glucose 15.0
(mmol/l) Type 2 diabetes
13.3
6.1 Normal subjects
4.4
120
Insulin 90
(mU/l) 60
Delayed/depressed
30
insulin response
0
140 Non-suppressed
130 glucagon
Glucagon 120
(ng/l) 110
100
90

-60 0 60 120 180 240 Time (min)

 Glucose-Dependent Effects of GLP-1 Infusion on Insulin
and Glucagon Levels in Patients With Type 2 Diabetes
15.0
250

mmol/L
12.5 Placebo
Glucose 200

mg/dL
10.0 GLP-1
7.5 150
5.0 100 *P<0.05
2.5 50 Patients with type 2
0 diabetes (N=10)
0

250 40
pmol/L

200
Insulin 30

mU/L
150
100 20
50 10
0 0

20 20
pmol/L

Glucagon 15 15

pmol/L
10 10
5 5
0 Infusion
0
–30 0 60 120 180 240
Minutes

Adapted from Nauck MA et al. Diabetologia. 1993;36:741–744. Copyright © 1993 Springer-Verlag.

 GLP-1 analogue timeline

Progessive renal
deterioration with
Exenatide exenatide
approval sometimes
‘Hemorrhagic/ requiring dialysis
necrotising & transplantation
Incretin
pancreatitis
defined Liraglutide
reported
launched

1930 Apr oct Apr

2010
05 07 09
 Liraglutide

Increases serum calcitonin level in 1%

:Risk of inducing thyroid C-cell tumors cannot be ruled out

Incidence of thyroid neoplasm : 0.5%

Produce Goitre : 0.8%

Thyroid adverse events

: 33.5 Vs 21 per 1000 patient years
:5.4 Vs 0.8 (serious adverse events)

Pancreatitis: risk present (says <0.2)

 DPP 4 Inhibitors
Glucose
dependent
 Insulin  Glucose
Ingestion of (GLP-1 and uptake by
food Pancreas GIP) peripheral
Release of tissues
active incretins β cells
GI tract GLP-1 and GIP α cells  Blood glucose in
fasting and
postprandial states

Sitagliptin
X DPP-4
enzyme
Glucose-
dependent
(DPP-4  Glucagon  Hepatic
inhibitor) (GLP-1) glucose
Inactive Inactive production
GLP-1 GIP

DPP-4 Is a Member of a
Family of Proline Specific Peptidases
 Function Unknown

DPP-6 PEP FAP DPP-9 DPP-8

FAP
DPP-4 Gene Family

Peptides degraded by DPP Gene

 Function Unknown

QPP Prolidase APP DPP-2

FAP
Other Proline Specific Peptidases

Peptides degraded by DPP Gene

Selectivity for the DPP-4 Enzyme

Upper Respiratory Infection

Enzyme Nasopharyngitis
IC50 (nM)
DPP-4 18

DPP-8
Hemorrhagic48,000
Necrotising pancreatitis
DPP-9 >100,000
Angioedema
DPP-2, DPP-7 >100,000

FAP >100,000
Exfoliative skin conditions
PEP >100,000

APP >100,000
Liver Injury

A/c Renal Failure requiring dialysis

(RFT monitoring )
UKPDS: Each % reduction in HbA1c gives …

Benefit

At what cost….

Does it outweigh the risk involved ?

Dont we have a safer alternative (insuli

UKPDS, Stratton et al.BMJ 2000;321;405-12

Epidemiological extrapolation showing benefit of a 1% reduction in mean HbA1c at 12 yrs
 Conclusion

When SU and MF fails….

BASAL IS BETTER

Thank You