Incretins based therapy :How Early

INCRETINS BASED THERAPY
HOW EARLY ?
MOHAMMAD O. DAOUD, MD
CONSULTANT ENDOCRINOLOGIST
KAMC –NGHA JEDDAH

AGENDA
Case oriented discussion
Combination Rx : Guidelines / Algorithms
Basal Insulin…what is next ?
DPP4 I / GLP1-RA Vs Bolus Insulin
Conclusion

CASE
A 51 year old male patient with type 2 DM diagnosed 6 years ago
Currently on Metformin 1 gm bd , Gliclazide MR 90 mg daily
Other Rx: ASA , Atorvastatin 40 mg , Lisinopril 10 mg
Excellent compliance to diet plan , activity and medication intake
Glucose monitoring is above target

What kind of monitoring would you like to know ?
Fasting , Pre-meals and @ Bed time
Vs
Fasting , Post-meals and @ Bed time

Post-prandial
hyperglycaemia
Post-prandial
hyperglycaemia
contributes HbA1c ~1%
B=breakfast; L=lunch; D=dinner.
Adapted from Riddle MC. Diabetes Care. 1990;13:676-686.
Plasmaglucose(mg/dL)
300
200
100
0
Time of day (h)
6 12 18 24 6
Uncontrolled Diabetes HbA1c 8.5%

B

L

D
Normal
HbA1c ~5%
Basal Hyperglycaemia Contributes More to Increased
HbA1c Levels Than Does Post-prandial Hyperglycaemia
Basal hyperglycaemia
contributes ~2%
Fasting
hyperglycaemia

Case # 1
With higher HbA1C :
Pre-meal glucose readings contribute more to
the HbA1C
With HbA1C closer to target ( ex: <8-8.5%)
Post-meal glucose readings contributes more to
the HbA1C value

Breakfast Lunch Dinner Bedtime
Before After Before After Before After
Day1 12.7 11.0 9.2 9.8
Day2 10.4 10 12.5 11.9
Day3 13.5 13.5 9.6 9.8
Day4 14.7 12.9 10.5
Day5 11.8 13 11.5 10.5
SMBG Record … your assessment ?

CASE
A 55 year old male patient with type 2 DM
On Metformin 1 gm bd , Gliclazide MR 90 mg daily
BP 128/78 , BMI 32 kg/m2
Labs:
HbA1c 9.7 %
Serum Cr 65 ( e-GFR 86 ml/minute )
Urinalysis : Hematuria ( > 2 urine samples: to Urology for evaluation )

CASE
BP 128/78 , BMI 32 kg/m2
Labs:
HbA1c 9.7 %
Urinalysis : Hematuria ( > 2 urine samples: to Urology for evaluation )
-What is next ?
-Patient wants to avoid injections !!

CASE
Labs :
HbA1c 9.7 % Serum Cr 65 ( e-GFR 86 ml/minute )
DPP4 inhibitor was added at full dose ( Sitagliptin 100 or Linagliptin 5mg …)
Wants to avoid injectable Rx.

Pioglitazone use and risk of bladder cancer:
population based cohort study
What this study adds
The use of Pioglitazone was associated with an overall
63% increased risk of bladder cancer, with the risk
increasing with increasing duration of use and dose
HR 1.63 (95% CI 1.22 to 2.19)
The use of Rosiglitazone was not
Likely to be a drug specific and not a class effect
Marco Tuccori,et al ; BMJ 2016; 352 doi:
http://dx.doi.org/10.1136/bmj.i1541
(Published 30 March 2016)Cite this as: BMJ 2016;352:i1541

Day1 11 11.0 9.2 9.8
Day2 10.4 10 10.3
Day3 9.5 11.2 10.6 10.5
Day4 11.9 10.8
Day5 11.0 13 11.5 9.5
SMBG on: MFN + SU + DPP4i 3 months later

CASE
A 51 year old male patient with type 2 DM ;
BMI 31kg/m2
On Metformin 1 gm bd , Gliclazide MR 90 mg daily & + DPP4 inhibitor
Labs 3 months late: HbA1c ( 9.7% to 9.1% )
So…3 oral agents at max doses … and still out of control ?

Type 2 DM
Medications Barriers
Efficacy Limits
Adverse Reaction
Hypoglycemia
Weight gain
GI side effects
PO / Injection / Frequency
Cost

Case
A 55 year old male patient with type 2 DM ;
BMI 32kg/m2
On Metformin 1 gm bd , Gliclazide MR 90 mg daily & + DPP4 inhibitor
Labs 3 months late: HbA1c ( 9.7% >>> 9.1% )
Does this patient need insulin?

ADA/EASD position statement 2015
DPP-4i, dipeptidyl peptidase-4 inhibitor; GLP-1RA, glucagon-like peptide-1 receptor agonist; SGLT-2i, sodium-glucose
co-transporter-2 inhibitor; SU, sulphonylurea; TZD, thiazolidinedione
Inzucchi et al. Diabetes Care 2015;38:140−149
Metformin + basal insulin + mealtime insulin or GLP-1RA
Healthy eating, weight control, increased physical activity
Not at target
HbA1c after
~3 months
Dual
therapy
Triple
therapy
Metformin
Combination
injectable
therapy
Monothera
py
Not at target
after 3 months:
combination
therapy
with insulin
TZD
DPP-4i
GLP-1RA
Insulin
SU
SU
TZD
Insulin
DPP-4i
GLP-1
RA
SU
TZD
Insulin
Insulin
TZD
DPP-4i
GLP-
1RA
Not at target
HbA1c after
~3 months
TZD
SU
DPP-4i
GLP-1RA
Insulin
Diseaseprogression
SU
TZD
DPP-4i
Insulin
SGLT-2i

Metformin + basal insulin + mealtime insulin or GLP-1RA
Not at target
HbA1c after
~3 months
Dual
therapy
Triple
therapy
Metformin
Combination
injectable
therapy
Monothera
py
Not at target
after 3 months:
combination
therapy
with insulin
DPP-4i
SU
SU
TZD
Insulin
DPP-
4i
GLP-1
RA
SU
TZD
Insulin
Insulin
TZD
DPP-4i
GLP-
1RA
Not at target
HbA1c after
~3 months
TZD
SU
DPP-4i
GLP-1RA
Insulin
Diseaseprogression
SU
TZD
DPP-4i
Insulin
SGLT-2i
HbA1c
9.7%
to
9.1%

Basal insulin
Not at target
HbA1c after
~3 months
Dual
therapy
Triple
therapy
Metformin
Combination
injectable
therapy
Monothera
py
Not at target
after 3 months:
combination
therapy
with insulin
DPP-4i
SU
SU
TZD
Insulin
DPP-
4i
GLP-1
RA
SU
TZD
Insulin
Insulin
TZD
DPP-4i
GLP-
1RA
Not at target
HbA1c after
~3 months
TZD
SU
DPP-4i
GLP-
1RA
Insulin
Diseaseprogression
SU
TZD
DPP-4i
Insulin
SGLT-2i

Case # 1
Basal insulin
Effective
Easy choice : single injection /Pen
(at bedtime)
“Breaks the Ice”

Basal Insulin: Pharmacokinetics
InsulinType Onset Peak Duration
Glargine 1-2 hrs ------- 24 hrs
Glargine -300 1-2 hrs ------- 24 hrs
Detemir 2-4 hrs ------- Up to 24 hrs
Degludec 30-90 mins ------- > 42 hrs
NPH 2 hrs 4-6 hrs 8-12 hrs

Case # Basal Insulin
 Example: body weight 0f 80 kg
16-24 units (0.2-0.3 u/kg) of
Glargine or Detemir added at Bedtime
Degludec ;flexible time
Or
Start a dose of 10 units
 Titrate every 2-3 days

SA- GLA-11-11-04
32
In T2DM ‘Fix fasting first’ –will lower the entire plasma
glucose through 24 hr
Adapted from Polonsky K. N Engl J Med 1988;318:1231–9 and Hirsch I, et al. Clin Diabetes 2005;23:78–86.
Theoretical simulation of diurnal blood glucose profile
Time of day (hours)
400
300
200
100
0
06:00 06:0010:00 14:00 18:00 22:00 02:00
Plasmaglucose(mg/dL)
Normal
Meal Meal Meal
20
15
10
5
0
Plasmaglucose(mmol/L)
Hyperglycaemia due to an increase in fasting glucose
T2DM

Day1 10 11.0 10.2 10
Day2 7.4 9.0 9.3
Day3 6.5 9.2 11.0 11
Day4 9.9 11.8
Day5 7.2 11 11.0 10.5
After add on Glargine /Detemir 24 units HS>> 40 u

SA- GLA-11-11-04
When Basal Insulin is “Not Enough”
• Step 1: Think first of titrating the basal insulin dose till reaching
FBG target (Often under-dosage) ; Max 0.5 units /kg
• Step 2: Shift to Basal Plus or Basal-bolus (MDI) regimen :
• Number of daily injections up to 4 (1+3)
• Inconvenience
• Risk of hypoglycemia & Weight gain
Or
Incretin-Based Rx

Basal insulin
Not at target
HbA1c after
~3 months
Dual
therapy
Triple
therapy
Metformin
Combination
injectable
therapy
Monothera
py
Not at target
after 3 months:
combination
therapy
with insulin
DPP-4i
SU
SU
TZD
Insulin
DPP-
4i
GLP-1
RA
SU
TZD
Insulin
Insulin
TZD
DPP-4i
GLP-
1RA
Not at target
HbA1c after
~3 months
TZD
SU
DPP-4i
GLP-
1RA
Insulin
Diseaseprogression
SU
TZD
DPP-4i
Insulin
SGLT-2i
HbA1c
9.1
to
8.0%

Basal insulin + Meal Related Insulin
Not at target
HbA1c after
~3 months
Dual
therapy
Triple
therapy
Metformin
Combination
injectable
therapy
Monothera
py
Not at target
after 3 months:
combination
therapy
with insulin
DPP-4i
SU
SU
TZD
Insulin
DPP-
4i
GLP-1
RA
SU
TZD
Insulin
Insulin
TZD
DPP-4i
GLP-
1RA
Not at target
HbA1c after
~3 months
TZD
SU
DPP-4i
GLP-
1RA
Insulin
Diseaseprogression
SU
TZD
DPP-4i
Insulin
SGLT-2i

Basal Insulin + GLP 1 RA
Not at target
HbA1c after
~3 months
Dual
therapy
Triple
therapy
Metformin
Combination
injectable
therapy
Monothera
py
Not at target
after 3 months:
combination
therapy
with insulin
SU
DPP-4i
GLP-
1RA
Insulin
SU
SU
TZD
Insulin
DPP-
4i
GLP-1
RA
SU
TZD
Insulin
Insulin
TZD
DPP-4i
GLP-
1RA
Not at target
HbA1c after
~3 months
TZD
SU
DPP-4i
GLP-
1RA
Insulin
Diseaseprogression
SU
TZD
DPP-4i
Insulin
SGLT-2i

Mechanism of action of GLP-1RAs and DPP-4
inhibitors
Food
Gut
Food-activated
GLP-1 response
The enzyme DPP-4
breaks down GLP-1
GLP-1RAs work like
natural GLP-1 and are
DPP-4-resistant
DPP-4
GLP-1R
Glucose-dependent insulin
secretion
Beta cell
DPP-4 inhibitors act to
block the DPP-4 enzyme

Additional physiological benefits are observed at pharmacological
levels of GLP-1
DPP-4is, dipeptidyl peptidase-4 inhibitors; GLP-1, glucagon-like peptide 1; GLP-1RAs, glucagon-like peptide 1 receptor agonists
Adapted from Holst et al.1
1. Holst JJ et al. Trends Mol Med 2008;14:161–168; 2. Flint A et al. Adv Ther 2011;28:213–226
 Gastric
emptying
Physiological
GLP-1 levels
Pharmacological
GLP-1 levels
GLP-1 effects
IncreasingplasmaGLP-1
concentrations
GLP-1RAs
DPP-4is
Insulin
 Glucagon
=  Plasma glucose2
 Appetite
 Food intake
= Weight loss2

The Incretin Therapy
Short Acting
– Exenatide bid
Lixisenatide OD
Long Acting:
Liraglutide
Exenatide LAR
Dulaglutide
Albiglutide
(Semaglutide)
 Incretin mimetics: GLP-1 receptor agonists
Stable peptide analogues of GLP-1
– Post-Prandial Glucose – Fasting Glucose

GLP-1RA vs. DPP-4 inhibitor: change in HbA1c
Data are LS mean. *p<0.0001 vs. sitagliptin; †p=0.01 vs. liraglutide 1.2 mg
Pratley et al. Int J Clin Pract 2011;65:397–407; Bergenstal et al. Lancet 2010;376:431–9
Baseline HbA1c:
LIRA–DPP-4i (52 weeks)
ChangeinHbA1c(%)
p<0.0001
p<0.0001
ADA target
(<7.0%)
27% 50%* 63%*†
DURATION-2 (26 weeks)
ChangeinHbA1c(%)
p<0.0001
Sitagliptin
100 mg OD
Exenatide
2 mg OW
Sitagliptin
100 mg OD
Liraglutide
1.2 mg OD
Liraglutide
1.8 mg OD
Baseline HbA1c: 8.5% 8.6% 8.5% 8.4% 8.4%
~30% ~58%*

GLP-1RA vs. DPP-4 inhibitor: change in body weight
Changeinbodyweight(kg)
p<0.0001
p<0.0001
Data are LS mean
Pratley et al. Int J Clin Pract 2011;65:397–407; Bergenstal et al. Lancet 2010;376:431–9
p=0.0002
Baseline
body weight: 87 kg 89 kg 93 kg 94 kg 95 kg
LIRA–DPP-4i (52 weeks)DURATION-2 (26 weeks)
Sitagliptin
100 mg OD
Exenatide
2 mg OW
Sitagliptin
100 mg OD
Liraglutide
1.2 mg OD
Liraglutide
1.8 mg OD

DURATION-2: safety and tolerability from Week 0 to
Week 26
Bergenstal et al. Lancet 2010;376;431–9; Bydureon. EMA: Summary of Product Characteristics. 2011;
available from: http://www.medicines.org.uk/emc/medicine/24665/SPC/ (accessed 2 November 2011)
0
5
10
15
20
25
30
35
40
Exenatide OW (100 mg) Sitagliptin (100 mg)
Adverseevents(%)
Nausea Diarrhoea Vomiting Injection site pruritis
• Incidence of minor hypoglycaemia was low and similar between
groups (1–3%)
• Nausea was predominantly mild

Switching from DPP-4 inhibitor to a GLP-1RA: change in
HbA1c
Data are LS mean. †Mean HbA1c at week 26 for all core study participants; *p<0.05 for change from switch
Pratley et al. Diabetes Care 2012;DOI:10.2337/dc11-2113; Wysham et al. Diabetic Medicine 2011;28:705–14
LIRA–DPP-4i
(Weeks 52–78)
ChangeinHbA1c(%)
p=0.006
p=0.0001
ADA target HbA1c
<7.0%
DURATION-2
(Weeks 26–52)
ChangeinHbA1c(%)
p=0.001
Week 26 HbA1c:
7.2% 7.6%
Week 52 HbA1c:
7.6%†
Sitalira 1.2 mg
Sitalira 1.8 mgSitaexenatide OW
50%*
30%30%
49%*
36%
53%*

Switching from a DPP-4 inhibitor to a GLP-1RA: change in body
weight
LIRA–DPP-4i
(Weeks 52–78)
p<0.0001
p<0.0001
p=0.0006
Week 26
body weight: 92.8 kg 91.6 kg
Week 52
body weight:
86 kg†
Sitalira 1.2 mg
Sitalira 1.8 mgSitaexenatide OW
Data are LS mean. †Mean body weight at week 26 for all core study participants
Pratley et al. Diabetes Care 2012;DOI:10.2337/dc11-2113; Wysham et al. Diabetic Medicine 2011;28:705–14
DURATION-2
(Weeks 26–52)

Basal Insulin- GLP-1RA
The Evidence
GLP-1RA, glucagon-like peptide-1 receptor agonist

52
4B Study:
Basal insulin glargine + exenatide B.i.d.
treatment or Basal insulin glargine + mealtime
Bolus insulin lispro treatment.
Michaela Diamant, Diabetes Care 2014;37:2763–2773

53
Study Design
Entry Criteria:
• T2DM HbA1c >7.0 to ≤10%
• IG + MET with or w/o SU*
• IG ≥20 IU/day
*SU, sulfonylurea discontinued upon study entry; MET, metformin
1. Yki-Jarvinen H, et al. Diabetes Care. 2007;30:1364-1369; 2. Rosenstock J, al. Diabetes Care. 2008;31:20-25.
Week
Basal Insulin Optimization (BIO)
Titrated Basal IG1
12-wk BIO Phase
0 30
30-wk Intervention Phase
Ex-BID 5mg Ex-BID 10mg
LisTID2
Titrated Basal IG1
+ MET continued throughout study
Randomization
-12-14
Screening

54
Titration of Basal Insulin Glargine Once Daily
( IG QD), Byetta and Prandial Lispro TID
Target fasting glucose <5.6 mmol/L (<100 mg/dL) with no hypoglycemia
BIO-phase: IG QD1
Lis TID2
Target pre-prandial glucose <6.1 mmol/L
(<109mg/dL) with no hypoglycemia
ExBID
Dose increased at wk 4 and tapered
thereafter if side-effects occurred
Target fasting glucose <5.6 mmol/L (<100 mg/dL) with no hypoglycemia
Intervention phase: IG QD1
ExBID+IG arm
IG decreased by ≥10% if HbA1c ≤8.0% &
at wk 4 with ExBID dose↑
LisTID+IG arm
½ up to ⅔ of IG daily dose maintained,
⅓- ½ divided into 3 pre-meal doses of Lis
At Randomization

55
Results: HbA1c at 30 Weeks
Values are LS Mean ± SE calculated using MMRM; *N’s for target achievement are patients with HbA1c values at 30 wk

56
Results: Fasting and Self-Measured Glucose
Per protocol population (N=510), Fasting glucose values are LS Mean ± SE; blood glucose values are Mean ± SE; *P<0.0001

57
Results: Mean Daily Insulin Doses
Per protocol population (N=510), Values are Mean ± SD

58
Results: Change in Body Weight

59
Results: Incidence of Hypoglycemia
Overall Rate per patient-year (Minor and Major): 2.1 (ExBID + IG) vs. 5.1 (LisTID + IG)
Conclusions:
Adding Exenatide to titrated Glargine with Metformin
resulted in similar glycemic control as add on Lispro insulin
GLP1- RA (Exenatide) is a safe, effective and well tolerated
non insulin Rx if Basal insulin fails

Compared with DPP-4 inhibitors, GLP-1 RA are associated with:
1-Greater HbA1c reduction and greater weight loss
2-Similar low risk of hypo-glycaemia but
an increased incidence of gastrointestinal events
Switching from a DPP-4 i to a GLP-1 RA was associated with:
1-Significant additional HbA1c reductions
2-Significant weight loss

Incretins based therapy ( DPP4 I and GLP1-RA) provides an
excellent combination with Insulin :Basal and MDI
GLP1-RA is an excellent effective alternative to
meal related insulin on top of basal insulin with:
-Equal postprandial efficacy
-Same or better HbA1c lowering and
-Same /lower risk of hypoglycemia
- Weight loss

GLP-1
1 .
2 .
3 .
SGLT2DPP4Metformin

Incretins based therapy :How Early

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