1. Developments in the Treatment of T2DM
Dr John Clark

2. Diabetes Prevalence 1 million 2 million 3 million 1995 2000 2013
1 million
2 million
3 million
1995
2000
2013
Type 1
Type 2

3. Audit of West Suffolk Hospital In-Patients
One day (23/9/12)
440 in-patients, in total, in WSH that day
75 known to have Diabetes
17% of in-patients are Diabetic (1 in 6)

4. Glycaemic Control Drugs to use (prior to 2010)
Drug of choice Metformin
Next Stage Metformin + Sulphonylurea or
Metformin + Pioglitazone
Next Stage Metformin + Pioglitazone + SU
Final Stage Metformin + basal insulin

5. New Developments The incretin effect and GLP-1
Treatments A) DPP-4 Inhibitors
Treatments B) GLP-1 Agonists

6. Plasma glucose (mmol/L)
UK/LR/0809/0384
Date of preparation: August 2009
The Incretin Effect
Plasma glucose
Insulin response
Insulin (mU/L) 80 60 40 20
–10 –5
120
180
Time (min)
Incretin effect 15 10
Plasma glucose (mmol/L) 5
–10 –5 60
120
180
Time (min)
The incretin hormones play a crucial role in a healthy insulin response
The effect of incretins on insulin secretion is clearly indicated in this study. Healthy volunteers (n=8) fasted overnight before they received an oral glucose load of 50 g/400 mL or an isoglycaemic intravenous glucose infusion for 180 minutes. As can be seen in the left figure, venous plasma glucose concentration was similar with both glucose interventions. However, insulin concentration was greater following oral glucose ingestion than following intravenous glucose infusion, demonstrating the contribution of incretins on insulin secretion.
Reference
Nauck et al. Diabetologia 1986;29:46–52.
Oral glucose load (50 g)
iv. glucose infusion
Insulin response is greater following oral glucose than i.v. glucose, despite similar plasma glucose concentration
Healthy volunteers (n=8); i.v.: intravenous Nauck et al. Diabetologia 1986;29:46–52 6

7. The Incretin Effect is Reduced in Subjects with Type 2 Diabetes
The Incretin Effect accounts for ~ 60% of total Insulin release following a meal 20 40 60 80
Insulin (mU/L) 30 90
120
150
180 *
Control subjects 20 40 60 80 30 90
120
150
180
Time (min) *
Subjects with type 2 diabetes
Insulin (mU/L)
DISCUSSION
The β-cell secretory response to glucose ingestion, as measured by increases in plasma insulin, was reduced in patients with type 2 diabetes.
Patients with type 2 diabetes exhibited a greater β-cell secretory response than control subjects, as indicated by higher insulin secretion levels, during the 180-minute course of intravenous glucose infusion.
BACKGROUND
Differences in insulin response to oral and intravenous glucose administration, which are attributed to factors other than glucose itself, describe the incretin effect; the incretin effect appears to be reduced in patients with type 2 diabetes. Measured insulin and C-peptide responses to a 50 g oral glucose load and an isoglycaemic intravenous infusion. Additionally, an attempt was made to correlate incretin effects to GIP responses.
Insulin measurements are shown here.
Plasma insulin responses were studied for 14 patients with type 2 diabetes in this study and 8 metabolically healthy control subjects.
Nauck MA, et al. Diabetologia 1986;29:46–52
Time (min)
Intravenous Glucose
Oral Glucose
Nauck MA, et al. Diabetologia 1986;29:46–52.
*P ≤.05 compared with respective value after oral load. 7

8. Studies of the entero-insular axis following pancreas transplantation in man: neural or hormonal control? Clark JDA, Wheatley T, Brons IG, Bloom SR, Calne RY. Department of Medicine and Surgery, Addenbrooke's Hospital, Cambridge, UK. Diabetic Medicine Dec,6,
To study the role of hormonal and neural factors in the control of the entero-insular axis, the responses to oral and intravenous glucose were investigated in 5 patients who had received a combined kidney and paratopic pancreas transplant
As the incretin effect was preserved, despite a denervated pancreas, hormonal rather than neural factors may be more important in mediating increased insulin secretion after oral carbohydrate. The normal GIP response is compatible with its proposed role as an insulinotropic hormone.

9. Incretin Effect
Larger insulin response to oral rather than IV glucose. Why?
Oral glucose stimulates release of GLP-1 from small intestine
GLP-1 augments insulin release from B cells of pancreas

10. What is glucagon-like peptide-1 (GLP-1)?
UK/LR/0809/0384
Date of preparation: August 2009
What is glucagon-like peptide-1 (GLP-1)?
A 31 amino acid peptide
Cleaved from proglucagon in L-cells in the GI tract
Secreted in response
to meal ingestion
Lys
His
Ala
Thr
Ser
Phe
Glu
Gly
Asp
Val
Tyr
Leu
Gln
Ile
Trp
Arg
What is glucagon-like peptide-1?
Glucagon-like peptide-1 (GLP-1) is a 31 amino acid peptide. It is an incretin hormone that is secreted from L-cells in the gastrointestinal system in response to calorie intake, causing the glucose-dependent secretion of insulin. Incretins are chemical excitants that promote pancreatic sections (glucose-dependent insulinotropic polypeptide [GIP] is another example).
Reference
Drucker and Nauck. Lancet 2006;368:1696–705.
GI: gastrointestinal Drucker & Nauck. Lancet 2006;368:1696–705

11. GLP-1: Effects in Humans
GLP-1 secreted upon the ingestion of food
Promotes satiety and reduces appetite
b-cells: Enhances glucose-dependent insulin secretion
Stomach: Helps regulate gastric emptying
GLP-1: Glucagon-like peptide 1
Adapted from Flint A, et al. J Clin Invest. 1998;101: ; Adapted from Larsson H, et al. Acta Physiol Scand. 1997;160: ; Adapted from Nauck MA, et al. Diabetologia. 1996;39: ; Adapted from Drucker DJ. Diabetes. 1998;47:

12. Native GLP-1 is rapidly degraded by DPP-4 (Di-Peptidyl Peptidase-4)
UK/LR/0809/0384
Date of preparation: August 2009
Native GLP-1 is rapidly degraded by DPP-4 (Di-Peptidyl Peptidase-4)
Human ileum,
GLP-1-producing
L-cells
Capillaries,
DPP-4
Native GLP-1 is rapidly degraded by DPP-4
GLP-1 is stored in intestinal L-cells. As active GLP-1 is secreted from these cells, it is rapidly degraded by the enzyme dipeptidyl peptidase 4 (DPP-4) resulting in the inactive, N-terminally truncated form, GLP-1-(9–36) amide. More than 50% of plasma GLP-1 appears to be in this inactive form.
In this slide, immunohistochemical staining shows the very close proximity of active GLP-1 in the L-cells and DPP-4 in the capillaries within the human ileum.
Reference
Hansen et al. Endocrinology 1999;140:5356–63.
Double immunohistochemical staining for DPP-4 (red) and GLP-1 (green) in the human ileum
Hansen et al. Endocrinology 1999;140:5356–63 12

13. The family of incretin-based therapies
UK/LR/0809/0384
Date of preparation: August 2009
The family of incretin-based therapies
Incretin-based
therapies
DPP-4 inhibitors, sitagliptin vildagliptin saxagliptin
linagliptin
GLP-1 receptor agonists
The family of incretin-based therapies
Incretin-based therapies can be broadly divided into:
DPP-4 inhibitors (i.e., sitagliptin, vildagliptin, saxagliptin)
GLP-1 receptor agonists (exenatide, liraglutide)
Within this second category however, the GLP-1 receptor agonists can be classed as either:
Exendin-based therapies (exenatide, exenatide LAR) which have ~50% sequence identity to human GLP-1
Human GLP-1 analogues (liraglutide) which have share a much higher percentage of amino acids with human GLP-1 (97%)
Exendin-based
therapies, exenatide + lixisenatide
Human GLP-1
analogues, liraglutide 13

14. DPP-4 Inhibitors (Gliptins)
Oral
Weight neutral
Minimal hypoglycaemia
NICE – must lower HbA1c by 0.5% within 6/12

15. Mr K S age 65 Type 2 Diabetes for 10 years
Gradual increase in OHA dosage
June 2010 HbA1c 7.8%
Metformin 500mg bd + glipizide 10mg bd

16. Mr K S June 2010 - Add in Sitagliptin 100 mg od
October HbA1c 7.4%
Glipizide reduced to 2.5 mg am, 5 mg pm.

18. Do Exenatide/Liraglutide/Lixisenatide Work?

19. Exenatide vs. Insulin Glargine Reductions in HbA1c
0.0 60
48% 50
46%
-0.5 40
DISCUSSION
HbA1c was significantly reduced from baseline at Week 26 in both treatment arms.
A similar percentage of patients (46% of patients in the exenatide group and 48% of patients in the insulin glargine group) reached an HbA1c goal of <7% for each treatment arm.
BACKGROUND
This randomized, open-label, Phase 3 clinical trial compared the effects of exenatide and insulin glargine on glycaemic control in patients with type 2 diabetes not achieving adequate glycaemic control with combination MET and SFU therapy at maximally effective doses.
Glycaemic control was defined as a reduction in HbA1c level.
Patients were randomized to two study arms. One arm received exenatide 5 µg BID for 4 weeks; the dose was increased to 10 µg twice daily for the remainder of the study.
A second arm received insulin glargine at an initial dose of 10 Units/day (U/d), then in self-titrated doses using a fixed-dose algorithm to achieve a fasting blood glucose target level of <100 mg/dL (5.6 mmol/L) on daily glucose monitoring.
Patients were 30 to 75 years of age and treated with stable and maximally effective doses of MET and SFU for at least 3 months prior to screening.
General inclusion criteria included a screening HbA1c of 7.0% to 10.0% and a BMI >25 kg/m2 and <45 kg/m2.
The proportion of patients achieving HbA1c <7% was a secondary endpoint.
32%
% Change in HbA1c
% Patients Achieving
HbA1c targets 30
25%
-1.0 20
-1.1%
-1.1% 10
-1.5
HbA1c <7%
HbA1c <6.5%
Exenatide
(n=275)
Insulin glargine
(n=260)
ITT population; Mean ± SE shown.
Heine RJ et al. Ann Intern Med. 2005;143:

20. Exenatide vs. Insulin Glargine Change in Body Weight2
+1.8 kg 1
4.1 kg
Change in body weight (kg) -1 * * * -2 *
-2.3 kg * -3 *
DISCUSSION
Insulin glargine patients gained weight throughout the trial period, while exenatide was associated with progressive reductions in weight.
Mean body weight was significantly different between the two treatments at 2 weeks, and this difference persisted throughout the study.
Adjusted mean change in body weight at endpoint was -2.3 kg for exenatide, +1.8 kg for insulin glargine.
Mean difference (exenatide–insulin glargine) was -4.1 kg, 95% CI for the difference -4.6 to -3.5 kg.
Baseline body weights were exenatide: 87.5 ± 16.9 kg and insulin glargine: 88.3 ± 17.9 kg.
STUDY BACKGROUND
Multi-centre, randomised, open-label phase III clinical trial comparing the effects of exenatide and insulin glargine on glycaemic control over 26 weeks, as measured by reduction in HbA1c, in patients with type 2 diabetes achieving inadequate glycaemic control using combination metformin and sulphonylurea therapy at maximally effective doses. 2 4 8 12 18 26
Time (weeks)
Exenatide (n = 275)
Insulin glargine (n = 260)

21. HbA1c and weight loss: from LEAD trials 1–6
Weight gain
HbA1c decrease
HbA1c increase
% patients 21

22. HbA1c and weight change: sulphonylurea
HbA1c decrease
LEAD-2. ITT, LOCF. n=232
Glimepiride 4 mg
Weight gain
51%
12%
HbA1c increase
Weight loss
32% 5%
Data on file Composite Endpoint,
Novo Nordisk 22

23. HbA1c and weight change: thiazolidinedione
HbA1c decrease
LEAD-1. ITT, LOCF. n=224
Pioglitazone
Weight gain
10%
15%
49%
26%
HbA1c increase
Weight loss
ITT, intention-to-treat; LOCF, last observation carried forward
Data on file, Composite Endpoint, Novo Nordisk 23

24. HbA1c and weight change: glargine
HbA1c decrease
LEAD-5. ITT, LOCF. n=224
Glargine 24 IU
Weight gain
63%
10%
HbA1c increase
Weight loss
25% 2%
Data on file Composite Endpoint, Novo Nordisk 24

25. HbA1c and weight change: exenatide
HbA1c decrease
LEAD-6. ITT, LOCF. n=196
Exenatide 10 μg BD
Weight gain
14% 5%
HbA1c increase
72%
Weight loss 9%
Data on file Composite Endpoint, Novo Nordisk 25

26. HbA1c and weight change: liraglutide 1.2 mg
LEAD-2. ITT, LOCF. n=231
Liraglutide 1.2 mg
Weight gain
10% 4%
HbA1c decrease
HbA1c increase
72%
Weight loss
13%
Data on file Composite Endpoint,
Novo Nordisk 26

27. Comparison : shifting the paradigm
Weight gain
HbA1c decrease
HbA1c increase
Pioglitazone
15%
Weight loss
25%
Glargine 24 IU
32%
Glimepiride 4 mg
72%
72%
Exenatide 10 μg BID
Liraglutide 1.2 mg
72%
Lixisenatide 20ug od
Data on file Composite Endpoint, Novo Nordisk 27

28. Diabetes Clinic (1/9/10) Weight HbA1c Exenatide
NJ – 92kg – year
JH – 96kg – months
NT 123 – 112kg – months

29. NICE Guidance 2010 (must satisfy all criteria)
HbA1c > 7.5%
Already on OHAs
Weight related health problems
BMI > 35
By 6 months must achieve both targets
weight loss of 3%
drop in HbA1c of 1%

30. 312 patients initiated on Exenatide since May 2008
WSH Audit 2011
312 patients initiated on Exenatide since May 2008
207 patients completed 6 months treatment by December 2010
31 months 30

31. WSH Outcome Data: Passed v Failed @ 6 months
(184)
HbA1c
Weight (Kg)
BMI
Baseline
9.6
SD 1.5
(7.4 to 14.0)
119.8
SD 20.9
(75.2 to 185.6)
41.5
SD 7.2
(26.0 to 84.8)
Change at 6/12
-1.6
SD 1.6
(-7.1 to +3.5)
-6.8
SD 5.4
(-25.6 to +5.6)
-2.4
SD 1.9
(-9.3 to +1.9)
P value
P < 00001
P <
6/12
(23)
9.3
(6.2 to 12.9)
126.4
(80.2 to 183.7)
SD 25.1
43.2
(33.8 to 59.1)
SD 7.9
-0.3
(-5.4 to +3.3)
-6.2
(-16.7 to +1.3)
SD 5.1
-2.1
(-5.0 to +0.4)
SD 1.7
P = 0.35
P =
P value (pass v non-pass)
P =
P = 0.57
P = 0.50

32. WSH Data: Exenatide success @ 6/12 Insulin v Non-Insulin Group
Total on Insulin (86)
HbA1c
Weight (Kg)
BMI
P value
Baseline
9.5
SD 1.3
(8.2 to 10.8)
118.7
SD 17.9
(100.8 to 136.6)
41.7
SD 6.2
(35.5 to 37.9)
Change at 6/12
-1.6
SD 1.4
(-3.0 to -0.2)
-7.3 (6.2%)
SD 5.2
(-12.5 to -2.1)
-2.6
SD 1.9
(-4.5 to -0.7)
P <0.0001
Non-insulin (98)
9.7
SD 1.6
(8.1 to 11.3)
120.8
SD 23.2
(97.6 to 144.0)
41.3
SD 8.0
(33.3 to 49.3)
Change at 6/12
SD 1.7
(-3.3 to 0.1)
-6.5 (5.4%)
SD 5.5
(-12.0 to -1.0)
-2.2
(-4.1 to -0.3)
p <
P = 0.83
P = 0.32
P = 0.23
Non insulin: HbA1c reduction 5.4% (5.7 to range) SD 4.6
Wt reduction 5.4% (5.7 to range) SD 4.5
Insulin: HbA1c reduction 6.2% (3.5 to range) SD 4.5
Wt reduction 6.2% (3.5 to range) SD 4.5 32

34. New Drug - Dapagliflozin
Blocks reabsorption of glucose in kidneys
Increased urinary glucose loss
Oral medication 5-10mg once daily

35. Dapagliflozin Benefits
HbA1c drops by %
Weight loss of 2-3 kg over 6 months
Low risk of hypos (not reliant on insulin)
Additive effect when combined with other diabetic treatments, including insulin.

36. Dapagliflozin Side-effects
Urinary tract infection
Polyuria
Genital fungal infection

37. Bariatric Surgery 30 Kg weight loss 50% achieve HbA1c < 6.5%
High rate of remission of diabetes
But no long term studies

38. Summary of Targets HbA1c < 7.5 % (Metformin)
BP 140 / 80 or less (ACE-I or ARB)
Cholesterol < (Statin)

39. Glycaemic Control Drugs to use
Drug of choice Metformin
Next Stage Metformin with Sulphonylurea
or Pioglitazone
or Sita/Vilda/Saxa/Lina

40. Glycaemic Control Drugs to use
Next Stage Metformin with GLP-1 injection
Final Stage Metformin with basal Insulin
Consider Dapagliflozin
Last resort Bariatric surgery

41. Glycaemic Control Drugs to use
Drug of choice Metformin
Next Stage Metformin with Sulphonylurea
or Pioglitazone
or Sita/Vilda/Saxa/Linagliptin
Next Stage Metformin with Exenatide/Liraglutide/Lixisenatide
Final Stage Metformin with basal Insulin
Consider Dapagliflozin
Last resort Bariatric surgery

42. WSH COST DATA Exenatide Success @ 6/12 Insulin v Non-Insulin Group
Extra Cost for Exenatide
(per person , per month)
Reduction in 6 months
Baseline
£68.24
On Insulin (86)
@ 6/12
£33.90
£34.34
Non-insulin (98)
£54.80
£13.44