Developments in the
Treatment of T2DM
Dr John Clark
Diabetes Prevalence
3 million
Type 1
Type 2
2 million
1 million
0
1995
2000
2013
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)
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
New Developments

The incretin effect and GLP-1

Treatments A) DPP-4 Inhibitors

Treatments B) GLP-1 Agonists
UK/LR/0809/0384
Date of preparation: August 2009
The Incretin Effect
Insulin response
80
15
Insulin (mU/L)
Plasma glucose (mmol/L)
Plasma glucose
10
5
0
–10 –5
60
120
Time (min)
180
Oral glucose load (50 g)
60
40
Incretin
effect
20
0
–10 –5
60
120
Time (min)
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
180
The Incretin Effect is Reduced in Subjects
with Type 2 Diabetes
The Incretin Effect accounts for ~ 60% of total Insulin release following a meal
Subjects with type 2 diabetes
80
80
60
60
Insulin (mU/L)
Insulin (mU/L)
Control subjects
40
* * *
*
*
*
*
20
30
60
90 120 150 180
Time (min)
Oral Glucose
Nauck MA, et al. Diabetologia 1986;29:46–52.
*P ≤.05 compared with respective value after oral load.
*
* *
20
0
0
40
0
0
30
60 90 120 150 180
Time (min)
Intravenous Glucose
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. 1989 Dec,6, 813-7.


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.
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
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
His Ala Glu Gly Thr Phe Thr Ser Asp
• Secreted in response
to meal ingestion
Val
Ser
Lys Ala Ala Gln Gly Glu Leu Tyr Ser
Glu
Phe
Ile Ala Trp Leu Val Lys Gly Arg Gly
GI: gastrointestinal
Drucker & Nauck. Lancet 2006;368:1696–705
GLP-1: Effects in Humans
GLP-1 secreted upon
the ingestion of food
Promotes satiety and
reduces appetite
b-cells:
Enhances glucosedependent insulin
secretion
Stomach:
Helps regulate
gastric emptying
GLP-1: Glucagon-like peptide 1
Adapted from Flint A, et al. J Clin Invest. 1998;101:515-520; Adapted from Larsson H, et al. Acta Physiol Scand. 1997;160:413-422;
Adapted from Nauck MA, et al. Diabetologia. 1996;39:1546-1553; Adapted from Drucker DJ. Diabetes. 1998;47:159-169.
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
Double immunohistochemical staining for DPP-4
(red) and GLP-1 (green) in the human ileum
Hansen et al. Endocrinology 1999;140:5356–63
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
Exendin-based
therapies,
exenatide +
lixisenatide
Human GLP-1
analogues,
liraglutide
DPP-4 Inhibitors (Gliptins)

Oral

Weight neutral

Minimal hypoglycaemia

NICE – must lower HbA1c by 0.5% within 6/12
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
Mr K S

June 2010 - Add in Sitagliptin 100 mg od

October 2010 - HbA1c 7.4%

Glipizide reduced to 2.5 mg am, 5 mg pm.
Do Exenatide/Liraglutide/Lixisenatide Work?
Exenatide vs. Insulin Glargine
Reductions in HbA1c
60
-0.5
-1.0
-1.1%
-1.1%
% Patients Achieving
HbA1c targets
% Change in HbA1c
0.0
50
46%
48%
40
32%
30
25%
20
10
-1.5
0
HbA1c <7%
Exenatide (n=275)
Insulin glargine (n=260)
ITT population; Mean ± SE shown.
Heine RJ et al. Ann Intern Med. 2005;143:559-569.
HbA1c <6.5%
Exenatide vs. Insulin Glargine
Change in Body Weight
Change in
body weight (kg)
2
+1.8 kg
1
0
4.1 kg
*
-1
*
*
-2
*
-2.3 kg
*
*
-3
0
2
4
8
12
18
Time (weeks)
Exenatide (n = 275)
26
Insulin glargine (n = 260)
from LEAD trials 1–6
Weight gain
HbA1c and weight loss:
% patients
Weight loss
HbA1c decrease
HbA1c increase
HbA1c and weight change: sulphonylurea
51%
Weight gain
LEAD-2. ITT, LOCF. n=232
32%
Weight loss
HbA1c decrease
Glimepiride 4 mg
12%
HbA1c increase
5%
Data on file Composite Endpoint,
Novo Nordisk
HbA1c and weight change: thiazolidinedione
49%
Weight gain
LEAD-1. ITT, LOCF. n=224
15%
ITT, intention-to-treat; LOCF, last observation carried forward
Weight loss
HbA1c decrease
Pioglitazone
26%
HbA1c increase
10%
Data on file, Composite Endpoint,
Novo Nordisk
HbA1c and weight change: glargine
63%
Weight gain
LEAD-5. ITT, LOCF. n=224
25%
Weight loss
HbA1c decrease
Glargine 24 IU
10%
HbA1c increase
2%
Data on file Composite Endpoint,
Novo Nordisk
HbA1c and weight change: exenatide
14%
Weight gain
LEAD-6. ITT, LOCF. n=196
72%
Weight loss
HbA1c decrease
Exenatide 10 μg BD
5%
HbA1c increase
9%
Data on file Composite Endpoint,
Novo Nordisk
HbA1c and weight change: liraglutide 1.2 mg
10%
Weight gain
LEAD-2. ITT, LOCF. n=231
72%
Weight loss
HbA1c decrease
Liraglutide 1.2 mg
4%
HbA1c increase
13%
Data on file Composite Endpoint,
Novo Nordisk
Weight gain
Comparison : shifting the paradigm
HbA1c decrease
15%
25%
32%
72%
72%
72%
Weight loss
Pioglitazone
HbA1c increase
Glargine 24 IU
Glimepiride 4 mg
Exenatide 10 μg BID
Liraglutide 1.2 mg
Lixisenatide 20ug od
Data on file Composite Endpoint,
Novo Nordisk
Diabetes Clinic
(1/9/10)

Weight
NJ 120 – 92kg
HbA1c
8.5 – 6.1
Exenatide
1year

JH 117 – 96kg
7.8 – 6.0
6 months

NT 123 – 112kg
9.2 – 7.3
6 months
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%
WSH Audit 2011


312 patients initiated on Exenatide since
May 2008
207 patients completed 6 months
treatment by December 2010
WSH Outcome Data: Passed v Failed @ 6 months
Passed @ 6/12
(184)
HbA1c
Weight (Kg)
BMI
Baseline
9.6
119.8
41.5
Change at 6/12
-1.6
-6.8
-2.4
P value
P < 00001
P < 0.0001
P < 0.0001
Failed @ 6/12
(23)
HbA1c
Weight (Kg)
BMI
Baseline
9.3
126.4
43.2
Change at 6/12
-0.3
-6.2
-2.1
SD 1.5
(7.4 to 14.0)
SD 1.6
(-7.1 to +3.5)
(6.2 to 12.9)
SD 1.6
(-5.4 to +3.3)
SD 1.6
SD 20.9
(75.2 to 185.6)
SD 5.4
(-25.6 to +5.6)
(80.2 to 183.7)
SD 25.1
(-16.7 to +1.3)
SD 5.1
SD 7.2
(26.0 to 84.8)
SD 1.9
(-9.3 to +1.9)
(33.8 to 59.1)
SD 7.9
(-5.0 to +0.4)
SD 1.7
WSH Data: Exenatide success @ 6/12
Insulin v Non-Insulin Group
Total on Insulin HbA1c
(86)
Weight (Kg)
BMI
Baseline
9.5
118.7
41.7
Change at
6/12
-1.6
-7.3 (6.2%)
-2.6
SD 1.9
(-4.5 to -0.7)
P <0.0001
Non-insulin
(98)
HbA1c
Weight (Kg)
BMI
P value
Baseline
9.7
120.8
41.3
Change at 6/12 -1.6
-6.5 (5.4%)
-2.2
P value
P = 0.32
P = 0.23
SD 1.3
(8.2 to 10.8)
SD 1.4
(-3.0 to -0.2)
SD 1.6
(8.1 to 11.3)
SD 1.7
(-3.3 to 0.1)
P = 0.83
SD 17.9
(100.8 to 136.6)
SD 5.2
(-12.5 to -2.1)
SD 23.2
(97.6 to 144.0)
SD 5.5
(-12.0 to -1.0)
P value
SD 6.2
(35.5 to 37.9)
SD 8.0
(33.3 to 49.3)
SD 1.9
(-4.1 to -0.3)
p < 0.0001
New Drug - Dapagliflozin



Blocks reabsorption of glucose in kidneys
Increased urinary glucose loss
Oral medication 5-10mg once daily
Dapagliflozin
Benefits




HbA1c drops by 0.5-1.0%
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.
Dapagliflozin
Side-effects



Urinary tract infection
Polyuria
Genital fungal infection
Bariatric Surgery




30 Kg weight loss
50% achieve HbA1c < 6.5%
High rate of remission of diabetes
But no long term studies
Summary of Targets

HbA1c < 7.5 %

BP 140 / 80 or less

Cholesterol < 4.0
(Metformin)
(ACE-I or ARB)
(Statin)
Glycaemic Control
Drugs to use

Drug of choice
Metformin

Next Stage
Metformin
with
Sulphonylurea
or
Pioglitazone
or
Sita/Vilda/Saxa/Lina
Glycaemic Control
Drugs to use

Next Stage
Metformin with GLP-1 injection

Final Stage
Metformin with basal Insulin

Consider
Dapagliflozin

Last resort
Bariatric surgery
Glycaemic Control
Drugs to use

Drug of choice
Metformin

Next Stage
Metformin
with
Sulphonylurea
or
Pioglitazone
or

Next Stage
Metformin
with

Final Stage
Metformin
with

Consider
Dapagliflozin

Last resort
Bariatric surgery
Sita/Vilda/Saxa/Linagliptin
Exenatide/Liraglutide/Lixisenatide
basal Insulin
WSH COST DATA
Exenatide Success @ 6/12
Insulin v Non-Insulin Group
Baseline
Extra Cost for
Exenatide
(per person , per
month)
£68.24
Reduction in
Cost @ 6
months
On Insulin (86) £33.90
@ 6/12
£34.34
Non-insulin
(98)
@ 6/12
£13.44
£54.80