Developments in the Treatment of T2DM

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Developments in the Treatment of T2DM

• Dr John Clark

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Diabetes Prevalence
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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)

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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
  

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New Developments

• The incretin effect and GLP-1
• Treatments A) DPP-4 Inhibitors
• Treatments B) GLP-1 Agonists

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The Incretin Effect
Date of preparation August 2009
UK/LR/0809/0384
Plasma glucose
15
10
Plasma glucose (mmol/L)
5
0
10
5
60
120
180
Time (min)

• Insulin response is greater following oral
  glucose than i.v. glucose, despite similar plasma
  glucose concentration

Healthy volunteers (n8) i.v. intravenousNauck
et al. Diabetologia 1986294652
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The Incretin Effect is Reduced in Subjects with
Type 2 Diabetes
The Incretin Effect accounts for 60 of total
Insulin release following a meal
Time (min)
Nauck MA, et al. Diabetologia 1986294652. P
.05 compared with respective value after oral
load.
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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.

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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

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What is glucagon-like peptide-1 (GLP-1)?
Date of preparation August 2009
UK/LR/0809/0384

• A 31 amino acid peptide
• Cleaved from proglucagon in L-cells in the GI
  tract
• Secreted in response
• to meal ingestion

GI gastrointestinalDrucker Nauck. Lancet
20063681696705
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GLP-1 Effects in Humans
GLP-1 secreted upon the ingestion of food
Promotes satiety and reduces appetite
b-cellsEnhances glucose-dependent insulin
secretion
Stomach Helps regulate gastric emptying
GLP-1 Glucagon-like peptide 1 Adapted from Flint
A, et al. J Clin Invest. 1998101515-520
Adapted from Larsson H, et al. Acta Physiol
Scand. 1997160413-422 Adapted from Nauck MA,
et al. Diabetologia. 1996391546-1553 Adapted
from Drucker DJ. Diabetes. 199847159-169.
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Native GLP-1 is rapidly degraded by DPP-4
(Di-Peptidyl Peptidase-4)
Date of preparation August 2009
UK/LR/0809/0384
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 1999140535663
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The family of incretin-based therapies
Date of preparation August 2009
UK/LR/0809/0384
Incretin-based therapies
DPP-4 inhibitors, sitagliptin vildagliptin
saxagliptin linagliptin
GLP-1 receptor agonists
Human GLP-1 analogues, liraglutide
Exendin-based therapies, exenatide lixisenatide
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DPP-4 Inhibitors (Gliptins)

• Oral
• Weight neutral
• Minimal hypoglycaemia
• NICE must lower HbA1c by 0.5 within 6/12

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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

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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.

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Do Exenatide/Liraglutide/Lixisenatide Work?
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Exenatide vs. Insulin Glargine Reductions in
HbA1c
0.0
60
48
50
46
-0.5
40
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Change in HbA1c
Patients Achieving HbA1c targets
30
25
-1.0
20
-1.1
10
-1.1
-1.5
0
HbA1c lt7
HbA1c lt6.5
Exenatide
(n275)
Insulin glargine
(n260)
ITT population Mean SE shown. Heine RJ et al.
Ann Intern Med. 2005143559-569.
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Exenatide vs. Insulin GlargineChange in Body
Weight
2
1.8 kg
1
0
4.1 kg
Change inbody weight (kg)

-1


-2

-2.3 kg


-3
0
2
4
8
12
18
26
Time (weeks)
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HbA1c and weight loss from LEAD trials 16
HbA1c increase
patients
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HbA1c and weight change sulphonylurea
LEAD-2. ITT, LOCF. n232
Glimepiride 4 mg
Weight gain
51
12
HbA1c increase
Weight loss
32
5
Data on file Composite Endpoint, Novo Nordisk
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HbA1c and weight change thiazolidinedione
LEAD-1. ITT, LOCF. n224
Pioglitazone
Weight gain
HbA1c increase
Weight loss
ITT, intention-to-treat LOCF, last observation
carried forward
Data on file, Composite Endpoint, Novo Nordisk
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HbA1c and weight change glargine
LEAD-5. ITT, LOCF. n224
Glargine 24 IU
Weight gain
63
10
HbA1c increase
Weight loss
25
2
Data on file Composite Endpoint, Novo Nordisk
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HbA1c and weight change exenatide
LEAD-6. ITT, LOCF. n196
Exenatide 10 µg BD
Weight gain
5
14
HbA1c increase
Weight loss
72
9
Data on file Composite Endpoint, Novo Nordisk
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HbA1c and weight change liraglutide 1.2 mg
LEAD-2. ITT, LOCF. n231
Liraglutide 1.2 mg
Weight gain
10
4
HbA1c decrease
HbA1c increase
Weight loss
72
13
Data on file Composite Endpoint, Novo Nordisk
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Comparison shifting the paradigm
Weight gain
HbA1c decrease
HbA1c increase
Pioglitazone
15
Weight loss
25
Glargine 24 IU
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Glimepiride 4 mg
72
72
Exenatide 10 µg BID
Liraglutide 1.2 mg
72
Lixisenatide 20ug od
Data on file Composite Endpoint, Novo Nordisk
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Diabetes Clinic (1/9/10)

• Weight HbA1c
  Exenatide
• NJ 120 92kg 8.5 6.1 1year
• JH 117 96kg 7.8 6.0 6 months
• NT 123 112kg 9.2 7.3 6 months

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NICE Guidance 2010(must satisfy all criteria)

• HbA1c gt 7.5
• Already on OHAs
• Weight related health problems
• BMI gt 35
• By 6 months must achieve both targets
• weight loss of 3
• drop in HbA1c of 1

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WSH Audit 2011

• 312 patients initiated on Exenatide since May
  2008
• 207 patients completed 6 months treatment by
  December 2010

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WSH Outcome Data Passed v Failed _at_ 6 months WSH Outcome Data Passed v Failed _at_ 6 months WSH Outcome Data Passed v Failed _at_ 6 months WSH Outcome Data Passed v Failed _at_ 6 months

Passed _at_ 6/12 (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 lt 00001 P lt 0.0001 P lt 0.0001

Failed _at_ 6/12 (23) HbA1c Weight (Kg) BMI
Baseline 9.3 (6.2 to 12.9) SD 1.6 126.4 (80.2 to 183.7) SD 25.1 43.2 (33.8 to 59.1) SD 7.9
Change at 6/12 -0.3 (-5.4 to 3.3) SD 1.6 -6.2 (-16.7 to 1.3) SD 5.1 -2.1 (-5.0 to 0.4) SD 1.7
P value P 0.35 P lt 0.0001 P 0.0014

P value (pass v non-pass) P 0.0004 P 0.57 P 0.50
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WSH Data Exenatide success _at_ 6/12Insulin 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 lt0.0001
Non-insulin (98) HbA1c Weight (Kg) BMI P value
Baseline 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 -1.6 SD 1.7 (-3.3 to 0.1) -6.5 (5.4) SD 5.5 (-12.0 to -1.0) -2.2 SD 1.9 (-4.1 to -0.3) p lt 0.0001
P value P 0.83 P 0.32 P 0.23
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New Drug - Dapagliflozin

• Blocks reabsorption of glucose in kidneys
• Increased urinary glucose loss
• Oral medication 5-10mg once daily

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DapagliflozinBenefits

• 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.

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DapagliflozinSide-effects

• Urinary tract infection
• Polyuria
• Genital fungal infection

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Bariatric Surgery

• 30 Kg weight loss
• 50 achieve HbA1c lt 6.5
• High rate of remission of diabetes
• But no long term studies

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Summary of Targets

• HbA1c lt 7.5 (Metformin)
• BP 140 / 80 or less (ACE-I or ARB)
• Cholesterol lt 4.0 (Statin)

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Glycaemic Control Drugs to use

• Drug of choice Metformin
• Next Stage Metformin with
  Sulphonylurea
• 
  
• 
  or Pioglitazone
• 
  or Sita/Vilda/Saxa/Lina

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Glycaemic Control Drugs to use

• Next Stage Metformin with GLP-1
  injection
• Final Stage Metformin with basal
  Insulin
• Consider Dapagliflozin
• Last resort Bariatric surgery

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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

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