Diabetes Update

1
Diabetes Update

• Lyn Higgs
• June 2008

2
Diabetes Care

• New NICE Guidelines for Type 2 Diabetes
• Old drugs, new guidelines
• New drugs
• Case discussions
• Debate - do current targets for HbA1c improve
  diabetes care and improve outcome?

3
Diabetes in the UK is increasing
Adapted from 1. Diabetes UK. Diabetes in the UK
2004. Diabetes UK, London, 2004. 2. Diabetes UK.
State of the Nation 2005. Diabetes UK, London,
2005.
4
Type 2 diabetes increases the risk of serious
morbidity
Adapted from The Information Centre. National
Diabetes Audit, Abridged report for the audit
period 2004/2005. London The Information
Centre, 2006.
5
Why treat to target?

• To reduce complications?
• To reduce mortality????
• The government says so (QOF targets)

6
Glycaemic control and complicationsUKPDS study
UKPDS 35. BMJ 2000 321 405-12
7
But!!!

• Glycaemic control deteriorates with time
• Most people with Type 2 diabetes die from
  vascular disease not microvascular complications

8

9
UKPDS showed HbA1c levels cannot be maintained in
Type 2 patients, even with intensive management
9
Conventional
8
()
1c
Intensive
HbA
7
6.2 upper limit of normal range
6
0
0
3
6
9
12
15
Years from randomisation
1. UKPDS 33. Lancet 1998352837853
2. UKPDS 34. Lancet 1998352854865
10
As b-cell function declines, blood glucose levels
increase
Adapted from Bailey CJ et al. Int J Clin Pract
2004 58 867876.
11
Progressive hyperglycaemia on monotherapy in Type
2 diabetes in UKPDS
9
8
HbA1c ()
7
6
0
0
2
4
6
8
10
Years from randomisation
Conventional
Glibenclamide
Insulin
Adapted from UKPDS Lancet 1998 352 837853.
12
Stepwise Management of Type 2 Diabetes
Insulin oral agents
Oral combination
Oral monotherapy
Diet exercise
13
The ideal drug for type 2 diabetes

• Durability of action in improving glycaemic
  control
• Reduce complications (especially vascular)
• Favourable effect on weight
• Good side effect profile

14
ADA/EASD guidelines 2006
Lifestyle metformin
If HbA1c ? 7
Add insulin sensitiser
Add basal insulin
Add sulphonylurea
If HbA1c ? 7
Add insulin sensitiser
Add basal insulin
Add basal insulin
Intensify insulin
Add sulphonylurea
If HbA1c ? 7
Further intensify insulin or add basal insulin
metformin insulin sensitiser
Bailey C et al. Br J Diabetes Vas Dis 2006 6
147148.
15
NICE 2008
16
Self - monitoring
17
Metformin (NICE 2008)

• Step up dose over several weeks to minimise GI
  side effects
• Consider trial of (Glucophage SR) if GI
  intolerability prevents the patient continuing
  with metformin
• Review metformin dose if serum creatinine gt130 or
  eGFR lt45.
• Stop metformin if serum creatinine gt 150 or eGFR
  lt30
• Prescribe metformin with caution to those at risk
  of acute deterioration in renal function or of
  eGFR falling to 45
• In patients with mild to moderate liver
  impairment or cardiac dysfunction, discuss
  potential benefits of its potential
  cardiovascular benefits before reducing dose

18
Are Glitazones good or bad for the patient with
type 2 Diabetes?

• Improving and maintaining blood glucose control
• Risk of vascular events
• Fracture risk
• Cardiac failure

19
Key trials

• ADOPT Study
• To compare the durability of glycaemic control
  using Rosiglitazone versus metformin or
  glibenclamide as initial monotherapy in patients
  with recently diagnosed Type 2 diabetes mellitus
• PROACTIVE study
• A Macrovascular Outcome Study in Type 2 Diabetic
  Patients Comparing Pioglitazone with Placebo in
  Addition to Existing Therapy

20
HbA1c over time - Adopt study
8.0
Glibenclamide
7.5
Metformin
Rosiglitazone
7.0

6.5
Rosiglitazone vs metformin,p
0.002 Rosiglitazone vs glibenclamide 0.001
6.0
0
5
2
3
4
0
1
Time (years)
Kahn SE et al. NEJM 2006 355 24272443.
21
Weight gain over time ADOPT study
Kahn SE et al. NEJM 2006 355 24272443.
22
Fractures incidence within ADOPT
Rosiglitazone (N 1456)
Metformin (N 1454)
Glibenclamide (N 1441)
28 (3.4)
29 (3.4)
32 (4.0)
Men , n ()
21 (3.5)
30 (5.1)
60 (9.3)
Women , n ()
22 (3.4)
9 (1.5)
10 (1.7)
Upper limb, n ()
8 (1.3)
18 (3.1)
36 (5.6)
Lower limb , n ()
Hip, n ()
0 (0.0)
2 (0.3)
2 (0.3)
1 (0.2)
1 (0.2)
Spine, n ()
1 (0.2)
p lt 0.05 vs. rosiglitazone
identified in a post-hoc analysis
Rosiglitazone is licensed as monotherapy in
patients (particularly overweight patients)
inadequately controlled by diet and exercise for
whom metformin is inappropriate because of
contraindications or intolerance
Adapted from Kahn SE et al. NEJM 2006 355
24272443.
23
Rosiglitazone safety concerns 2007
Nissen et al NEJM May 2007
24
EMEA Guidelines on RosiglitazoneJanuary 2008
25
What about Pioglitazone?
26
ProActive Study
27
Erdmann E, AHA November 2005, Dallas
28
Time to Fatal or Non-Fatal Stroke in Patients
with Previous Stroke versus no Previous Stroke
Previous Stroke
No Previous Stroke
Wilcox RG et al, Stroke 2007 38 865-873
29
Rosiglitazone, Pioglitazone or neither?

• Rosiglitazone
• Sustained effect on glycaemic control
• But
• ?? Small increased cardiac risk
• Contraindicated in ACS, IHD, PVD
• Cardiac failure
• Fracture risk

• Pioglitazone
• Improves glycaemic control
• Additional small effect on lipid profile
• Possible cardiac benefit
• May be combined with insulin
• But
• Cardiac failure
• Fracture risk

30
Glitazones and congestive heart failure

• Both glitazones can cause fluid retention which
  may exacerbate or precipitate signs or symptoms
  of congestive heart failure.
• Both glitazones are contraindicated in patients
  with cardiac failure or history of cardiac
  failure (NYHA class I to IV).

AVANDIA SPC, GlaxoSmithKline, December 2006.
31
Incretins
32
GLP-1 effects in humansunderstanding the natural
role of incretins
GLP-1 secreted upon the ingestion of food
5.Brain Promotes satiety and reduces appetite4,5
2.a-cell Suppresses postprandialglucagon
secretion1
3.Liver reduces hepatic glucose output2
1.?-cellEnhances glucose-dependent insulin
secretion in the pancreas1
4.Stomach slows the rate of gastric emptying3
Adapted from 1Nauck MA, et al. Diabetologia
199336741744 2Larsson H, et al. Acta Physiol
Scand 1997160413422 3Nauck MA, et al.
Diabetologia 19963915461553 4Flint A, et al.
J Clin Invest 1998101515520 5Zander et al.
Lancet 2002359824830.
33
The incretin effect is reduced in patients with
type 2 diabetes
Intravenous Glucose
Oral Glucose
Control subjects
Patients with type 2 diabetes
80
80
60
60
Insulin (mU/L)
Insulin (mU/L)
40
40
20
20
0
0
0
30
60
90
120
150
180
0
30
60
90
120
150
180
Time (min)
Time (min)
P .05 compared with respective value after oral
load. Nauck MA, et al. Diabetologia
1986294652.
34
Physiological effects of incretins

• ? prandial insulin secretion
• ? glucagon secretion
• ? Acid secretion and GI motility (? gastric
  emptying
• ? satiety and ? food intake
• ? ß cell protection
• ? Cardiovascular effects

35
Physiology
36
Exenatide

• Synthetic equivalent of exendin-4
• Found in the saliva of the Gila monster
• 53 homology with human GLP-1
• Now available for treatment of T2D (Byetta)
• Given as bd sc injection simple pen device
• Licensed as adjunct to MFN, SU or both

37
Exenatide MFN SU
N733, HbA1c 8.5
Diabetes Care (2005) 28 1083
38
Exenatide vs Glargine
Ann Int Med 2005 143 559
39
Bath Exenatide data

• 3 months treatment with Exenatide in patients
  with Type 2 diabetes and poor glycaemic control
  on maximum oral therapy showed
• Mean HbA1c reduction of 0.64 (max 3)
• Mean weight loss of 3.4 kg (Max 10kg)
• 22 patients discontinued because of side effects
  or poor control
• No predictable relationship between initial
  weight, BMI or HbA1c and response

40
NICE Guidance on Exenatide

• May be considered only if
• BMI gt35
• Specific psychological, biochemical or physical
  problems arising from high body weight
• HbA1c gt 7.5 after a trial of Metformin and
  sulphonylurea
• Would otherwise start other high cost medication
  (glitazone or insulin)
• Continue only if beneficial response
• 1 reduction in HbA1c at 6 months
• At least 5 weight loss at 1 year.

41
Other new drugs

• DPP 4 Inhibitors
• Sitagliptin

42
Mode of action of sitagliptin8
Bloodglucose control
Sitagliptin is a DPP-4 inhibitor and inhibits the
breakdown of incretins and thereby increases
active incretin levels
DPP-4enzyme rapidly degrades incretins
DPP-4 dipeptidyl peptidase 4 inhibitor
Adapted from 8. Miller S, St nge EL. Ann
Pharmacother 2006401336-1343.
43
52-week Sitagliptin vs Sulphonylureaa Add-on
Therapy to Metformin Study Greater reductions in
HbA1c are associated with higher baseline HbA1c11
Baseline HbA1C category
lt7
7 to lt8
8 to lt9
³9
n117
112
179
167
82
82
33
21
0.0
n117
-0.2
-0.14
-0.4
-0.26
-0.6
-0.53
-0.59
-0.8
Change from baseline in HbA1c ()
-1.0
-1.2
-1.11
-1.13
-1.4
-1.6
Sitagliptin 100 mg o.d metformin (n382)
-1.68
-1.8
Glipizide 5-20 mg/day metformin (n411)
-1.76
-2.0
44
Sitagliptin vs Sulphonylureaa Add-on Therapy to
Metformin Study Sitagliptin provided weight
reduction (vs weight gain) and lower incidence of
hypoglycaemia11
Hypoglycaemiab
LS mean change in body weight over timeb
50
3
40
2
32
Plt0.001
1
30
Incidence ()
0
Body weight (kg SE)
20
-1
10
5
-2
0
-3
0
12
24
38
52
Week 52
Weeks
45
Comparison
46
Cases
47
Rob - Case Study 1

• Points to consider
• limited time to do exercise
• concerned about weight gain
• works at heights

48
Maureen - Case Study 2

• Points to consider
• recent weight gain
• feeling lethargic after lunch
• And what if her creatinine was 144?

49
Jack - Case Study 3

• Points to consider
• diabetes diagnosed when admitted for MI
• lives on his own
• concern about hypoglycaemia
• history of unexplained falls
• complaining of GI upsets

50
Fahd - Case Study 4

• Points to consider
• concerned about insulin because of occupation
• limited time to do exercise
• concerned about putting on additional weight

51
Gillian - Case Study 5

• Points to consider
• MI 8 months previously,
• no cardiac failure
• stopped smoking post
• recent MI

52
David - Case Study 6

• Points to consider
• concerned about additional weight gain
• busy lifestyle
• irregular meals to entertain clients
• very concerned about diabetes diagnosis and
  long-term effects
• obsessive about glucose testing

53
Fiona - Case Study 7

• Points to consider
• lost 5 kg in last 5 months
• regular exerciser

54
DebateGlycaemic targets

• QOF targets for HbA1c
• HbA1c lt 7.5 50
• HbA1c lt10 85
• Do they?
• improve diabetes care?
• improve morbidity and mortality?

55
A local GP practice vs consultant diabetologist,
who is delivering best care?
56
DCCT the price of improved diabetic control
hypoglycaemia
Rate pf progression of retinopathy (per 100
patient years)
Rate of severe hypoglycaemia (per 100 patient
years)
Adapted from N Engl J Med 199332997786
57
Glycaemic control and complicationsUKPDS study
UKPDS 35. BMJ 2000 321 405-12
58
Median Glycated Hemoglobin Levels at Each Study
Visit Accord study
The Action to Control Cardiovascular Risk in
Diabetes Study Group. N Engl J Med
200810.1056/NEJMoa0802743
59
Kaplan-Meier Curves for the Primary Outcome and
Death from Any Cause Accord Study
The Action to Control Cardiovascular Risk in
Diabetes Study Group. N Engl J Med
200810.1056/NEJMoa0802743
60
The patients agenda may not be yours
61
So remember

• Type 2 diabetes is largely asymptomatic and the
  treatments are inconvenient, impose on daily life
  and employment
• The patients agenda may be very different from
  yours
• Lifestyle change is the most important but the
  most difficult to achieve
• In insulin-treated patients, hypoglycaemia is a
  major risk, especially in the young, elderly and
  long-standing Type 1 patients

62
Summary

• Recent NICE Guidelines have clarified the
  treatment pathway for Type 2 diabetes. Changes in
  QOF targets are likely to follow.
• QOF targets have improved diagnosis of type 2
  diabetes and process of care
• Most patients with type 2 diabetes still die of
  cardiovascular disease regardless of their blood
  glucose control.
• Patients with highest HbA1c have most to gain
  from any improvement in blood glucose control

63
Thankyou