Whats new in Diabetes?
Dr Simon Page
Consultant Diabetologist
Nottingham University Hospitals
Trent Occupational Medicine Symposium 2011
Agenda
• Diabetes and CVD
– Recent epidemiological data
• Diagnosis – changes afoot
• HBA1c changes
• Treatments
– ‘CV’ drugs and diabetes risk – implications for management
• Recent CV outcome trials and implications
– UKPDS
– ACCORD/ADVANCE/VADT
– Meta-analyses
• New/emerging diabetes therapies
– Incretin system
– Dual αγ PPAR agonists
– SGLT2 inhibitors
• Diabetes and Employment
– Driving and diabetes
Profile of Patients with T2D
• Relative (parent or sibling)
with T2D
• Higher risk ethnic groups
• Obesity (especially
abdominal adiposity)
• Previous IGT, IFG or
gestational diabetes
• Dyslipidaemia
–  TG + small, dense LDL-C
–  HDL-C
• Sedentary lifestyle
• Cigarette smoking
• Small birth weight
1. Adapted from Krentz & Bailey. In: Type 2 diabetes in practice 2005 pp9–10
2. Haffner SM et al. Diabetes Care 1999; 22, 4: 567
92% of T2D patients have
insulin resistance2
UK Trends for Diabetes
4.0
Prevalence ( % of population)
Equivalent to
3.9% of the
population
4.5
Patients (millions)
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
1960
1980
1996
2008
Total Number With Diabetes
Diabetes UK Report “Diabetes in the UK” (2009)
2025
Diabetes and survival
SMR for Diabetes and risk of death
from:
Any cause
1.80
Cancer
1.25
Vascular causes 2.32
Other causes
1.73
A 50 year old with diabetes died on
average 6 yrs earlier than a
non-diabetic subject.
~ 60% attributable deaths vascular
~ 40% of non vascular deaths
ERFC NEJM 2011, 364, 829-841
Diabetes and CV risk
HRs for CHD and ischaemic stroke in diabetes vs non diabetes, progressively adjusted for baseline
levels of conventional risk factors
Analysis based on 264,353 participants (11 848 cases) for CHD and 157,315 participants (2858 cases)
for ischaemic stroke with complete information on all covariates listed.
ERFC. Lancet 2010, 375, 2215-2222
Proteinuria
Baseline CV disease
Event rates/1000 patient yrs
Present
Not present
All cause death
28.9
10.0
CV death
16.7
3.6
MI
23.1
5.2
Stroke
12.1
5.4
Proteinuria
Event rates/1000 patient yrs
Present
Not present
All cause death
39.9
6.3
CV death
18.7
1.2
Preiss et al., 2011, AHJ 2011, 161, 2010-2019
Diagnosis
HBA1c ≥ 6.5%
Stringent quality assurance tests are in place
Assays are standardised to criteria aligned to the international
reference values
No conditions present which preclude accurate measurement.
A value less than 6.5% does not exclude diabetes diagnosed
using glucose tests
The expert group concluded there is currently insufficient
evidence to make any formal recommendation on the
interpretation of HbA1c levels below 6.5%
WHO/NMH/CHP/CPM/11.1 – Jan 2011
Assessment of glucose tolerance
Diagnostic
category
Fasting
glucose
2hr post 75G
glucose
Normal
< 5.6
< 7.8
IFG
6 - 6.9
< 7.8
IGT
< 7.0
≥ 7.8 - 11.0
IFG + IGT
6 - 6.9
≥ 7.8 - 11.0
Diabetes
≥ 7.0
≥ 11.1
Random
HBA1c
≥ 11.1
≥ 6.5%
Diabetes
7.5
IFG
6.5
5.5
(mmol/l)
Fasting Glucose
8.5
Normal
Glucose
4.5
3.5
IFG + IGT
3
4
6
IGT
8
10
2-h Postload Glucose
12
(mmol/l)
14
HBA1c changes
HBA1c
% Mmol/mol
DCCT (%) IFCC-HBA1c (mmol/mol)
6.0
42
6.5
48
7.0
53
7.5
59
8.0
64
9.0
75
10.0
86
11.0
97
Two minus two
rule
Treatment
More than managing glucose
Benefit of different interventions per
200 diabetic patients treated for 5 yrs
4
2
-12.5
-8.2
-2.9
0
CV events
-2
-4
-6
-8
-10
-12
-14
Per 4mm lower
SBP
Per 1 mmol/l lower
LDL-C
Per 0.9% lower
HBA1c
Ray et al., Lancet 2009, 373, 1765-1772
Antihypertensive
therapy,
Lipid lowering therapy
and
Diabetes Risk
Emergent diabetes mellitus with antihypertensive
treatment
Copyright © American Heart Association
Messerli F H et al. Circulation 2008;117:2706-2715
Aged under
55 years
Aged over 55 years
or black person of
African or Caribbean
family origin of any
age
C2
A
A+
C2
Draft 2011 NICE
guidelines
Step 1
Step 2
A+C+D
Step 3
Resistant hypertension
Step 4
A + C + D + consider further
diuretic3, 4 or alpha- or
beta-blocker5
Consider seeking expert advice
Key
A – ACE inhibitor or low-cost
angiotensin II receptor
blocker (ARB)1
C – Calcium-channel
blocker (CCB)
D – Thiazide-like diuretic
Statins and emergent diabetes
Statin
Odds ratio (95% CI)
Overall (n=91 140)
1.09 (1.02–1.17)
Atorvastatin only (n=7773)
1.14 (0.89–1.46)
Simvastatin only (n=18 815)
1.11 (0.97–1.26)
Rosuvastatin only (n=24 714)
1.18 (1.04–1.33)
Pravastatin (n=33 627)
1.03 (0.90–1.19)
Lovastatin (n=6211)
0.98 (0.70–1.38)
Sattar N et al. Lancet 2010; available at: http://www.lancet.com.
12% increase in diabetes risk
with high dose statins
NNT
prevent 1 CV event
‘cause’ 1 case new diabetes
Preiss D et al. JAMA 2011; 305:2556-2564
155
498
Glucose control and
CV outcomes
‘Legacy’ Effect - UKPDS
Intensive vs
conventional treatment
1977-1991
Randomization
10-year Post Trial Follow-up
(non-interventional)
2007
30 years
1997
20 years (Trial end)
9%*
12%*
15%*
16%**
25%*
24%*
*p<0.05
**p=0.052 – intensive vs conventional treatment
UKPDS=UK prospective diabetes study Holman R et al. UKPDS 80. NEJM 2008; 359: 1577–1589.
Results
Trial /
(enrolled)
Mean age
/ dis
duration
Aic at
entry
Aic C
Aic I
Micro
Macro
Severe
Hypo
UKPDS
(5,102)
53
New Δ
7.1%
7.9%
7.0%

+/-
I 1.8%
C 0.7%
ADVANCE
(11,140)
66
10 yrs
7.5%
7.3%
6.5%


I 0.7%
C 0.4%
VADT
(1,792)
60
11.5 yrs
9.4%

I ?
C?

I 3.1%
C 1.0%
Renal
8.4%
6.9%

ACCORD
62deaths: All8.1%
6.4%
Excess
causes 7.5%
257 vs 203
(p=0.04)

CV death 135 vs 94 (p=0.02)
(10,251)
10 yrs
Cochrane metaanalysis 2011
Outcome
Comparative risks / 1000
Conventional
All cause
mortality
CV mortality
Non-fatal MI
Severe
Hypoglycaemia
88
45
48
30
RR
(95% CI)
P value
No of
patients
Median
follow-up
89
1.01
(0.9-1.13)
P=0.92
29731
23.1 mths
48
1.06
(0.9-1.26)
P=0.46
29731
23.1 mths
42
0.87
(0.76-1.0)
P=0.054
29174
51 mths
61
2.05
(1.39-3.02)
P=0.00031
28127
35 mths
Intensive
Hemmingsen et al., Cochrane Library 2011, 10.1002/14651858.CD008143.pub2
Risk benefit and duration of
Higher risk of harm
disease
Individualise HBA1c targets
Previous IHD
High CV risk
Hazard ratio
As tight glycaemic control as
possible for as long as
possible as soon after
diagnosis as possible
1.0
Duration of diabetes
Update on T2D therapy
Currently Available Treatments for
Glycaemic Control in T2D
Biguanides
(metformin)
Decrease hepatic glucose
production and increase
glucose uptake
Pioglitazone
Increase insulin sensitivity and
glucose uptake in skeletal
muscle. Decrease lipolysis in
adipose tissue and decrease
hepatic glucose output.
-glucosidase
inhibitors
Delay intestinal carbohydrate
digestion and absorption
DDP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1; T2DM=Type 2 diabetes mellitus
Adapted from Cheng AY, Fantus IG. CMAJ 2005; 172: 213–226.
Sulphonylureas and
Meglitinides
Increase insulin secretion
from pancreatic -cells
DPP-4 inhibitors
Prolong GLP-1 action,
stimulate insulin secretion,
suppress glucagon release
GLP-1 agonists
Improve glucose-dependent
insulin secretion, suppresses
glucagon secretion, slow
gastric emptying
Insulins
Increase glucose uptake in
skeletal muscle and reduce
hepatic glucose production
Sulphonylurea – slim, metforminintolerant, rapid response needed
Glinide – erratic lifestyle
Gliptin / glitazone – risk of
hypos/job/age
Sitagliptin / glitazone – if insulin
unacceptable
GLP1 agonist – obesity or insulin
unacceptable
T2D drug problems
Metformin
GI side effects, C/I in CKD4, B12 deficiency,
lactic acidosis (rare)
Sulphonylureas/
Glinides
Hypoglycaemia, weight gain, ?CV risk
Acarbose
GI side effects, poorly tolerated
Pioglitazone
Weight gain, fluid retention, heart failure,
anaemia, fractures, ca bladder
Insulin
Hypoglycaemia, weight gain, compliance,
regimens can be complex
DPP4 inhibitors
Nasal congestion, concerns over potential ca
pancreas risk
GLP-1 analogues
GI side effects, pancreatitis, concerns over
potential ca pancreas risk, C/I in CKD 3B/4
Incretin pathway
GLP-1: The Glucoregulatory Role of Incretins
GLP-1 secreted
upon the ingestion
of food
Other effects
? Skeletal muscle
? Adipose Tissue
Hypothalamus
-cells:
Promotes satiety and
reduces appetite
Enhances glucosedependent insulin
secretion
Stomach:
Slows gastric
emptying
Cardiac Tissue
Pulmonary
-cells:
↓ Postprandial
glucagon secretion
Liver:
↓ Glucagon reduces
hepatic glucose
output
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.
Mechanisms for glucose lowering utilising
the incretin effect
DPP-IV
GLP-1
DPP-IV inhibitor GLIPTINS
HAEGT FTSDV SSYLE GQAAK EFIAW LVKGR
EXENDIN-4 HGEGT FTSDL SKQME EEAVR LFIEW LKNGG PSSGA PPPSG
EXENATIDE
LIRAGLUTIDE
Weight gain
GLP-1 analogues: benefits
Consistent effect on BP
~ 5/3 mmHg
HbA1c decrease
Rosiglitazone 4 mg
15%
HbA1c increase
Weight loss
SBP/DBP
25%
Glargine 24 IU
27%
72%
75%
70%
Glimepiride 4 mg
Exenatide 10 μg BID
Liraglutide 1.2 mg
Liraglutide 1.8 mg
Data on file (Composite Endpoint/01/02), Novo Nordisk
What about insulin resistance?
Insulin resistance - options
Lifestyle
Dual α/γ agonists - Aleglitazar
Improved management of
dyslipidemia, associated with
PPAR α activation.
Improvements in insulin
sensitivity associated with
PPAR γ activation.
SGLT2 inhibitors
Glucose Transporters in the Renal Proximal
Tubule in Normal Individuals
•SGLTs 1 – 6 – active
energy dependent glucose
transporters
SGLT2 receptors upregulated in diabetes,
increasing glucose
reabsorption
•SGLT 1 – low
capacity/high affinity:
Intestine
•SGLT 2 – high capacity/
low affinity : Kidney
•SGLT 3 – widespread
glucose sensor
•SGLTs 4 – 6 – roles to be
defined
Familial renal glycosuria – nonsense mutation in SGLT2
Bays H. CMRO. 2009;25:671-681.
SGLT2 Inhibition - Dapagliflozin
Benefits
• ↑ glucose control
independent of insulin
• Can be used in T1D and
T2D
• Low risk of
hypoglycaemia
• Weight loss
• Consistent fall in BP ~ 6/3
mmHg
Potential Side Effects
• Polyuria
• Recurrent UTI
• Dehydration
• Electrolyte imbalance
Problems
• Less effective in CKD 3B
and greater
• FDA concerns over ca
bladder/breast
Canagliflozin and Empagliflozin in phase III trials, 8 others in phase 1/2 studies
14 ongoing hard end point trials
ACE
Acarbose vs usual care
T2D at high CV risk
ALLECARDIO
Aleglitazar vs placebo
T2D, recent ACS
CANVAS
Canagliflozin vs placebo
T2D at high CV risk
CAROLINA
Linagliptin vs placebo
T2D
ELIXA
Lixesenatide vs placebo
T2D, recent ACS
EXAMINE
Alogliptin vs placebo
T2D
EXSCEL
Exenatide vs usual care
T2D, low and high risk groups
IRIS
Pioglitazone vs placebo
Insulin resistant, non diabetic,
recent stroke or TIA
LEADER
Liraglutide +/- standard care
T2D at high CV risk
LOOKAHEAD
Intensive lifestyle vs diabetes support and
education
T2D
ORIGIN
Glargine vs placebo; omega 3 fatty acids
vs placebo. 2x2 factorial.
IGT, IFG or recent diabetes
REWIND
Dulagutide vs placebo
T2D at high CV risk
SAVOR-TIMI 53
Saxagliptin vs placebo
T2D at high CV risk
TECOS
Saxagliptin vs usual care
T2D at high CV risk
Diabetes and Employment
Diabetes and Employment
• 608 diabetic, 25554 non-diabetic subjects
• RR unemployment
• With complications
• Without complications
RR 2.07 (CI 1.49-2.87)
RR 1.20 (0.93-1.56) Kraut et al., Diabetes Care 2001, 24, 64-68
• 400 diabetic, matched non-diabetic subjects
• Sickness absence
diabetes 31.7 days: non-diabetes 16.6 days
Skerjanc Occup Environ Med 2001, 58, 432-436
•
Metaanalysis: diabetes and socioeconomic position.
– High education income – lower levels
– Occupation - lower grade
– Income – lower level
1.41 increase with diabetes
1.31 increase with diabetes
1.40 increase with diabetes
Aquard et al., Int J Epodemiology 2011, 40, 804-818
Diabetes and Employment
• Individualised assessment
–
–
–
–
–
–
Requirements of the job
Treatment/monitoring demands
Risk of hypoglycaemia with treatment
Complications and their impact
Safety considerations
Employer accommodating management needs
•
•
•
•
Testing
Insulin administration
Meals/breaks
Shift patterns
Employment and diabetes: Patient guide www.diabetes.org.uk
General guidelines
Diabetes Care 2010, 33, S82-S86
Diabetes and Driving
Diabetes and driving
• Oct 2011: Insulin treated
patients:
Group 2 entitlement
Since 1991 – patients on insulin
barred from holding Group 2
licence
– May apply for Group 2 licence
– No hypoglycaemia needing
assistance in preceding 12
mths
– Full hypo awareness
– Regular monitoring
– Memory meter
– Understanding of hypo risks
– No complications which would
barr driving
– Annual review from an
INDEPENDENT Consultant
Diabetologist
Diabetes and Driving
• Group 2 licence – on
SU/glinides
– No hypoglycaemia needing
assistance in preceding 12
mths
– Full hypo awareness
– Regular monitoring
– Understanding of hypo
risks
– No complications which
would barr driving
– Regular medical review
• Group 2 licence – on
other OHA or non-insulin
injectables
– Licence granted unless
they have driving relevant
disabilities
– Advised to monitor blood
glucose levels especially at
times relevant to driving
– Regular medical review.
Driving
• Taxis
– Regulated by local councils
– DVLA recommend Group 2
regulations
– Inconsistently applied in
England
• 50% of local councils permit
insulin-treated patients to hold
a Taxi license
• ? Impact of new Group 2
regulations
• Cannot drive Police,
Ambulance or Health
Service vehicles if insulintreated.
Take home messages
•
•
•
•
HBA1c 6.5% or more accepted for diagnosis
HBA1c units changing
Control BP and lipids – new BP guidelines
Intensive control does not reduce CVD in
patients with established T2D
• New therapies may offer advantages
• Driving regulations have changed.
Thanks for your attention