Whats new in Diabetes?

Dr Simon PageConsultant 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

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

1960 1980 1996 2008 2025

Pa

tie

nts

(mill

ion

s)

Total Number With Diabetes

Diabetes UK Report “Diabetes in the UK” (2009)

Equivalent to 3.9% of the population

Pre

vale

nce

( %

of

po

pu

lati

on

)

Diabetes and survival

SMR for Diabetes and risk of death from:

Any cause 1.80 Cancer 1.25 Vascular causes 2.32Other 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 diseaseEvent rates/1000 patient yrs Present Not presentAll 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%

WHO/NMH/CHP/CPM/11.1 – Jan 2011

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%

Assessment of glucose toleranceDiagnostic category

Fasting glucose

2hr post 75G glucose

Random HBA1c

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 ≥ 11.1 ≥ 6.5%F

ast

ing

Glu

co

seF

ast

ing

Glu

co

se

(mm

ol/l

)(m

mo

l/l)

3.5

4.5

5.5

6.5

7.5

8.5

3 4 6 8 10 12 14

2-h Postload Glucose2-h Postload Glucose (mmol/l)(mmol/l)

Diabetes

IFG + IGT

NormalGlucose

IGT

IFG

HBA1c changes

HBA1c

% Mmol/molDCCT (%) 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

-14

-12

-10

-8

-6

-4

-2

0

2

4

CV

ev

en

ts

Per 4mm lowerSBP

Per 1 mmol/l lowerLDL-C

Per 0.9% lowerHBA1c

-12.5 -8.2 -2.9

Ray et al., Lancet 2009, 373, 1765-1772

Antihypertensive therapy,

Lipid lowering therapy and

Diabetes Risk

Emergent diabetes mellitus with antihypertensive treatment

Messerli F H et al. Circulation 2008;117:2706-2715Copyright © American Heart Association

Step 4

Draft 2011 NICE guidelines

Aged over 55 years or black person of African or Caribbean family origin of any age

Aged under55 years

C2A

A + C2

A + C + D

Resistant hypertension

A + C + D + consider further diuretic3, 4 or alpha- or

beta-blocker5

Consider seeking expert advice

Step 1

Step 2

Step 3

KeyA – ACE inhibitor or low-cost angiotensin II receptor blocker (ARB)1 C – Calcium-channel blocker (CCB) D – Thiazide-like diuretic

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)

Statins and emergent diabetes

Sattar N et al. Lancet 2010; available at: http://www.lancet.com.

NNT prevent 1 CV event 155‘cause’ 1 case new diabetes 498

12% increase in diabetes risk with high dose statins

Preiss D et al. JAMA 2011; 305:2556-2564

Glucose control and CV outcomes

‘Legacy’ Effect - UKPDS

1977-1991Randomization

199720 years (Trial end)

200730 years

Intensive vs conventional treatment

10-year Post Trial Follow-up(non-interventional)

*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.

12%*

25%*

16%**

9%*

24%*

15%*

ResultsTrial / (enrolled)

Mean age / dis duration

Aic at entry

Aic C Aic I Micro Macro SevereHypo

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% Renal

I 0.7%

C 0.4%

VADT

(1,792)

60

11.5 yrs

9.4% 8.4% 6.9% I ?

C ?

ACCORD

(10,251)

62

10 yrs

8.1% 7.5% 6.4% I 3.1%

C 1.0%Excess deaths: All causes 257 vs 203 (p=0.04)

CV death 135 vs 94 (p=0.02)

Cochrane metaanalysis 2011Outcome Comparative risks / 1000 RR

(95% CI)

P value

No of patients

Median follow-up

Conventional Intensive

All cause mortality 88 89

1.01

(0.9-1.13)

P=0.92

29731 23.1 mths

CV mortality45 48

1.06

(0.9-1.26)

P=0.46

29731 23.1 mths

Non-fatal MI48 42

0.87

(0.76-1.0)

P=0.054

29174 51 mths

Severe Hypoglycaemia 30 61

2.05

(1.39-3.02)

P=0.00031

28127 35 mths

Hemmingsen et al., Cochrane Library 2011,

10.1002/14651858.CD008143.pub2

Risk benefit and duration of disease

Hazard ratio

1.0

Duration of diabetes

Higher risk of harm

Individualise HBA1c targets

Previous IHD

High CV risk

As tight glycaemic control as possible for as long as possible as soon after diagnosis as possible

Update on T2D therapy

Currently Available Treatments for Glycaemic Control in T2D

DDP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1; T2DM=Type 2 diabetes mellitusAdapted from Cheng AY, Fantus IG. CMAJ 2005; 172: 213–226.

-glucosidase inhibitorsDelay intestinal carbohydrate digestion and absorption

PioglitazoneIncrease insulin sensitivity and glucose uptake in skeletal muscle. Decrease lipolysis in adipose tissue and decrease hepatic glucose output.

Sulphonylureas and MeglitinidesIncrease insulin secretion from pancreatic -cells

Biguanides (metformin)Decrease hepatic glucose production and increase glucose uptake

InsulinsIncrease glucose uptake in skeletal muscle and reduce hepatic glucose production

GLP-1 agonists

Improve glucose-dependent insulin secretion, suppresses glucagon secretion, slow gastric emptying

DPP-4 inhibitorsProlong GLP-1 action, stimulate insulin secretion, suppress glucagon release

Sulphonylurea – slim, metformin-intolerant, rapid response needed

Glinide – erratic lifestyleGliptin / glitazone – risk of hypos/job/age

Sitagliptin / glitazone – if insulin unacceptableGLP1 agonist – obesity or insulin unacceptable

T2D drug problemsMetformin 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

HypothalamusPromotes satiety and

reduces appetite

GLP-1: Glucagon-like peptide 1Adapted 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.

-cells:Enhances glucose- dependent insulin

secretion

-cells:↓ Postprandial

glucagon secretion

Stomach: Slows gastric

emptying

GLP-1 secreted upon the ingestion

of food

Other effects

? Skeletal muscle? Adipose Tissue

Cardiac TissuePulmonary

Liver: ↓ Glucagon reduces

hepatic glucose output

GLP-1 HAEGT FTSDV SSYLE GQAAK EFIAW LVKGR

DPP-IV

EXENATIDELIRAGLUTIDE

DPP-IV inhibitor GLIPTINS

EXENDIN-4 HGEGT FTSDL SKQME EEAVR LFIEW LKNGG PSSGA PPPSG

Mechanisms for glucose lowering utilising the incretin effect

GLP-1 analogues: benefits

Data on file (Composite Endpoint/01/02), Novo Nordisk

Glargine 24 IU

Rosiglitazone 4 mg

Glimepiride 4 mg

Exenatide 10 μg BID

Liraglutide 1.8 mg

25%

70%

72%

75%

Liraglutide 1.2 mg

27%

15%

HbA1c increaseHbA1c decrease

Weig

ht

loss

Weig

ht

gainConsistent effect on BP

SBP/DBP ~ 5/3 mmHg

What about insulin resistance?

Insulin resistance - optionsLifestyle

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

Bays H. CMRO. 2009;25:671-681.

•SGLTs 1 – 6 – active energy dependent glucose transporters

•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

SGLT2 receptors up-regulated in diabetes,

increasing glucose reabsorption

Familial renal glycosuria – nonsense mutation in SGLT2

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 trialsACE 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 RR 2.07 (CI 1.49-2.87) • Without complications 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 1.41 increase with diabetes– Occupation - lower grade 1.31 increase with diabetes– Income – lower level 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:– 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

Group 2 entitlement

Since 1991 – patients on insulin barred from holding Group 2

licence

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

• Cannot drive Police, Ambulance or Health Service vehicles if insulin-treated.

• 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

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