management of t2 dm beyond glycemic control

1

MANAGEMENT OF T2DM(Beyond glycemic control)

Alaa Wafa MD.Associate Professor of Internal Medicine

PGDIP Diabetes CARDIFF University UK

Diabetes & Endocrine unit.

Mansoura university

2014

Mr. Ahmed

Mr. Ahmed is a 70-year-old man who was

diagnosed with T2DM 10 years ago. He was initially

treated with lifestyle management and metformin.

3 years later, his doctors advised him to add long

acting basal insulin analogue to metformin, reached

to 40U/day .

Other current medical conditions include:

hypertension, hypothyroidism, and mild

osteoporosis without fracture history.

Physical exam:

BMI 26 kg/m2,

BP 140/80 mmHg, otherwise unremarkable.

His current FPG 140 mg/Dl

HbA1c 8.8%.

Kidney and liver functions are normal.

Current medications;

Metformin 1000 mg bid,

long acting basal insulin analogue 40U/day ,

Candesartan 16 mg qd,

Alendronate 70 mg once weekly,

Levothyroxine 100 mg .

Does his age should be a concern and why ?

• Diabetes-related complications are the major

causes of morbidity, disability and mortality in

older patients with type 2 diabetes:

• There is now overwhelming evidence that the

level and duration of glycemia influences the

development of diabetes-related complications

Sinclair 2004. Clinical guidelines for type 2 diabetes mellitus. EDWOP 2004

Microvascular: Neuropathy,Retinopathy,Nephropathy

Macrovascular: Cardiovascular disease, Stroke

What Kind of Care should this patient receive relared to

glycemic control specifically

Ageing, diabetic microvascular and macrovascular complications,

hyperglycaemia, hypoglycaemia, multiple morbidity and lack of

social support are risk factors for the geriatric syndromes

T2DM=type 2 diabetes mellitus.

Araki A, Ito H. Geriatr Gerontol Int. 2009; 9: 105–114.

Ageing

Diabetes

complications

Comorbidity

Lack of social

support

Hyperglycaemia

Hypoglycaemia

Increased

mortality

Depression

Disability

Malnutrition

Urinary

incontinence

Cognitive

impairment

Falling

Risk factors Geriatric

syndromes

Cognitive decline

Depression

Intolerance

to side effects

Po

or

Gly

cem

icC

on

tro

l

“Frailty”

Co-morbidities

Poly-pharmacy

Compromised

renal function

1. Gregg et al. Arch Intern med 2000 ; 160 : 174-80; 2. Ott et al. Diabetologia 1999 ; 53 : 1937-42

3. Rockwood et al. Drugs Aging 2000 ; 17 : 295-302; 4. Wolff et al. Arch Intern med 2002 ; 162 : 2269-76

5. Shorr et al. Arch Intern med 1997 ; 157 : 1681-6

1. Market research, data on file, Novartis.

2. Cryer PE. Diabetes 2008; 57: 3169-76

Hypoglycemia

Other factors

Glycemic targets

Man

ag

em

en

t ch

all

en

ges

Q1. Based on the patient's age, physical examination, history,

and laboratory values, what is an appropriate glycemic target

for him?

A. 9.0%

B. 8.0%

C. 7.0%

D. 6.5%

E. 7-8%

• Glycemic targets for elderly with long-standing or

more complicated disease should be less

ambitious than for the younger, healthier

individuals

• If lower targets cannot be achieved with simple

interventions, an HbA1c of 7.5–8.0% may be

acceptable, transitioning upward as age

increases and capacity for self-care decline

Q2. Do you think increasing insulin dose is the best

choice for Mr. Ahmed?

A. Yes

B. No

Q. What is the suitable antidiabetic therapy

should be added to his medication to

reach the target glycemic control?

ADA 2014: Treatment Goals

according to health status

Why are We Concerned about Diabetes?

Every 24 hours...

3,600 new cases of diabetes are diagnosed

580 people die of diabetes-related complications

225 people have a diabetes-related amputation

120 people with diabetes progress to end-stage renal disease

55 people with diabetes become blind

18

Goals of treatment

Complete elemenation of overt clinical

manifestation

Prevention of ketoacidosis

Prevention and treatment of hypoglycemia

Control if hyperglycemia and glucosuria to

minimize the caloric loss

Maintenance of high levels of physical fitness

19

GOALS

Achievement of normal growth including proper

timing of puberty.

Encourage the patient for full participation in all

activities appropriate for his age.

Education of patient and his families regarding

diabetic process.

Prevention of complication.

20

Higher HbA1c Levels Is Associated with High Risk

of Mortality

n=97,450 T2DMRRR= relative risk reduction

Adapted from Nicholas J, et al. PLoS One. 2013;8(7):e68008.

*A nested case-control study was implemented using

data from family practices between 1 July 2000 and 30

April 2008

21

UKPDS :Acheiving early glycaemic control may generate

a good legacy effect

Pts who initially received intensive therapy had a lower incidence of any

compl.

HbA1c=haemoglobin A1c.;

Holman RR, et al. N Engl J Med. 2008; 359: 1577–1589;

UKPDS 33. Lancet. 1998; 352: 837–853.

Me

dia

n H

bA

1c (

%)

06

7

8

9

UKPDS 1998

Conventional

Intensive

Holman et al 20081997

Difference in HbA1c was lost after first

year but patients in the initial intensive arm still

had lower incidence of any complication:

• 24% reduction in microvascular

complications

• 15% reduction in MI

• 13% reduction in all-cause mortality

2007

22

P=0.14

Reaching target in late stages of the disease

does not reduce vascular complications

Primary outcome: first occurrence of a major cardiovascular event (a composite of myocardial infarction, stroke, death from cardiovascular causes,

congestive heart failure, surgery for vascular disease, inoperable coronary disease, and amputation for ischaemic gangrene).

Duckworth W, et al. N Engl J Med. 2009; 360: 129–139.

1.0

0.8

0.6

0.4

0.2

0.0

0 2 4 6 8

Pro

babili

ty o

f surv

ival

Years

Standard

therapy

Intensive

therapy

892

899

774

770

707

693

No. at risk

Intensive

Standard

639

637

582

570

510

471

252

240

62

55

0

0

VADTPrimary outcome

23

Metabolic – haemodynamic alterations

CVDMicrovascular

Diabetes

Rela

tive

risk

1.0

Disease duration (years)

Early Diabetes Control Improves

Prognosis

Dysglycaemia

Tre

atm

en

t

Adapted from - Rodbard H, Jellinger P. AACE/ACE Glycemic Control Algorithm Consensus Panel. Endocr Pract. 2009;15:541–59

NICE guidelines, Type 2 Diabetes. The Management of type 2 diabetes. Clinical Guidelines 87 2009, NICE, London

NICE short clinical guideline 87. Type 2 diabetes: newer agents for blood glucose control in type 2 diabetes. Available at

http://www.nice.org.uk/nicemedia/live/12165/44318/44318.pdf (PDF). Accessed November 9, 2010

24

aHbA1c ≤6.5%.

HbA1c=haemoglobin A1c; T2DM=type 2 diabetes mellitus.

Liebl A, et al. Diabetologia. 2002; 45: S23–S28.

In the CODE study of a European cohort of over 7000

patients with T2DM, ONLY 31% of patients had adequate

glycemic control

Pa

tie

nts

with

ad

eq

ua

te g

lyca

em

ic

co

ntr

ol (%

)

Approximately 70% of patients with T2DM do not

reach HbA1c goals

25

They need a treatment to overcome

challenges beyond glycaemia

So

The problems faced by patients and

physicians in the management of T2DM

Physician

Anxiety / depression around diabetes,

weight in particular is a big thing

Patients do not understand

hypoglycaemia

Patients intend to miss doses due to

fairness of side effect

Patients want to avoid the disabling long-term

consequences and insulin

Physicians can not do it all

Do not feel encouraged to use new modification

Patient

Physicians are receptive to patients’ fear of

potential hypos8 but dismiss their frequency /

impact on the patients

Huge frustration for patients

and physicians to manage

weight

26

Targeting beyond glycaemia: The challenges

Sustainability

Hypoglycaemia

Confused

Shaking

Sweating

Feels hungry

Feels weak

Adherence to therapy

Helping

patients stick

to their

therapy!

Weight gain/obesity

Diabesity: The new epidemic

27

Hypoglycaemia

A major limiting factor to achieve

intensive glycaemic control in people

with T2DM1

Hypoglycaemia makes clinicians less

likely to implement glycaemic

targets2

28

Hypoglycemia is defined as...

(ADA) Workgroup on Hypoglycemia defined

hypoglycemia as

“Any abnormally low plasma glucose concentration that

exposes the subject to potential harm”

Plasma glucose <70 mg/dL (<3.9 mmol/L), with or without

symptoms.

Minimizing the Risk of Hypoglycemia with Vildagliptin Diabetes Ther (2011) 2(2)

29

Symptoms of hypoglycemia

Autonomic Neuroglycopenic

* Trembling * Bad concentration* Palpitations * Confusion* Sweating * Weakness* Anxiety * Drowsiness* Hunger * Vision changes*Nausea * Difficulty speaking*Tingling * Headache

* Dizziness* Tiredness

30

Hypoglycaemia in type 2 diabetes

Hypoglycaemia symptoms are common in type 2

diabetes (38% of patients)1

It is Associated with:

Reduced quality of life

Reduced treatment satisfaction

Reduced therapy adherence

More common at HbA1c < 7%

1. Diabetes, Obesity and Metabolism 2008 Jun;10 Suppl 1:25-32.

31

Classification of hypoglycemia according to

severity: American Diabetes Association

1- Documented

symptomatic

hypoglycemia.

An event during which typical symptoms of hypoglycemia

are accompanied by a measured plasma glucose

concentration ≤ 70 mg/dl (3.9 mmol/l).

2- Asymptomatic

hypoglycemia.

An event not accompanied by typical symptoms of

hypoglycemia but with a measured plasma glucose

concentration ≤ 70 mg/dl (3.9 mmol/l).

3- Probable symptomatic

hypoglycemia.

An event during which symptoms of hypoglycemia are not

accompanied by a plasma glucose determination.

4- Relative

hypoglycemia.

An event during which the person with diabetes reports any

of the typical symptoms of hypoglycemia, and interprets

those as indicative of hypoglycemia, but with a measured

plasma glucose concentration >70 mg/dl (3.9 mmol/l).

5- Severe An event requiring assistance of another person to actively

administer carbohydrate, glucagons, or other resuscitative

actions.

31American Diabetes Association Workgroup on Hypoglycemia. Defining and Reporting Hypoglycemia in Diabetes. Diabetes Care . 2005;28 (5):1245–1249.This material can only be shown reactively to answer specific questions from physicians.

32

• Advanced age

• Recent hospitalization

• Intercurrent illness

• Chronic liver, renal or

cardiovascular disease

• Endocrine deficiency

(thyroid, adrenal, pituitary)

• Loss of normal counter-

regulation

• Hypoglycaemic

unawareness

SU=sulfonylurea.

Adapted from Chelliah A, Burge MR. Drugs Aging. 2004; 21: 511–530.

I. Patient risk factors

• Poor nutrition or fasting

• Prolonged physical

exercise

• Alcohol (ethanol)

• Use of SU and / or insulin

• Drug interactions with SUs

III. Drug risk factors

II. Lifestyle risk factors

33

Oral antidiabetic agents and hypoglycaemic risk

in type 2 diabetes Agents with increased hypoglycaemic potential

Those which enhance insulin secretion/β-cell function in non-glucose

dependent manner

Sulfonylureas

Short-acting secretagogues (rapaglinide/nateglinide)

Agents with minimal/very ow hypoglycaemic risk

Improve insulin resistance

Metformin

Thiazolidinediones (pioglitazone)

Incretin-based therapies-(insulin secretion in glucose-dependent manner)

Incretin enhancers: DPP-IV inhibitors (sitagliptin, vildagliptin, saxagliptin, )

Reduce glucose absorption

Alpha-glucosidase inhibitors (acarbose, )

34MAOI=monoamine oxidase inhibitor; SU=sulfonylurea.

Adapted from Chelliah A, Burge MR. Drugs Aging. 2004; 21: 511–530.

Displacement of

SUs from the

plasma proteins

Reducing the

hepatic

metabolism of

SUs

Decreasing the

urinary excretion

of SUs or their

metabolites

35

The consequences of

hypoglycaemia...

Hypoglycaemia

Cardiovascular

complications3

Weight gain

by defensive eating5

Coma3

Increased risk

of car accident6

Hospitalisation

costs4

Loss of

consciousness3

Increased risk

of seizures3

Death2,3

Increased risk

of dementia1

1Whitmer RA, et al. JAMA. 2009; 301: 1565–1572; 2Bonds DE, et al. Br Med J. 2010; 340: b4909; 3Barnett AH. Curr Med Res Opin. 2010; 26: 1333–1342; 4Jönsson L, et al. Value Health. 2006; 9: 193–198;5Foley JE, Jordan J. Vasc Health Risk Manag. 2010; 6: 541–548; 6Begg IS, et al. Can J Diabetes. 2003; 27: 128–140; 7McEwan P, et al. Diabetes Obes

Metab. 2010; 12: 431–436.

.

Reduced

quality of life7

36

Hypoglycaemia in T2DM is possible link to

increased CV risk/events

• Haemodynamic changes:

‒ activation of autonomic nervous system

‒ 10-50 fold increased secretion of

adrenaline & noradrenaline

• ECG changes:

‒ longer QT interval

‒ hypokalaemia

Possible mechanisms1,2 Hypoglycaemia as link to tissue ischemia3

Study of 72-h continuous glucose monitoring and

simultaneous cardiac Holter monitoring in patients with

T2DM treated with insulin and history of frequent

hypoglycaemia and coronary artery disease (n=19)

54 episodes of hypoglycaemia reported (BGL <70 mg/dl)

59 episodes of hyperglycemia reported (BGL >200 mg/dl)1Desouza CV, et al. Diabetes Care 2010;33:1389–1394;2Robert TC, et al. Diabetes 2003;52:1469–74;3Desouza C, et al. Diabetes Care 03; 26:1485–1489

*P <0.01 vs episodes during hyperglycaemia and normoglycaemia

Ep

iso

de

s a

cc

om

pan

ied

by

ca

rdia

c s

ym

pto

ms

(%

)

*

*

20

15

10

5

0

37

Pathophysiological cardiovascular

consequences of hypoglycaemia

CRP=C-reactive protein; IL-6=interleukin 6; VEGF=vascular endothelial growth factor.

Desouza CV, et al. Diabetes Care. 2010; 33: 1389–1394.

VEGF IL-6 CRP

Neutrophil

activation

Platelet

activation

Factor VII

Blood coagulation

abnormalities

Sympathoadrenal response

Inflammation

Endothelial

dysfunction

Vasodilation

Heart rate variability

Rhythm abnormalities Haemodynamic changes

Adrenaline

Contractility

Oxygen consumption

Heart workload

HYPOGLYCAEMIA

37

38

Less

6-6.5%More

<8%

< 7% in most patients to reduce the

incidence of microvascular disease

• For selected

patients: with

short disease

duration, long

life

expectancy,

no significant

CVD

• BUT... if this

can be

achieved

without

significant

hypoglycemia

• For patients

with a history

of severe

hypoglycemia

, limited life

expectancy,

advanced

complications

especially

CVD and

extensive co

morbid

conditions

How????

40

Smoking

Lifestyle

Control blood

pressureEducation

Statin

Metformin

Aspirin

Control blood

glucose

Individualised

care of patients:

based on

evidence for each

intervention

Type 2 diabetes management is multifactorial

What’s missing

5 principles in selecting

Antihyperglycemic interventions

1. Efficacy

2.

Hypoglycemia

3. Weight

4. Side effects

5. Cost

42Diabetes Care, Diabetologia.

19 April 2012 [Epub ahead of print]

ADA Issues New Standards of Care in

Diabetes 2015

The researchers note that all

individuals, including those with

diabetes, should be encouraged

to limit the amount of sedentary

time by breaking up extended

amounts of time (more than 90

minutes) spent sitting


Diabetes 2015

Premeal blood glucose targets

were revised to reflect new data.

With respect to cardiovascular

disease and risk management


Diabetes 2015

the recommended goal for

diastolic blood pressure was

changed from 80 to 90 mm Hg for

most people with diabetes and

hypertension


Diabetes 2015

Recommendations for statin treatment and lipid

monitoring were changed; initiation of treatment

and initial statin dose are now recommended

primarily based on risk status.

Based on the new recommendations, lipid

monitoring guidelines suggest a screening lipid

profile at diabetes diagnosis, at an initial

medical evaluation, and/or at age 40 years, and

periodically thereafter


Diabetes 2015

The big change here is to

recommend starting either

moderate- or high-intensity

statins based on the patient's risk

profile rather than on low-density

lipoprotein leve

management of t2 dm beyond glycemic control

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