GLYCEMIC CONTROL CARRY MANY CHALLENGES TO ANY DIABETIC INDIVIDUALS TO REACH GLYCEMIC TARGETS WITHOUT ANY HYPOGLYCEMIC ATTACKS

1. 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

2. 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.

3. 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.

4. 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 .

5. Does his age should be a
concern and why ?

6. • 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

7. What Kind of Care should this
patient receive relared to
glycemic control specifically

8. 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

9. Cognitive decline
Depression
Intolerance
to side effects
PoorGlycemicControl
“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

10. 1. Market research, data on file, Novartis.
2. Cryer PE. Diabetes 2008; 57: 3169-76
Hypoglycemia
Other factors
Glycemic targets
Managementchallenges

11. 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%

12. • 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

13. Q2. Do you think increasing insulin dose is the best
choice for Mr. Ahmed?
A. Yes
B. No

14. Q. What is the suitable antidiabetic therapy
should be added to his medication to
reach the target glycemic control?

15. ADA 2014: Treatment Goals
according to health status

17. 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. 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. 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. 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. 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.
MedianHbA1c(%)
0
6
7
8
9
UKPDS 1998
Conventional
Intensive
Holman et al 2008
1997
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. 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
Probabilityofsurvival
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
VADT
Primary outcome

23. 23
Metabolic – haemodynamic alterations
CVD
Microvascular
Diabetes
Relativerisk
1.0
Disease duration (years)
Early Diabetes Control Improves
Prognosis
Dysglycaemia
Treatment
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. 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
Patientswithadequateglycaemic
control(%)
Approximately 70% of patients with T2DM do not
reach HbA1c goals

25. 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. 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. 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. 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. 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. 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. 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. 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. 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, )

34. 34
MAOI=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. 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. 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
Episodesaccompaniedby
cardiacsymptoms(%)
*
*
20
15
10
5
0

37. 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. 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????

39. 39

40. 40
Smoking
Lifestyle
Control blood
pressure
Education
Statin
Metformin
Aspirin
Control blood
glucose
Individualised
care of patients:
based on
evidence for each
intervention
Type 2 diabetes management is multifactorial

41. What’s missing
5 principles in selecting
Antihyperglycemic interventions
1. Efficacy
2.
Hypoglycemia
3. Weight
4. Side effects
5. Cost

42. 42Diabetes Care, Diabetologia.
19 April 2012 [Epub ahead of print]

50. 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

51. ADA Issues New Standards of Care in
Diabetes 2015
Premeal blood glucose targets
were revised to reflect new data.
With respect to cardiovascular
disease and risk management

52. ADA Issues New Standards of Care in
Diabetes 2015
the recommended goal for
diastolic blood pressure was
changed from 80 to 90 mm Hg for
most people with diabetes and
hypertension

53. ADA Issues New Standards of Care in
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

54. ADA Issues New Standards of Care in
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

55. 55