2. Barriers to Achieving
Glycaemic Goals:
A Focus on Hypoglycemia
and Weight Gain
Lobna F El toony
Head Of Diabetes & Endocrinology Unit
Internal Medicine Department Assuit
University
UEDA – Aswan 2012

3. Diabetes is the epidemic of the new
century

4. Egypt will face explosive
growth of diabetes
9,000
Due to a rapidly increasing &
ageing population, Egypt will
8,000
Source: Diabetes Atlas,
have the larg umber of 2003
people
7,000
6,000 2025
with diabetes in the region by
2nd edition, IDF
5,000
4,000 2025
3,000
2,000
1,000
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5. Dual Defects in Type 2 Diabetes
Genes Environment Genes Environment
Insulin Resistance ß-cell Dysfunction
IGT
Type 2 Diabetes

6. ADA and AACE/ACE Guidelines:
Treatment Goals for A1C, FPG, and PPG
Normal1,2 ADA3 AACE/ACE2
Parameter Level Goal Goal
FPG, mg/dL <100 90–130 <110
PPG, mg/dL <140 <180 <140
A1C, % 4–6 <7a ≤6.5
aThe goal for an individual patient is to achieve an A1C as close
to normal (<6%) as possible without significant hypoglycemia.
FPG=fasting plasma glucose; PPG=postprandial glucose; ADA=American Diabetes Association; AACE=American Association of Clinical Endocrinologists;
ACE=American College of Endocrinology.
1. Adapted from Buse J et al. In: Williams Textbook of Endocrinology. 10th ed. 2003. Permission requested.
2. AACE Diabetes Mellitus Clinical Practice Guidelines Task Force. Endocr Pract. 2007;13:(suppl 1)3–68.
3. ADA. Diabetes Care. 2007;30:S4–S41.

7. Two thirds of individuals do not
achieve target HbA1c
Saydah SH, et al. JAMA 2004; 291:335–342.
Liebl A, et al. Diabetologia 2002; 45:S23–S28.

8. Diabetes management guidelines:
a sense of urgency
HbA1c“...
the results of the UKPDS
mandate that treatment of type 2 diabetes
include aggressive efforts to lower blood
glucose levels as close to
normal as possible” American Diabetes Association
Diabetes must be… diagnosed earlier.
And once diagnosed, all types of
diabetes must then be managed
much more aggressively”
Canadian Diabetes Association
“
1American Diabetes Association. Diabetes Care 2003; 26:S28–S32.
2Canadian Diabetes Association. Can J Diabetes 2003; 27 (Suppl. 2):S1–S152.

9. Deaths related to
21% diabetes
HbA1c
Microvascular
37% complications
1%
Myocardial
14% infarction
Stratton IM, et al. BMJ 2000; 321:405–412.

10. Tight Glycaemic
control
• Hypoglycaemia
Macrovascular
•Weigh gain
&
Microvascular
Risk Reduction

11. Barriers to Achieving
Glycaemic Goals:
A Focus on Hypoglycaemia
422HQ11NP 027

12. Classification of Hypoglycemic Episodes
Based on whether individuals can treat
themselves.
 Symptomatic definitions:
 Mild hypoglycemia: Adrenergic Symptoms
(BG<70mg/dl)
 (The patient is able to self-treat))
Moderate hypoglycemia: Cognitive impairment
(BG<50mg/dl)
 “Severe Hypoglycemia”: Unconscious (BG
???)
 Unconsciousness and seizures.
12

13. Causes of hypoglycaemia
The main cause of hypoglycaemia in people
with type 2 diabetes is their diabetes medication
 Hypoglycaemia occurs when there is an absolute or relative excess
of therapeutic insulin in the presence of impaired counter-regulatory mechanisms
 This commonly occurs with the use of insulin secretagogues or insulin, which raise
insulin levels independently of blood glucose
Amiel SA, et al. Diabet Med. 2008;25:245-54.

14. Severe hypoglycaemic episodes
increase with duration of
Proportion reporting at least one episode of
T2D sulphonylureas (n= 103)
treatment 0.6
T2D
T2D
T1D
<2 years insulin (n= 85)
>5 years insulin (n= 75)
<5 years (n= 46)
severe hypoglycaemia
T1D >15 years (n= 54)
0.4
Annual
0.2 Prevalence
= 7%
0.0
Treated with <2 yrs >5 yrs <5 yrs >15 yrs
sulphonylurea of insulin treatment of insulin treatment
Type 2 diabetes (T2D) Type 1 diabetes (T1D)
Error bars, 95% confidence interval.
 The proportion of patients with type 2 diabetes experiencing severe
hypoglycaemia was similar for those treated with sulphonylureas or insulin
for <2 years (7% in both groups)
UK Hypoglycaemia Study Group. Diabetologia. 2007;50:1140-7.

15. Consequences
of hypoglycaemia
422HQ11NP 027

16. History of hypoglycaemia and risk of
cognitive decline in older type 2 diabetes
patients
History of severe hypoglycaemic episodes are associated
with a significantly greater risk of dementia
No. of Antecedent Severe Adjusted Hazard Ratio* for Incident Dementia
Hypoglycaemic Episodes (95% Confidence Interval)
≥1 1.44 (1.25-1.66)
1 1.26 (1.10-1.49)
2 1.80 (1.37-2.36)
≥3 1.94 (1.42-2.64)
*Adjusted for age (as time scale), BMI, race/ethnicity, education, sex, duration of diabetes, comorbidities, 7-year mean HbA1c level,
diabetes treatment, and years of insulin use
Whitmer RA, et al. JAMA. 2009;301:1565-72.

17. Hypoglycaemia was a major predictor of
cardiovascular death in the VADT study
Hazard Ratio
(confidence limits) P Value
Hypoglycaemia 4.042 (1.449, 11.276) 0.01
HbA1c 1.213 (1.038, 1.417) 0.02
HDL 0.699 (0.536, 0.910) 0.01
Age 2.090 (1.518, 2.877) <0.01
Prior event 3.116 (1.744, 5.567) <0.01
0 2 4 6 8 10 12
 Previous hypoglycaemia may impair cardiovascular autonomic function
Hazard ratio (confidence limits)
 Cardiovascular autonomic testing in 20 healthy subjects showed reduced
baroreflex sensitivity and reduced mucsle response to vasodilation in those
who had experienced a previous hypoglycaemic episode
Duckworth W. Presented at the ADA 68th Scientific Sessions, 2008. Available at:
http://professional.diabetes.org/presentations_details.aspx?session=3167. Accessed: 12 Nov, 2010.

18. Potential impact of hypoglycaemia
Likely consequences of hypoglycaemia include:
 Physical and psychological morbidity and, in severe cases,
fatality
 Compromised physiological and behavioural defences
against subsequent falling plasma glucose concentrations,
causing a vicious cycle of recurrent episodes
Hypoglycaemia may preclude the maintenance of
euglycaemia over a lifetime of diabetes and therefore
limits the vascular benefits from glycaemic control
Cryer PE. Diabetes. 2008;57:3169-76

19. Current goals and the importance
of individualisation
Current guidelines generally recommend:1-4
HbA1c level ≤7.0% (53 mmol/mol) to lower the risk of micro and macrovascular complications
OR
HbA1c level ≤6.5% (48 mmol/mol) to achieve near normoglycaemic control
- Episodes of hypoglycaemia should be carefully titrated against this
- Individuals with hypoglycaemia unawareness or severe hypoglycaemia should
raise their glycaemic targets to avoid further episodes of hypoglycaemia
Selecting the most appropriate therapy and individualising
treatment are key to reducing the prevalence of hypoglycaemia
Education and motivation are important to avoid hypoglycaemia
1. Canadian Diabetes Association. Can J Diabetes. 2008;32(Supp1):S1-S201. 2. American Diabetes
Association. Diabetes Care. 2009;32(Suppl 1):S13-61. 3. Matthaei S, et al. Exp Clin Endocrinol Diabetes.
2009;117:522-57. 4. Rydén L, et al. Eur Heart J. 2007;28:88-136.

20. Risk factors for hypoglycaemia
Behavioural Physiological Therapeutic
 Missed or irregular meals  Advancing age  Glucose-lowering therapy
 Alcohol or drug use  Longer diabetes duration  Concurrent
medication (e.g. aspirin,
 Exercise  Presence of comorbidity
warfarin, NSAIDs)
 Incorrect use  Deterioration of renal and
of glucose-lowering hepatic function
medication
 Loss of awareness of
hypoglycaemia
Amiel SA, et al. Diabetic Med. 2008;25:245-54.

21. Glucose-lowering agents classified
by risk of hypoglycaemia
High risk1,2 Low risk1,2
Insulin Metformin
Sulphonylureas -glucosidase inhibitors
Glinides Pioglitazone
GLP-1 receptor agonists
DPP-4 inhibitors
1. Nathan DM, et al. Diabetologia. 2009;52:17-306. 2. Cefalu WT. Nature. 2007;81:636-49.

22. Hypoglycaemia
in elderly people with
type 2 diabetes
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23. The problem of hypoglycaemia in
elderly patients
Potentially serious, sometimes life-threatening consequences
• Impairment in heart and brain function
• Cardiovascular events
• Falls and injury
• Cognitive decline
Detection is more problematic
• Blunted symptoms (may be different from younger patients)
• Impaired cognition
Presence of multiple risk factors
•Multiple comorbidities and medication
•Renal impairment
•Poorly-adapted behaviour response
•Rare use of self-monitoring and lack of education
Lecomte P. Diabetes Metab. 2005;31:5S105-5S111.

24. Hypoglycaemia may be underestimated in
elderly people with type 2 diabetes
Symptoms of hypoglycaemia are not specific in nature:
 Weakness
 Unsteadiness
 Sleepiness
 Feeling faint
 Feeling light-headed
 Poor concentration
Neurological symptoms of hypoglycaemia may be misinterpreted as...
 Transient cerebral ischaemia
 Vertebrobasilar insufficiency
 Vasovagal attacks
 Cardiac dysrhythmia
McAulay V, et al. Diabet Med. 2001;18:690-705.

25. Summary 1
Hypoglycaemia is a potentially serious complication in type 2
diabetes, especially in the elderly
 Hypoglycaemic episodes may be associated with
cardiovascular death, MI, cardiac arrhythmias, nervous
system abnormalities and cardiac ischaemia
 Individualised treatment is key in order to avoid
hypoglycaemia and glucose-lowering medication must be
adapted to each person’s needs and lifestyle.
 Several glucose-lowering agents (e.g. insulin secretagogues
and insulin therapy) may increase the risk of
hypoglycaemia
 Fear of hypoglycaemia and the risks associated with
treatment may cause individuals to stop taking their
medication – a major barrier to achieving glycaemic
control

26. Barriers to Achieving
Glycaemic Goals:
A Focus on Weight
Gain and Obesity

28. Overweight/obesity: classification
Cut-off points for overweight and obesity
in European and Asian populations
BMI (kg/m2) BMI (kg/m2)
European1 Asian2
Normal 18.5–24.9 18.5–22.9
Overweight (pre-obese) 25–29.9 23–24.9
Obese ≥30 ≥25
The optimum population BMI is considered to be ~213
1. Tsigos C, et al. Obes Facts. 2008;1(2):106-16. 2. WHO Expert Consultation. Lancet. 2004 Jan
10;363(9403):157-63. 3. James WPT. J Intern Med. 2008;263:336-52.

30. The vast majority of people with type 2
diabetes are overweight or obese
Normal A large proportion of
10% people have metabolic
syndrome
90%
Overweight/obese
Individuals with type 2 diabetes
World Health Organization Fact sheet: Obesity and overweight. Available at:
http://www.who.int/dietphysicalactivity/publications/facts/obesity/en/. Accessed: 12 Nov, 2010.

31. Prevalence of Sedentary Life &
Obesity in Egypt
Prevalence of sedentary lifestyle & obesity in the Egyptian population
aged ≥ 20 years by residence and socio-economic status (1992-1994)
Residence & Prevalence of Sedentary Prevalence of Obesity
Socio- economic Lifestyle (%)
Status (%)
 Rural 52 16
 Urban (Lower SES) 73 37
 Urban (Higher SES) 89 49
 Total 63 27
SES= Socio-economic status

32. Visceral fat independently predicts
all-cause mortality in men
Modeled data for odd ratios for mortality with increasing visceral
fat mass after control for age and follow-up time
6 N=291
p<0.05
5
Odds ratios for mortality
4
3
2
1
0
0 0.25 0.5 0.75 1 1.25
Visceral Fat (kg)
Kuk JL, et al. Obesity. 2006;14:336-41.

33. Atherosclerosis in youth is linked to
obesity Mean extent of right coronary artery lesions by BMI
and panniculus thickness in young men (N=2133)
Panniculus thickness ≤ median for sex and BMI
Panniculus thickness > median for sex and BMI
12 4
Fatty Streaks Raised Lesions
Surface area involved (%)
Surface area involved (%)
10
3
8
6 2
4
1
2
0 0
<25 25-30 >30 <25 25-30 >30
Body mass index (kg/m2) Body mass index (kg/m2)
McGill HC, et al. Circulation. 2002;105:2712-8.

34. Overweight/obesity is an
important risk factor
for cardiometabolic disease
Abdominal obesity = cardiometabolic risk
Excess body weight, especially intra-abdominal fat,
adversely impacts many cardiometabolic risk factors,
including:
 Hypertension
 Dyslipidaemia
 Insulin resistance
 Type 2 diabetes
Hamdy O, et al. Curr Diabetes Rev. 2006 Nov;2(4):367-73.

35. Mechanisms linking
excess body fat and
obesity to disease
422HQ11NP057

36. Adipose tissue is a dynamic
endocrine organ
↑Insulin Hypertension
↑IL-6 ↑Angiotensinogen
Inflammation ↑Insulin
↑ Insulin ↑TNF ↑FFA Dyslipidaemia
Adipose
tissue ↑Resistin ↑Insulin
↑Adipsin
(Complement D) ↑Leptin ↑Insulin
↑Leptin Type 2 Diabetes
↓Adiponectin ↑PAI-1
Atherosclerosis
Thrombosis
↑Insulin
Lyon CJ, et al. Endocrinology 2003;144:2195-200.
Trayhurn P, Wood IS. Br J Nutr 2004;92:347-55.

37. Adiponectin has beneficial effects
on the cardiovascular system
Adiponectin protects cardiovascular tissues
under conditions of stress
TZDs
Caloric restriction
Adiponectin
Angiogenesis Hypertrophy 
Apoptosis Fibrosis 
Inflammation 
Cardiovascular protection
Shibata R, et al. Circ J 2009; 73: 608-14.

38. People with diabetes, especially obese
individuals, are characterised by elevations
in free fatty acids (FFAs)
In diabetes, elevated plasma FFAs fail to
decline normally in response to insulin
Similar abnormalities in FFA metabolism are found
in individuals with impaired glucose tolerance and in
non-diabetic, insulin-resistant, obese individuals
Increased visceral fat is specifically related to
FFA-associated insulin resistance
Subcutaneous fat Visceral fat
Bays H, et al. J Clin Endocrinol Metab. 2004;89:463-78.

39. Involvement of adipose tissue, liver
and muscle in obesity-induced CV
Macrophage
recruitment
disease NEFAs
RBP-4
(visceral) Ectopic
Myocellular fat
adipose tissue ectopic fat
IL-6
MCP-1
NEFAs
TNF- Insulin Diabetes
Adiponectin  resistance
VLDL ROS
INFLAMMATION
CRP PAI-1 LDL-ox ICAM-1
Endothelial dysfunction
Atherosclerosis
Van Gaal LF, et al. Nature. 2006;444(7121):875-80.

40. Cross-talk among adipocytes, macrophages
and endothelial cells in inflamed adipose
tissue
Monocyte rolling Attachment Transendothelial
migration
Cross-talk CCR2
CCL2
Macrophage
Adipocyte
MCP-1 Insulin Adipokines
resistance
IL-6
IL-1b
TNF- Local insulin resistance?
Systemic insulin resistance?
Local angiogenesis
Proinflammatory cytokines/chemokines
Angiogenic factors
Neels JG, Olefsky JM. J Clin Invest. 2006;116:33-5.

41. Increased body weight is associated with
increased death rates for cancer
Mortality from cancer according to BMI for men
Type of Cancer (highest BMI category)
Prostate (35) 1.34
Non-Hodgkin’s lymphoma 1.49
(35)
All cancers (40) 1.52
All other cancers (30) 1.68*
Kidney (35) 1.70
Multiple myeloma (35) 1.71
Galbladder (30) 1.76
Colon and rectum (35) 1.84
Oesophagus (30) 1.91*
Stomach (35) 1.94
Pancreas (35) 2.61*
4.52
Liver (35)
1 2 3 4 5 6 7
Relative Risk of Death (95% Confidence Interval)
For each relative risk, the comparison was between men in the highest body-mass-index (BMI) category (indicated in
parentheses) and men in the reference category (body-mass index, 18.5 to 24.9). Asterisks indicate relative risks for
men who never smoked. Results of the linear test for trend were significant (P≤0.05) for all cancer sites
Calle EE, et al. N Engl J Med 2003;348:1625-38.

42. Obstructive sleep apnoea (OSA) associated
with type 2 diabetes and obesity
 Excess weight is an important risk factor for OSA1
 41–58% of OSA is estimated to be attributable to excess
weight
 Increasing evidence suggests that OSA has adverse
effects on glucose metabolism and risk of diabetes,
independent of degree of obesity2
 OSA is also a significant risk factor for CV disease and
mortality2
Physicians should be aware of the extremely high
prevalence (>86%) of undiagnosed OSA
1. Young T, et al. J Appl Physiol. 2005;99:1592-9. 2. Tasali E, et al. Chest. 2008;133;496-506. 3. Foster
in GD, et al. Diabetes Care. 2009;32:1017-9.
obese individuals with type 2 diabetes3

43. Mechanistic Links: Sleep Apnea and
Metabolic Dysfunction
Sleep Fragmentation
Sympathetic Activation
Insulin
Sleep Apnea HPA dysregulation Type 2 Diabetes
Resistance
Systemic Inflammation
b-cell
Dysfunction
?
Intermittent
Hypoxemia

44. Weight gain as a
consequence of treatment
422HQ11NP057

45. overweight/obesity, diabetes and CV risk:
potential impact of treatment-related
weight gain
+ Weight
gain/
obesity
Treatment-
related weight +
gain, and/or
weight gain
through Diabetes CV risk
“defensive
snacking”
because of -
hypoglycaemia
Glucose-
lowering therapy
Increases CV risk
Decreases CV risk
Peters AL. Cleve Clin J Med. 2009 Dec;76 Suppl 5:S20-7.

46. Most current therapies result in weight gain
over time
UKPDS: up to 8 kg ADOPT: up to 4.8 kg
in 12 years1 in 5 years2
8 100 Annualised slope (95% CI)
Insulin (n=409)
Rosiglitazone, 0.7 (0.6 to 0.8)
7 Metformin, -0.3 (-0.4 to -0.2)
Glibenclamide, -0.2 (-0.3 to 0.0)
6 96
Change in weight (kg)
5
Weight (kg)
Glibenclamide (n=277)
4
92
3
2 Conventional (n=411)*
88
Treatment difference (95% CI)
1 Rosiglitazone vs metformin
6.9 (6.3 to 7.4); P<0.001
Rosiglitazone vs glibenclamide,
0 2.5 (2.0 to 3.1); P<0.001
Metformin (n=342)
0
0 3 6 9 12 0 1 2 3 4 5
Years Years
* Conventional treatment; diet initially then sulphonylureas, insulin and/or metformin if FPG >15 mmol/L (>270 mg/dL)
n=at baseline
On 23 September 2010, the European Medicines Agency recommended suspension of
marketing authorisations for rosiglitazone
1. UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:854-65. 2. Kahn SE, et al (ADOPT).
N Engl J Med. 2006;355:2427-43.

47. Glucose-lowering medications and
weight profile
Range of weight change (kg) in response
to diabetes medications
Sulphonylureas
Glinides
Thiazolidinediones
Insulin
DPP-4 inhibitor (sitagliptin)
Metformin
GLP-1 receptor agonist (exenatide)
-6 -4 -2 0 2 4 6 8 10
Range of weight change (kg)
Mitri J, Hamdy O. Expert Opin Drug Saf. 2009;8:573-84.

48. Combination therapy and weight
gain
Consensus statements from the AACE-ACE
Insulin + SUs
Combined use of any 2 or all 3
Insulin + TZDs of these agents may result in an
increased risk of weight gain
SUs + TZDs
AACE: American Association of Clinical Endocrinologists
ACE: American College of Endocrinology
Rodbard HW, et al. Endocr Pract. 2009;15:540-59.

49. Some medications have a weight-
neutral effect
DPP-4 inhibitors have weight-neutral effect in T2D patients,
either as monotherapy and as add-on therapy to other oral agents
Intestinal TG
 Apo B-48 - absorption
DPP-4
inhibitors + Lipolysis
FFA
+ Fat oxidation
- Blocks
+Promotes
Foley JE, et al. Vasc Health Risk Manag. 2010 Aug 9;6:541-8.

50. Defensive snacking as a potential
mechanism for weight gain in diabetes
 In the DCCT, insulin-treated patients with severe hypoglycaemia had a
significantly (P<0.05) greater increase in weight than those without severe
hypoglycaemia during the study
Patients with severe
hypoglycaemia +6.8 kg
Patients without severe
hypoglycaemia +4.6 kg
0 2 4 6 8
Weight gain (kg)
 A potential explanation for this is “defensive snacking” – an increase in
a patient’s carbohydrate intake following hypoglycaemia due to their fear of
further events
Russell-Jones D, Khan R. Diabetes Obes Metab. 2007;9:799-812.

51. Beneficial effects of
modest and major weight
reduction
422HQ11NP057

52. Weight loss: a cost-effective means
of controlling diabetes
 The advantages of weight loss are its pleiotropic benefits, safety profile and low
cost1
Improves blood glucose, blood pressure and lipids1
Reduces the risk of progression from pre-diabetes
to overt diabetes2
Body weight
May help to avoid other comorbidities
associated with obesity (e.g. degenerative joint
disease and urinary incontinence)3
Needs to be maintained
in the long term1
1. Nathan DM, et al. Diabetologia. 2009;52:17-306. 2. Knowler WC, et al. N Engl J Med. 2002;346:393-403.
3. Bouldin MJ, et al. Am J Med Sci. 2006;331:183-93.

53. Major weight reduction (>10-15%):
Recommendations for bariatric
surgery
Surgery should be considered:
 For patients with a BMI of 30−35* kg/m2
whose diabetes is not adequately
controlled by optimal medical regimens,
especially when there are other major co-
morbidities
Surgery should be an accepted option:
 For individuals with type 2 diabetes and
a BMI of 35 kg/m2 or more
*In Asian and some other ethnicities of increased risk, BMI action points may be reduced by 2.5 kg/m2
1. IDF position statement. Available at:http://www.idf.org/webdata/docs/IDF-Position-Statement-
Bariatric-Surgery.pdf. Accessed 2 Aug 2011.

54. Different bariatric procedures

55. Major weight loss may be associated with
recovery of type 2 diabetes in some
individuals1,2
Recovery of type 2 diabetes in severely* obese individuals
receiving either bariatric surgery or conventional therapy2
100
Patients with diabetes remission (%)
p<0.001
N = 2037
80
72% p<0.001
60
40 36%
21%
20 13%
0
Surgical Control Surgical Control
(N=342) (N=248) (N=118) (N=84)
2 Years 10 Years
*With a BMI of approximately 40 kg/m2
Recovery based on fasting plasma glucose <7.0 mmol/l and not receiving hypoglycaemic therapy
1. Colquitt JL, et al. Cochrane Database Syst Rev. 2009;(2):CD003641 2. Buchwald H, et al.
Am J Med. 2009;122:248-256.e5. 3. Sjostrom L, et al. N Engl J Med. 2004;351:2683-93.

56. Summary 2
 Most people with type 2 diabetes (T2D) are overweight or
obese
 T2D as a result of obesity is responsible for a significant
proportion of obesity-related disability and life-years lost
 Abdominal obesity is most strongly associated with a
constellation of risk factors linked with diabetes and
cardiovascular disease
 Other comorbidities such as obstructive sleep apnoea and
depression may be associated with obesity in type 2
diabetes
 Glucose-lowering medications provide options to
choose weight-neutral or weight-loss drugs
 Bariatric surgery should be considered for severely
obese patients with T2DM

57. THANK YOU
FOR TRYING
TO STAY
AWAKE
Lobna F El Toony