This document discusses diabetes and hypoglycemia. It begins with statistics showing diabetes is a growing global epidemic, with over 366 million people affected in 2011 and projections of over 552 million by 2030. It then discusses the top 10 countries by diabetes prevalence and how chronic conditions like heart disease and diabetes are overtaking infectious diseases as leading causes of death globally. The rest of the document discusses hypoglycemia in detail, including definitions, treatments, risks, associations with medications and hospitalizations, and how severe hypoglycemia can increase risks of other adverse health outcomes.

1. DR MOHAMED SANDI
CONSULTANT ENDOCRINOLOGY
RCMC YANBU
Diabetic hypoglycemia

2. Diabetes is a Worldwide Epidemic
2011 2030
Total world population (billions) 7.0 8.3
Adult population (20–79 years, billions) 4.4 5.6
Diabetes
Global prevalence (%) 8.3 9.9
Number of people with diabetes (millions) 366 552
In 2011, there were an estimated 366 million people with diabetes
(8.3% of the world’s population)
By 2030, the prevalence is projected to rise to 522 million (9.9%)
International Diabetes Federation. IDF Diabetes Atlas. Update 2012.
International Diabetes Federation. Global burden. IDF Diabetes Atlas. 5th edition 2011.

4. Prevalence of Diabetes:
Top 10 Countries
Country/territor
y
Prevalence of
diabetes (%)
Country/territor
y
Prevalence of
diabetes (%)
Kiribati 25.7 Kiribati 26.3
Marshall Islands 22.2 Marshall Islands 23.0
Kuwait 21.1 Kuwait 21.2
Nauru 20.7 Tuvalu 20.8
Lebanon 20.2 Nauru 20.7
Qatar 20.2 (6)Saudi Arabia 20.6
(7)Saudi Arabia 20.0 Lebanon 20.4
Bahrain 19.9 Qatar 20.4
Tuvalu 19.5 Bahrain 20.2
United Arab
Emirates
19.2 United Arab
Emirates
19.8
International Diabetes Federation. Global burden. IDF Diabetes Atlas. 5th edition 2011.

5. Leading Causes of Global Death:
2004 and 2030
2004 2030
Disease Deaths Rank Rank Deaths
Heart disease 12.2 1 1 14.2
CVD 9.7 2 2 12.1
Pneumonia 7.0 3 4 3.8
HIV/AIDS 3.5 6 10 1.8
Lung cancer 2.3 8 6 3.4
Diabetes 1.9 12 7 3.3
Malaria 1.7 13 41 0.4
Breast cancer 0.9 23 19 1.1
Chronic conditions have overtaken infectious diseases
as the leading causes of global death.
World Health Statistics. World Health Organization; 2008.

8.  Poorly controlled diabetes is associated with
the development of macrovascular disease
and microvascular disease.
 Macrovascular complications are the major
cause of death in people with diabetes.
 There appears to be no glycemic threshold
either microvascular or macro vascular
complications; the lower the HBA1c,the lower
the risk.

9.  until recently, the predominant focus of therapy
has been on lowering HBA1c level, with a strong
emphasis on fasting plasma glucose. Although
control of fasting hyperglycemia is necessary, it
is usually insufficient to obtain optimal glycaemic
control.
 A growing body of evidence suggests that
reducing post meal plasma glucose excursions is
as important for achieving HBA1c goals.

10. Contributions of Basal and Postprandial Hyperglycemia Over a Wide
Range of A1C Levels Before Treatment Intensification in T2DM
Riddle et al. Diabetes Care 34:2508–2514, 20

11. Contributions of Basal and Postprandial Hyperglycemia Over a Wide
Range of A1C Levels After Treatment Intensification in T2DM
Riddle et al. Diabetes Care 34:2508–2514, 20

12. Hypoglycemia in
Diabetes:
the limiting factor
to optimal control

13. RECOGNIZE hypoglycemia and CONFIRM
DIFFERENTIATE mild-moderate vs. severe
TREAT hypoglycemia but AVOID overtreatment
AVOID hypoglycemia in the future
Canadian Diabetes Association Clinical
Practice Guidelines
Hypoglycemia

14. Definition of Hypoglycemia1. Development of neurogenic or neuroglycopenic symptoms
2. Low blood glucose (<4 mmol/L if on insulin or
secretagogue)
3. Response to carbohydrate load
Neurogenic
(autonomic)
Neuroglycopenic
Trembling Difficulty Concentrating
Palpitations Confusion
Sweating Weakness
Anxiety Drowsiness
Hunger Vision Changes
Nausea Difficulty Speaking
Dizziness

15. • Mild
– Autonomic symptoms present
– Individual is able to self-treat
• Moderate
– Autonomic and neuroglycopenic symptoms
– Individual is able to self-treat
• Severe
– Requires the assistance of another person
– Unconsciousness may occur
– Plasma glucose is typically <2.8 mmol/L
Severity of Hypoglycemia

16. Drug Induced Hypoglycemia
 Can result in significant morbidity and mortality
 Serious obstacle to meet glycemic targets
 Counsel patients who drive on insulin or
secretagogues re: self-monitoring of blood
glucose and taking appropriate precautions

17. Steps to Address Hypoglycemia
1. Recognize autonomic or neuroglycopenic symptoms
2. Confirm if possible (blood glucose <4.0 mmol/L)
3. Treat with “fast sugar” (simple carbohydrate) (15 g)
to relieve symptoms
4. Retest in 15 minutes to ensure the BG >4.0 mmol/L
and retreat (see above) if needed
5. Eat usual snack or meal due at that time of day or a
snack with 15 g carbohydrate plus protein

18. Examples of 15 g Simple
Carbohydrate
 15 g of glucose in the form of glucose
tablets
 15 mL (3 teaspoons) or 3 packets of sugar
dissolved in water
 175 mL (3/4 cup) of juice or regular soft
drink
 6 Lifesavers (1=2.5 g of carbohydrate)
 15 mL (1 tablespoon) of honey

19. Recognize Risk Factors for Severe
Hypoglycemia
Risk factors in Type 1 DM
patients
Risk factors in Type 2 DM
patients
Adolescence Elderly
Children unable to detect and/or
treat mild hypoglycemia
Poor health literacy, Food
insecurity
A1C <6.0% Increased A1C
Long duration of diabetes Duration of insulin therapy
Prior episode of severe
hypoglycemia
Severe cognitive impairment
Hypoglycemia unawareness Renal impairment
Autonomic neuropathy Neuropathy

20. Treatment of SEVERE Hypoglycemia
in Conscious Person
1. Treat with oral “fast sugar” (simple
carbohydrate) (20 g) to relieve symptoms
2. Retest in 15 minutes to ensure the BG> 4.0
mmol/L and retreat with a further 15 g of
carbohydrate if needed
3. Eat usual snack or meal due at that time of day
or a snack with 15 g carbohydrate plus protein

21. Treatment of SEVERE Hypoglycemia
in Unconscious Person with no IV
Access
1. Treat with 1 mg of glucagon subcutaneously or
intramuscularly
2. Call 911
3. Discuss with diabetes healthcare team

22. Treatment of SEVERE Hypoglycemia in
Unconscious Person with IV Access
1. Treat with 10-25 g (20-50 cc of D50W) of
glucose intravenously over 1-3 minutes
2. Retest in 15 minutes to ensure the BG >4.0
mmol/L and retreat with a further 15 g of
carbohydrate if needed
3. Once conscious, eat usual snack or meal due at
that time of day or a snack with 15 g
carbohydrate plus protein

23. Hypoglycemia and Driving
 If BG <5.0 mmol/L prior to driving:
 Take 15 g carbohydrate, re-check in 15 minutes
 If BG was <4.0 mmol/L, wait at least 45 minutes after the
BG ≥5.0 mmol/L  safe to drive
 If BG was 4.0-4.9 mmol/L, safe to drive once BG ≥5.0
mmol/L
 Need to re-check BG every 4 hours of continuous
driving and carry simple carbohydrate snacks
Iain S. Begg et al . Canadian Journal of Diabetes. 2003;27(2):128-140.
Safe blood glucose (BG) prior to
driving
BG ≥ 5.0 mmol/L

24. Recommendation 1
1. Mild to moderate hypoglycemia should be
treated by oral ingestion of 15 g carbohydrate;
glucose or sucrose tablets/solutions are
preferable to orange juice and glucose gels [Grade
B, Level 2]
Patients should retest blood sugar in 15
minutes and retreat with another 15 g of
carbohydrates if BG remains <4.0 mmol/L [Grade
D, Consensus]

25. Recommendation 2
2. Severe hypoglycemia in a conscious person
should be treated by oral ingestion of 20 g of
carbohydrate, preferable as glucose tablets or
equivalent.
Blood sugar should be retested in 15 minutes,
and then retreated with a further 15 g of
glucose if BG remains <4.0 mmol/L [Grade D,
Consensus]

26. Recommendation 3
3. Severe hypoglycemia in an unconscious
individual:
 No IV access: 1 mg of glucagon should be
administered subcutaneously or intramuscularly.
Caregivers or support persons should call for
emergency services and the episode should be
discussed with the diabetes healthcare team as
soon as possible [Grade D, Consensus]
 With IV access: 10-25 g (20-50 cc of D50W) of
glucose should be given intravenously over 1-3
minutes [Grade D, Consensus]

27. Recommendation 4
4. For individuals at risk of severe hypoglycemia,
support persons should be taught how to
administer glucagon by injection [Grade D, Consensus]

28. Recommendation 5
5. Once the hypoglycemia has been
reversed, the person should have the usual
meal or snack that is due at that time of
the day to prevent repeated hypoglycemia
[Grade D, Consensus].If a meal is > 1 hour away, a snack (including 15 g of carbohydrate
and protein source) should be consumed [Grade D, Consensus]

29. Recommendation 6
 Patients receiving antihyperglycemic agents that
may cause hypoglycemia should be counselled
about strategies for prevention, recognition and
treatment of hypoglycemia related to driving and
be made aware of provincial driving regulations
[Grade D, Consensus].

30. The Diabetes Control and Complications Trial (DCCT) showed
an inverse relationship between HbA1c and risk of
hypoglycaemic events.
DCCT Research Group. N Engl J Med 1993;329:977–86
141312111098765
0
20
40
60
80
100
Severehypoglycemia
(per100patient-years)
HbA1c (%)
0
2
4
6
8
10
12
14
16
Retinopathy
(per100patient-years)
Conventional
group
Intensive group
Retinopathy
DCCT, Diabetes Control and Complications Trial

31. The Physician’s Dilemma
Adapted from DCCT Research Group N Engl J Med 1993;329:977–
Rateofprogressionofretinopathy
(per100patient-years)
12
10
8
6
4
2
0
5.0 6.0 7.0 8.0 9.0 10.09.5 10.58.57.56.55.5
80
60
40
20
0
100
Rateofseverehypoglycaemia
(per100patient-years)
HbA1c (%)
Retinopathy risk Hypoglycaemia rate

32. 1. ADVANCE. N Engl J Med 2008;358:2560–72; 2. ACCORD. N Engl J Med 2008;358:2545–59; 3. VADT. N Engl J Med
2009;360:129–39
Standard Intensive
p<0.001 p<0.01p<0.001
Per 100-patients per year
0.4 0.7
4.0
12.0
3
6
9
12
15
VADT3ACCORD2ADVANCE1
Per 100-patients per year
1.0
0
Per 100-patients per year
Severehypoglycaemicevents
Severehypoglycaemicevents
Severehypoglycaemicevents
3
6
9
12
15
0
3
6
9
12
15
0
3.0
Standard Intensive Standard Intensive
Intensive glucose lowering contributes to an increased risk of hypoglycemia by 2- to 3-
fold, particularly in advanced type 2 diabetes
Intensive Insulin Therapy is Associated with
Increased Incidence of Severe Hypoglycemia

33. Definition of Hypoglycemia
 Clinical definition of hypoglycaemia:
Low plasma glucose causing neuroglycopenia
 Mild: self-treated
 Severe: requiring help for recovery
 Biochemical definition of a low plasma glucose:
 European Medicines Agency :3.0 mmol/L (<54.1
mg/Dl)
 American Diabetes Association: 3.9 mmol/L (≤70
mg/dL) (ADA)2
 Canadian Diabetes Association: 4.0 mmol/L (<72
mg/dL) for clinical use in patients treated with insulin or
an insulin secretagogue (CDA)31. EMA. CPMP/EWP/1080/00. 2006; 2. ADA. Diabetes Care 2005;28:1245–9; 3. Yale et al. Canadian J Diabetes 26:22–35
ADA, American Diabetes Association; CDA, Canadian Diabetes Association; EMA, European Medicines Agency

34. Hypoglycemia Accounts for Most Endocrine-related Emergency
Hospital Admissions
Budnitz et al. N Engl J Med 2011;365:21

35. Medications Most Commonly Associated with
Emergency Admissions in Patients >65 Years of Age
0%
5%
10%
15%
20%
25%
30%
35%
0
5,000
10,000
15,000
20,000
25,000
30,000
35,000
Percentageofadmissions
Numberofhospitaladmissions
Budnitz et al. N Engl J Med 2011;365:21
Data given are number and percentage of annual national estimates of hospitalisations. Data from the NEISS-CADES project.
ER visits n=265,802/Total cases n=12,666

36. Severe Hypoglycemia in T2DM is as Common
as in T1DM with Increasing Duration of Insulin
Therapy
SU, sulfonylurea; T1D, type 1 diabetes; T2D, type 2 diabetes
UK Hypoglycaemia Study Group. Diabetologia 2007;50:1140–7
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
SU <2 yr >5 yr <5 yr >15 yr
T1DT2D
Severe hypoglycemia
Proportionreportingatleastone
hypoglycaemicepisode
0.0
0.2
0.4
0.6
0.8
1.0
SU <2 yr >5 yr <5 yr >15 yr
T1DT2D
Mild hypoglycemia

37. • Hypoglycemia Increases
morbidity and mortality

38. ADVANCE: Severe Hypoglycemia is Associated with
Increased Risk of Adverse Outcomes
Zoungas at al. N Engl J Med 2010;363:1410–8, for the ADVANCE Collaborative Group
Severe
hypoglycaemia
(n=231)
No severe
hypoglycaemia
(n=10,909)
No. patients with events (%)
Major macrovascular events 33 (15.9) 1114 (10.2) 3.53 (2.41–5.17)
Major microvascular events 24 (11.5) 1107 (10.1) 2.19 (1.40–3.45)
Death from any cause 986 (9.0)45 (19.5) 3.27 (2.29–4.65)
Cardiovascular disease 520 (4.8)22 (9.5) 3.79 (2.36–6.08)
Non-cardiovascular disease 466 (4.3)23 (10.0) 2.80 (1.64–4.79)
Respiratory system events 656 (6.0)18 (8.5) 2.46 (1.43–4.23)
Digestive system events 867 (7.9)20 (9.6) 2.20 (1.31–3.72)
Diseases of the skin 146 (1.3)6 (2.7) 4.73 (1.96–11.40)
Cancer 149 (1.4)5 (2.2) 2.11 (0.65–6.82)
0.1 1.0 10.0
Hazard ratio (95% CI)Events
“Severe hypoglycemia (SH) was strongly
associated with increased risk of a range of
adverse clinical outcomes… (it either) contributes
to adverse outcomes or is a marker of vulnerability
to such events”

39. Association of Hypoglycemia with Acute
Cardiovascular Events in T2DM
 Retrospective, observational study (n=860,845) assessing
association between hypoglycaemia and acute CV events
 3.1% patients had a hypoglycemic event during evaluation
period (1 year)
 Patients who experienced hypoglycemia had a 79%
higher odds of an acute CV event than patients without
hypoglycaemia
Johnston et al. Diabetes Care 2011;34:1164–70

40. Clinical Outcome HR p-value
Macrovascular events 4.0 <0.001
Microvascular events 2.4 <0.001
Death from any cause 4.9 <0.001
Death from CV cause 4.9 <0.001
Death from non-CV cause 4.8 <0.001
ADVANCE:
Hazard Ratios (HR) of Cardiovascular Disease,
Microvascular Events and Death Among Patients that
Experienced
Severe Hypoglycemia vs. Those Who Did Not
Zoungas at al. N Engl J Med 2010;363:1410–8, for the ADVANCE Collaborative Group

41. Severe Hypoglycemia Increases the Risk of CVD and
Microvascular Complications in the Elderly
Zhao et al. Diabetes Care 2012 ;35:1126-113
Outcome HR P
value
CVD 2.0
<0.001
PVD 2.6
<0.001
Stroke 2.3

42. ACCORD: Severe Hypoglycemia is Associated with
Increased Risk of Death
Launer et al for the ACCORD Study Group. Diabetes Care 2012 ;35:787-

43. • Hypoglycemia Decreases
compliance with treatment
and has long-term effects

44. ADVANCE: Severe Hypoglycemia is Associated
with Increased Risk of Adverse Outcomes
Zoungas at al. N Engl J Med 2010;363:1410–8, for the ADVANCE Collaborative Group

45. Neurological Consequences of Hypoglycemia
Short-term:
 Cognitive dysfunction
 Behavioural abnormalities
 Confusional state
 Coma
 Seizures
 TIAs; transient hemiplegia
 Focal neurological deficits
(rare)
Long-term:
•Cerebrovascular events –
hemiparesis
•Focal neurological deficits
•Ataxia; choreoathetosis
•Epilepsy (rare)
•Vegetative state (rare)
•Cognitive impairment with
behavioural and psychosocial
problems
TIA, transient ischaemic attack
Frier. Diabetes and the Brain; Eds Biessels & Luchsinger 2010:131–57

46. Impact of Severe Hypoglycaemic* Event
on Patient’s Behavior
Response to major
hypoglycaemic event (%)
Type 1
diabetes
Type 2
diabetes
Stayed at home next day 20.0 26.3
Feared future hypoglycaemic
events
63.6 84.2
Changed insulin dose 78.2 57.9
Leiter L et al. Can J Diabetes 2005;29:186–92
*Severe hypoglycaemia defined as any event requiring external assistance and with a PG <2.8 mmol/L

47. Fear of Hypoglycemia is Related to
Preceding History of Hypoglycemia
0
4
8
12
16
20
History of
hypoglycaemia
(n=136)
No history of
hypoglycaemia
(n=264)
MeanHFS-IIworryscore
19.0
10.2
p<0.0001*
*Based on the t-test.
HFS-II, Hypoglycaemia Fear Survey-II.
Vexiau et al. Diabetes Obes Metab 2008;10(suppl 1):16–24

48. Socioeconomic Consequences of Non-Severe
Symptomatic Hypoglycemia in Type 2 Diabetes
(France, Germany, UK, USA)
Productivity loss: up to $90 per
event
*Following a daytime event:
• 18% lose an average of 10 h
of work time
• 24% miss a meeting/deadline
*Following a nocturnal
hypoglycaemic event:
• 23% arrive late/miss work
• 32% miss a meeting/deadline
• 15 h of work are lost
• 5.6 extra blood glucose tests
within
7 days after event
• Risk of suboptimal insulin dose
(25% of patients reduce dose)
• 25% contact a healthcare
provider after an episode
• Out-of-pocket costs due to
extra/special groceries, extra
testing supplies and transport:
~$25 per month
Direct impact of reduced
productivity
Indirect impact through
increased treatment cost
Brod et al. Value Health 2011;14:665–71

49. prevent hypoglycemia:
 Keep in mind hypoglycemia risk factors.
 Individualize diabetes therapy.
 Take advantage of anti-diabetic medications
associated with less hypoglycemia.

50. Prevention of hypoglycemia
Keep in mind hypoglycemia
risk factors :

51. Causes and risk factors for
hypoglycaemia
 General causes of hypoglycaemia1,2
 Inadequate, delayed or missed meal
 Exercise
 Too much insulin or oral anti-diabetes medications
 Drug/alcohol consumption
 Increased insulin sensitivity
 Reduced insulin clearance
 lipodystrphy
 Risk factors for severe hypoglycaemia3,4
 Age/duration of insulin treatment
 Strict glycemic control
 Impaired awareness of hypoglycemia
 Sleep
 History of previous severe hypoglycemia
 Renal failure
1.Briscoe and Davis. Clin Diabetes 2006;24(3):115–21; 2. Workgroup on Hypoglycemia, American Diabetes Association. Diabetes
Care 2005;28(5):1245–9; 3. Frier. Diabetes Metab Res Rev 2008;24(2):87–92; 4. Cryer. Diabetes 2008;57(12):3169–76

52. Beware of Patients with Hypoglycemia
Unawareness
• Hypoglycemia
unawareness affects
• 20–25% of adults T1DM
• 10%1 insulin-treated
T2DM
• Risk of severe
hypoglycaemia is 3 to 6
fold greater2
• Broad spectrum of
severity
1. Gold et al. Diabetes Care 1994;17:697-
703
2. Geddes et al. Diabetic Med 2008;25:
501–4
3. Pramming et al. Diabetic Med
Severe hypoglycaemia
without warning3
100
Diabetes duration (years)
0–9 10–19 20–29 30–39 >40
50
0
%events

53. Hypoglycemia is Frequently
Unrecognized by Patients
 Many episodes are asymptomatic; CGMS data show
that unrecognised hypoglycaemia is common in people
with insulin-treated diabetes
 In one study, 63% of patients with type 1 diabetes and 47% of patients with
type 2 diabetes had unrecognised hypoglycaemia as measured by CGMS
(n=70)1
 In another study, 83% of hypoglycaemic episodes detected by CGMS were
not detected by patients with type 2 diabetes (n=31)2
CGMS, continuous glucose monitoring system
1. Chico et al. Diabetes Care 2003;26(4):1153–7; 2. Weber et al. Exp Clin Endocrinol Diabetes 2007;115(8):491–4
74% of all events occurred at night
54% of hypoglycaemic episodes were nocturnal,
none of which were detected

54. Risk of Hypoglycemia during Sleep
 No symptoms detectable during sleep
 Catecholamine responses are diminished1
 May not impair cognitive function the next
day2,3
 Subjective well-being affected with greater
fatigue during exercise3
 May induce impaired awareness of
hypoglycaemia the next day4
1. Jones et al. New Engl. J Med 1998;338:1657-62; 2. Bendtson et al. Diabetologia1992;35:898-903; 3.
King et al. Diabetes Care 1998;21:341-5; 4. Veneman et al. Diabetes 1993;42:1233-7.

55. Risk of Severe Hypoglycemia Increases with Baseline Poor
Cognitive Function:
Importance of early recognition when starting insulin
Launer et al for the ACCORD Study Group. Diabetes Care 2012 ;35:787-

56. Prevention of hypoglycemia
Individualize diabetes
therapy

57. Published in 19th of April 2012
Patient-centered care is defined as:
an approach to “providing care that is respectful of
and responsive to individual patient preferences,
needs, and values and ensuring that patient values
guide all clinical decisions”

58. The elements that may guide the clinician in choosing an
HbA1c target for a specific patient.

59. Glycemic targets
 The ADA’s “Standards of Medical Care in Diabetes” recommends
lowering HbA1c to ,7.0% in most patients to reduce the incidence of
micro vascular disease.
 More stringent HbA1c targets (e.g., 6.0– 6.5%) might be considered
in selected patients (with short disease duration, long life expectancy,
no significant CVD) if this can be achieved without significant
hypoglycemia or other adverse effects of treatment.
 Conversely, less stringent HbA1c goals (e.g., 7.5–8.0% or even
slightly higher) are appropriate for patients with a history of severe
hypoglycemia, limited life expectancy, advanced complications,
extensive comorbid conditions and those in whom the target is difficult
to attain despite intensive self-management education, repeated
counseling, and effective doses of multiple glucose-lowering agents,
including insulin.

60. KEY POINTS:
 Glycemic targets and glucose-lowering therapies must be
individualized.
 Diet, exercise, and education remain the foundation of any type 2
diabetes treatment program.
 Unless there are prevalent contraindications, metformin is the optimal
first-line drug.
 After metformin, there are limited data to guide us. Combination
therapy with an additional 1–2 oral or injectable agents is reasonable,
aiming to minimize side effects where possible.
 Ultimately, many patients will require insulin therapy alone or in
combination with other agents to maintain glucose control.
 All treatment decisions, where possible, should be made in
conjunction with the patient, focusing on his/her preferences, needs,
and values.
 Comprehensive cardiovascular risk reduction must be a major focus of
therapy.

61. Prevention of hypoglycemia
Take advantage
of anti
diabetes
preparations
associated
with less
hypoglycemia

62. Insulin analogues
 Normal physiological insulin profiles consist of a
stable, basal component and meal-related surges in
secretion. Conventional insulin regimens cannot
mimic this profile accurately due to pharmacokinetic
limitations: Human insulin has a slow onset of action,
thus patients are advised to inject about 30 min
before a meal. This is clearly impractical for many and
can lead to pre-meal hypoglycaemia if the meal is
delayed. Furthermore, it only partially overcomes the
unphysiological insulin profile and patients experience
postprandial hyperglycaemia and are vulnerable to
postabsorptive hypoglycaemia.

63.  . Insulin aspart and insulin lispro are rapid-acting
analogues that allow a more physiological
replacement of mealtime insulin secretion. They
reduce postprandial glucose and usefully reduce the
incidence of hypoglycaemia when used in a basal-
bolus regimen in tightly controlled patients.
 Pre-mixed insulins, containing a combination of
rapid-acting and intermediate-acting insulin, are
widely used, particularly in Type 2 diabetes. They
have limitations achieving tight glucose targets but
early data suggest that the combination of 30% insulin
aspart and 70% protaminated insulin aspart may also
reduce severe hypoglycaemia.

64. Confirmed hypoglycaemia (events/patient-year)
HbA1c and Hypoglycemia in Patients
with Type 2 Diabetes
Hermansen et al. Diabetes Care 2006;29:1269–74
Insulin detemir
NPH insulin
0
5.0
12
8
4
6.0 7.0 8.0 9.0
Hypoglycaemiceventsper
patient-year
HbA1c (%)
2
6
10
14

65. Role of Insulin Analogues in the
Prevention of Hypoglycemia
11109876
10
20
30
40
50
60
Hypoglycaemiceventsper
patient-year
Insulin A
Insulin B
HbA1c (%)
Adapted from DCCT Research Group N Engl J Med 1993;329:977–

66. Decreased
Glucose
Production
Increased
Glucose
Uptake
Liver
Insulin Secretion
Fat
Glucose
HomeostasisPancreas
Liver
FatSaxagliptin, a DPP-4 inhibitor,
sustains the effects of incretins in
adults with T2DM
1
Incretins (GIP/GLP-1)
Pancreatic alpha cell
Pancreatic beta cellβ
α
Saxagliptin
DPP4 INHIBITOR (saxagliptin) Mechanism
of Action1,2
Pancreatic cells
respond to higher
levels of incretins
2
O
Glucagon Secretion
α
β Indirect
suppression
of glucagon
1. Kim W et al. Pharmacol Rev. 2008;60:470-512.
2. Drucker DJ. Cell Metab. 2006;3:153-165.
Incretin Effect
GI Tract
DPP-4
Enzymes
O

67. DPP4 INHIBITOR provided statistically significant
reductions in A1C at 6 months when partnered
with MET, GLY, a TZD, or as monotherapy
DPP4 INHIBITOR also reduced FPG and 2-hour
PPG

68. Reported Hypoglycemia During
52-Week Treatment Period*
* Safety analysis set.
† P<0.0001.
MET=metformin.
Göke B et al. Poster presented at: 70th Annual Scientific Sessions of the American Diabetes Association; June 25-29, 2010; Orlando, FL.
Saxagliptin vs Glipizide Study
ProportionofPatients(%)
Proportion of Patients With
≥1 Hypoglycemic Episode
Saxagliptin+
MET
Up-titrated
Glipizide
+MET
36.3
3.0†
0
10
20
30
50
40
12* higher

69. both reported and confirmed events of hypoglycemia in
subjects treated with saxagliptin 5 mg and comparator
during the 24-week short-term period. [1]
* Excludes rescue therapy.
† Confirmed hypoglycemia is defined as symptoms of hypoglycemia and with fingerstick blood glucose measurement ≤50 mg/dL.
Bristol-Myers Squibb Company. Endocrinologic and Metabolic Drugs Advisory Committee: Saxagliptin BMS-477118. Part One.
http://www.fda.gov/ohrms/dockets/ac/09/slides/2009-4422s1-04-sponsor.pdf. Published April 1, 2009. Accessed May 19, 2009.
Percent of Patients
Saxagliptin
(saxagliptin)
5 mg Comparator
Add-On to MET (N=743)
Reported
Confirmed†
5.8%
0.5%
5.0%
0.6%
Add-On to the SU Glyburide (N=768)
Reported
Confirmed†
14.6%
0.8%
10.1%
0.7%
Add-On to a TZD (N=565)
Reported
Confirmed†
2.7%
0%
3.8%
0%
Pooled Monotherapy (N=766)
Reported
Confirmed†
5.6%
0%
4.1%
0%
Initial Combo With MET (N=1306)
Reported
Confirmed†
3.4%
0%
4.0%
0.3%

70.  Incidence of reported hypoglycemia was 5.8% for Saxagliptin™ 5 mg
added on to MET vs 5.0% for placebo plus MET .
 In medication-naive patients given Saxagliptin 5 mg coadministered with
MET, the incidence of reported hypoglycemia was 3.4% compared to
4.0% in those patients given MET plus placebo.
 In the add-on to SU glyburide study, the overall incidence of reported
hypoglycemia was 14.6% for Saxagliptin 5 mg vs 10.1% for placebo.
However, the incidence of confirmed hypoglycemia in this study, defined
as symptoms of hypoglycemia accompanied by a fingerstick glucose
value of ≤50 mg/dL, was 0.8% for Saxagliptin 5 mg and 0.7% for placebo .
 It is important to note that insulin secretagogues, such as SUs, cause
hypoglycemia. Therefore, a lower dose of the insulin secretagogue may
be required to reduce the risk of hypoglycemia when used in
combination with Saxagliptin.
 The incidence of reported hypoglycemia for Saxagliptin 5 mg vs placebo
as add-on therapy to a TZD was 2.7% vs 3.8%, and the incidence of
reported hypoglycemia for Saxagliptin 5 mg given as monotherapy was
5.6% compared to 4.1% for placebo.

71. conclusion
Prevention of hypoglycemia is essential to
success:
1-The impact of hypoglycemia:
 Added cost to diabetes treatment.
 Effect on morbidity and mortality.
 Role in compliance with treatment.
2-How can we prevent hypoglycemia?
 Who is at greater risk? When? (i.e., nocturnal
hypoglycemia).
 Individualizing diabetes therapy.
 Choosing the right anti diabetes to avoid