This document discusses evidence that intensive glycemic control can reduce cardiovascular risk for patients with type 2 diabetes, but that this risk reduction may come at the price of increased risk of hypoglycemia. Some key points discussed include: 1) trials like UKPDS and ACCORD showed glycemic control reduced microvascular and cardiovascular complications but increased risk of hypoglycemia; 2) hypoglycemia is associated with increased cardiovascular risk and mortality in some studies; and 3) the benefits of intensive control may depend on patient characteristics like age and diabetes duration, with shorter-duration patients experiencing more benefit. The document evaluates how best to fit treatment targets and medications to individual patients to maximize benefits and minimize hypoglycemia risk.

1. Hypoglycemia and Cardiovascular Events
Choosing right therapies and targets, and the right patient
Mathew John
Endocrinologist
Providence Endocrine & Diabetes Specialty Centre
Trivandrum, India
www.endocrinologydiabetes.com

2. Plan
• Show evidence that CV disease is increased in type 2
diabetes
• Show evidence that multifactorial interventions including
glycemic control will reduce risk of CV disease
• Evaluate hypoglycemia in recent trials
• How hypoglycemia is related to CV outcomes
• Fitting targets and drugs to the right patient

3. Improved Glycemic Control Has Been Shown
to Reduce the Risk of Complications
According to the United Kingdom Prospective Diabetes
Study (UKPDS) 35, Every 1% Decrease in A1C Resulted in:
14% 12%
21%
37%
Decrease Decrease Decrease Decrease
in risk of any in risk of MI in risk of in risk of
diabetes-related (P<.0001) stroke microvascular
end point (P=.04) complications
(P<.0001) (P<.0001)
Stratton IM et al. BMJ. 2000;321:405-412.

4. Intervention Works...but at a
Price: DCCT and UKPDS
Severe Hypoglycemia
100 DCCT (Type 1) UKPDS (Type 2)
Major Episodes
5
Major Episodes Incidence (%)
80
Rate/100 Patient Years
4
60
Intensive 3
Intensive
40
2
20 1
Conventional Conventional
0 0
5 6 7 8 9 10 11 12 13 14 0 3 6 9 12 15
HbA1c (%) During Study Years from Randomization
DCCT Research Group, Diabetes. 1997;46:271-286 UKPDS Group (33), Lancet. 352: 837-853, 1998

5. Asymptomatic Episodes of
Hypoglycemia May Go Unreported
100
75 • In a cohort of patients with
62.5
diabetes, more than 50% had
Patients, %
55.7
50 46.6 asymptomatic (unrecognized)
hypoglycemia, as identified by
continuous glucose
25 monitoring1
• Other researchers have
n=70 n=40 n=30
0 reported similar findings2,3
All patients Type 1 Type 2
with diabetes diabetes
diabetes
Patients With ≥1 Unrecognized Hypoglycemic Event, %
1. Chico A et al. Diabetes Care. 2003;26(4):1153–1157. Permission pending.
2. Weber KK et al. Exp Clin Endocrinol Diabetes. 2007;115(8):491–494.
3. Zick R et al. Diab Technol Ther. 2007;9(6):483–492.

6. Reporting hypoglycemia
• Documented symptomatic hypoglycemia: plasma
glucose < 70 + symptoms
• Severe hypoglycemia: requiring assistance of
another person for resuscitation
• Asymptomatic hypoglycemia
• Probable symptomatic hypoglycemia
• Relative hypoglycemia: symptoms of hypoglycemia+
plasma glucose > 70 mg/dl
ADA Working Group on Hypoglycemia Diabetes Care 2005: 28(5): 1245-1249.

7. Severe hypoglycemia : definition in
ACCORD
Requiring medical or paramedical attention in which
there was either a documented capillary glucose level 50
mg/dL (2.8 mmol/L) or in which prompt recovery was
achieved with oral carbohydrate, intravenous glucose, or
glucagons
Severe Hypoglycemia Monitoring and Risk Management Procedures in the Action to Control Cardiovascular
Risk in Diabetes (ACCORD) Trial . Am J Cardiol 2007;99[suppl]:80i–89i)

8. Counter regulatory hormone response
82 mg/dl Inhibition of endogenous insulin secretion
70 mg/dl Counterregulatory hormone release
GLUCAGON, CATECHOLAMINES
Onset of autonomic and
50-60 mg/dl neuroglycopenic symptoms
Cognitive dysfunction
< 50 mg/dl
coma,
< 30 mg/dl convulsions
Zammitt NN, Frier BM. Hypoglycemia in type 2 diabetes
Diabetes Care 2005: 28: 12: 2948-2961

9. Counter regulatory hormone response
Counter regulation: physiological mechanisms
that normally prevent or rapidly correct hypoglycemia
• Glucagon : predominant hormone
• Catecholamines
• Cortisol
• Growth hormone
Zammitt NN, Frier BM. Hypoglycemia in type 2 diabetes
Diabetes Care 2005: 28: 12: 2948-2961

10. Complications and Sequelae
of Hypoglycemia
Plasma glucose level
110
6
100 Increased risk of
5 90
cardiac arrhythmia
• Abnormal prolonged cardiac repolarization—
80 Release of ↑in QTc and QTd—associated with ↑ levels of
epinephrine and
4 epinephrine and hypokalemia
70 norepinephrine
• Cardiac death
60
3 Neuroglycopenia
50
• Reduced attention span
40 • Inability to focus
2
• Personality change
30
• Confusion
1 20
• Seizure
mmol/l
• Coma
10
mg/dl • Brain death
Cryer PE. J Clin Invest. 2006:116:1470–1473.

11. Cardiovascular benefits of
glycemic control and Multifactorial
Interventions
UKPDS legacy effect
ACCORD study : subgroups
VADT : subgroups

12. ACCORD : Kaplan–Meier Curves for the Primary
Outcome and Death from any cause
Composite primary outcome Death from any cause
Nonfatal MI + nonfatal stroke +
Intensive vs. Std
death from CV causes 257 vs. 203
(6.9% in Intensive vs. 7.2% in std therapy group 5 % vs. 4 % , HR 1.22 95 %
HR 0.90 CI 0.78-1.04, p: 0.16) CI : 1.01-1.46, p=0.04)
Not significant

13. Why was mortality increased ?
• Not certain
• Speed of HbA1c reduction ( 1.4 % vs. 0.6% in 4 months)
• Drug combinations
• Unidentified hypoglycemia
• Weight gain
• Hypoglycemia unawareness (associated cardiac autonomic
neuropathy)
Analysis proves that the increased mortality rates are not
related to
1. Specific OAD ( Rosiiglitazone, SU , Insulin etc)
2. Changes in other medications( Statins,Aspirin etc)
Intensive Glycemic Control and the Prevention of Cardiovascular Events: Implications of the ACCORD,
ADVANCE, and VA Diabetes Trials Diabetes Care January 2009 vol. 32 no. 1 187-192

14. Increased Mortality, Myocardial Infarction, and
Hypoglycemia With Intensive Therapy:
ACCORD Trial
Mortality (% per year)1
≥1 severe hypoglycemia
3.1
(n = 705)
No hypoglycemia
1.2
(n = 9,546)
a Defined by requirement for medical or paramedical intervention, with
documented glucose <50 mg/dL and relief by parenteral or oral glucose
or by glucagon.
1 Bloomgarden ZT. Diabetes Care. 2008;31(9):1913–1919. 2. Dluhy RG, McMahon GT. N Engl J Med. 2008;358:2630–2633.

15. ACCORD
• Rate of 1-year change in A1c showed that a greater
decline in A1c was associated with a lower risk of death
• 20% higher risk of death for every 1% higher A1c level
above 6%, suggesting that lower blood glucose levels
may be a worthy target in some patients
• Patients with the [consistently] lowest A1c levels had
the lowest risk. The excess mortality risk was in
those patients who failed to achieve and sustain
A1c levels between 6% and 7%.
Update on ACCORD. International Diabetes Federation 2009 World Diabetes
Congress. October 22, 2009; Montreal, QC. American Diabetes Association (ADA) 69th Scientific Sessions:
Abstract 468-P. Presented June 9, 2009

16. ACCORD: Adjusted mortality rates by
treatment strategy
Riddle MC, Ambrosius WT Epidemiologic relationships between A1C and all cause mortality during a median 3.4-
year follow-up of glycemic treatment in the ACCORD trial. Diabetes Care 2010;33: 983–990

17. ACCORD : Adjusted log HR by
treatment strategy
The excess risk associated with intensive
glycemic treatment occurred among
those participants whose average A1C,
contrary to the intent of the strategy, was
>7%.
Riddle MC, Ambrosius WT Epidemiologic relationships between A1C and all cause mortality during a median 3.4-
year follow-up of glycemic treatment in the ACCORD trial. Diabetes Care 2010;33: 983–990

18. Higher risk of hypoglycemia
• Age > 65 years
• Longer duration of insulin use
• Higher HbA1c
• Use of insulin
• Use of SU
• Older age
• Renal dysfunction,
• Mental health issues,( e.g. dementia)

19. UKPDS: long-term follow-up and legacy
effect
Intervention
ends
UKPDS UKPDS
10
Active Follow-up 0
9 –5
Conventional
Median HbA1c (%)
Relative risk reduction (%)
9%
–10 P = 0.040 13%
8 Biochemical
15%
data no P = 0.007
longer
–15
P = 0.014
7 Intensive collected
–20
24%
6 –25 P = 0.001
0 5 10 15 5 10 –30
1977 1997 2007
Years from randomization
Bailey CJ & Day C. Br J Diabetes Vasc Dis 2008; 8:242–247.
Holman RR, et al. N Engl J Med 2008; 359:1577–1589.

20. Legacy Effect of Earlier Glucose Control
After median 8.5 years post-trial follow-up
Aggregate Endpoint 1997 2007
Any diabetes related endpoint RRR: 12% 9%
P: 0.029 0.040
Microvascular disease RRR: 25% 24%
P: 0.0099 0.001
Myocardial infarction RRR: 16% 15%
P: 0.052 0.014
All-cause mortality RRR: 6% 13%
P: 0.44 0.007
RRR = Relative Risk Reduction, P = Log Rank

21. Lessons from UKPDS:
Legacy Effect of Earlier Metformin Therapy
UKPDS Trial POST-Trial
Intervention Monitoring
1977 - 1997 Diabetes-related deaths 1997 - 2007
-42% -30%
All –Cause Mortality
-36% -27%
Myocardial Infarction
-39% -33%
CV Complications
CV Complications
reduced and Survival
reduced and Survival
increased versus other
increase maintained
therapies
UKPDS 34. Lancet 1998; 352: 854-65
UKPDS 80. NEJM 2008; 359: 1577-89

22. Legacy Effect
A treatment has a legacy effect if the
intervention, when discontinued, leads to
long term decreased risk of outcome.
http://www.ganfyd.org/index.php?title=Legacy_effect

23. VADT
• Older patients > 60 yrs
• 12% reduction in risk of cardiovascular events with
intensive control, but that did not nearly reach statistical
significance,"
• The risk of having a primary cardiovascular event
among patients with diabetes of 10 to 15 years'
duration was reduced 40% with intensive glucose
control
• Increased incidence of severe hypoglycemia in the
intensive treatment group.
Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Glucose control and vascular complications in veterans with
type 2 diabetes. N Engl J Med 2009;360:129–139

24. Predictions from VADT: impact of bad
glycemic legacy
Before entering VADT intensive treatment arm After entering VADT intensive
treatment arm
9.5 Generation of a Drives risk of
‘bad glycemic complications
9.0 legacy’
8.5
HbA1c (%)
8.0
7.5
7.0
6.5
6.0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Time since diagnosis (years)
Del Prato S. Diabetologia 2009; 52:1219–1226.

25. VADT: relationship between coronary
calcification and outcome
*
*
* Significant event reduction with CAC score <100, not >100

26. VADT: Diabetes duration vs. intensive
treatment CVD benefit
Diabetes duration, years

27. Copyrighted art
deleted from here
“ There is a time for everything”
http://connect.in.com/nadodikattu/photos-390645-4018893.html

28. Multifactorial intervention and CV
event reduction : The Steno Trial
Intensive therapy was associated with a lower risk of death from cardiovascular causes
(hazard ratio, 0.43; 95% CI, 0.19 to 0.94; P=0.04) and of cardiovascular events
(hazard ratio, 0.41; 95% CI, 0.25 to 0.67; P<0.001).

29. Steno 2 trial: 13year follow up
Total mortality in the intensive arm was reduced by 46% (RRR) corresponding
to an absolute risk reduction of 20%
N Engl J Med. 358:580-591,2008

30. Hypoglycemia and CV events
• 14,670 patients with coronary artery disease, recruited
for the Bezafibrate Infarction Prevention study over an
8-year mean follow-up, hypoglycemia was a predictor
of increased all-cause mortality (with a HR of 1.84)
• Veterans Affairs Cooperative Study on Glycemic
Control and Complications in Type 2 Diabetes:
more cardiac events were documented in patients after
institution of intensive glycemic control versus standard
control (32 vs. 20%)
Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Glucose control and vascular complications in veterans with
type 2 diabetes. N Engl J Med 2009;360:129–139

31. CEREBRAL ISCHEMIA, STROKE, AND
DEMENTIA
• Severe hypoglycemia has been known to induce focal
neurological deficits and transient ischemic attacks,
which are reversible with the correction of blood glucose
• Recurrent or severe hypoglycemia may predispose to
long-term cognitive dysfunction and dementia.
• Conversely, severe cognitive dysfunction has been
associated with increased risk of hypoglycemia

32. Cardiac Ischemia Associated With Hypoglycemia
Episodes: More Episodes of Chest Pain and ECG
Abnormalities
Study included patients (n=19, mean age, 58±16 years) with type 2 diabetes, history of
frequent hypoglycemia, HbA1c of 8%, and coronary artery disease (defined as history of
myocardial infarction, coronary bypass surgery, or angioplasty).
CGMS and Holter monitoring abnormalities Episodes with Episodes
Total chest pain/ with ECG
episodes angina abnormalities
Hypoglycemia 54 10* 6*
Symptomatic 26 10* 4*
Asymptomatic 28 — 2
Normoglycemia without rapid changes N/A 0 0
Hyperglycemia 59 1 0
Rapid changes in glucose (>100 mg dl-1 h-1) 50 9* 2
*P<0.01 vs episodes during hyperglycemia and normoglycemia.
ECG=electrocardiographic; CGMS=continuous glucose monitoring system.
Desouza C et al. Diabetes Care. 2003;26:1485–1489.

33. Meta-analysis: impact of intensive glucose
control on coronary heart disease* events
Intensive treatment/standard Odds ratio Odds ratio
treatment (95% CI) (95% CI)
Participants Events
UKPDS 3,071/1549 426/259 0.75 (0.54–1.04)
PROactive 2,605/2633 164/202 0.81 (0.65–1.00)
ADVANCE 5,571/5,569 310/337 0.92 (0.78–1.07)
VADT 892/899 77/90 0.85 (0.62–1.17)
ACCORD 5,128/5123 205/248 0.82 (0.68–0.99)
Overall 17,267/15,773 1,182/1,136 0.85 (0.77–0.93)
0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0
Intensive treatment better Standard treatment better
*Included non-fatal myocardial infarction and death from all cardiac mortality.
Reproduced from Ray KK, et al. Lancet 2009; 373:1765–1772.

34. Mechanisms by which hypoglycemia
may affect cardiovascular events
Souza CV . Hypoglycemia, Diabetes, and Cardiovascular Events DIABETES CARE, VOLUME 33, NUMBER 6, JUNE 2010

35. Which TARGET for WHOM?

36. WHOEVER
WINS….
WE
LOSE.
Hypoglycemia vs. Hyperglycemia

37. Factors deciding the target HbA1c
Several factors can be taken into consideration when
tailoring treatment including
• Duration of diabetes
• Stage of disease
• Life expectancy
• Risk of hypoglycemia
• Risk factors for CV disease (CVD).

38. Categorize patients into different
groups
• Newly diagnosed patients
Obese patients
Lean patients
• Patients with inadequate glycemic control, but
no co morbidities
• Patients with CVD
• Individuals at risk of hypoglycemia
S. Del Prato; J. LaSalle; S. Matthaei; C. J. Bailey Tailoring Treatment to the Individual in Type 2 Diabetes Practical Guidance
from the Global Partnership for Effective Diabetes Management Int J Clin Pract. 2010;64(3):295-304

39. Newly diagnosed patients
•Aggressive glycemic control
UKPDS
Legacy
•Use agents with minimum risk of Effect
hypoglycemia
•Target HbA1c < 6.5-7 %
•Chose therapies with likely beta cell
preservation
•Address cardiovascular risk factors
•Consider insulin if HbA1c > 9 %
S. Del Prato; J. LaSalle; S. Matthaei; C. J. Bailey Tailoring Treatment to the Individual in Type 2 Diabetes Practical Guidance
from the Global Partnership for Effective Diabetes Management Int J Clin Pract. 2010;64(3):295-304

40. Patients with inadequate glycemic
control, but no co morbidities
• Bad glycemic legacy UKPDS
Legacy
•Likely to have one /more microvascular Effect
complication
•Aggressive glycemic control
•Gradual reduction in HbA1c
•Diabetes education
•Assess risk of hypoglycemia
S. Del Prato; J. LaSalle; S. Matthaei; C. J. Bailey Tailoring Treatment to the Individual in Type 2 Diabetes Practical Guidance
from the Global Partnership for Effective Diabetes Management Int J Clin Pract. 2010;64(3):295-304

41. Patients with CVD
•Long duration of DM ACCORD
•Poor glycemic control VADT
•
•Large pill burden ADVANCE
• Benefits of good glycemic control vs. risk
of hypoglycemia
•Gradual reduction in HbA1c
• Consider contraindications of agents used
• Assess risk of hypoglycemia
S. Del Prato; J. LaSalle; S. Matthaei; C. J. Bailey Tailoring Treatment to the Individual in Type 2 Diabetes Practical Guidance
from the Global Partnership for Effective Diabetes Management Int J Clin Pract. 2010;64(3):295-304

42. High risk group in ACCORD
Patients with a history of CVD who do not respond to
aggressive glucose-lowering strategies may be more
susceptible to CV events
Calles J, Banerji M, Bonds DE et al. Baseline characteristics and mortality in ACCORD. Diabetes 2009; 58
(Suppl. 1): A24.

43. Patients with risk of hypoglycemia
•Long duration of DM ACCORD
•Previous history of hypoglycemia VADT
•Reduced Creatinine clearance ADVANCE
•Irregular eating/lifestyle habits
• Less stringent HbA1c targets
•Gradual reduction in HbA1c
• Consider agents with less hypoglycemia
• Assess risk of hypoglycemia
S. Del Prato; J. LaSalle; S. Matthaei; C. J. Bailey Tailoring Treatment to the Individual in Type 2 Diabetes Practical Guidance
from the Global Partnership for Effective Diabetes Management Int J Clin Pract. 2010;64(3):295-304

44. Adverse event concerns of add on
therapy
Insulin Sulphonylurea TZD GLP-1 / DPP4
inhibitors
Hypoglycemia
Weight gain
CV safety Ischemic MI
Preconditioning Fluid
UKPDS/ UGDP retention
Other concerns Fractures Pancreati
Macular tis
edema Nausea

45. Effective interventions

46. Messages
• Glycemic control reduces Cardiovascular events
• Benefits of intensive glycemic control on CV events is
pronounced when it is achieved early in the course of
diabetes
• Identify patients with high CV risk and high
hypoglycemia risk
• Individualize treatment

48. Disclaimer
The material for these slides were derived from various sources
including pictures and cartoons from the world wide web. I have
tried my best to acknowledge all possible sources and references.
However, if I have overlooked any particular reference, it is not
done intentionally. Anyone reproducing materials from this
presentations should acknowledge the author of the original work.
Cartoons are made to simplify certain concepts. The presenter
should attach explanations to all cartoons or else it will appear quite
amateurish.