Prepared on January, 2015 to be presented in a seminar in Dhaka, Bangladesh.

1. Diabetes
and
Cardiovascular disease
Dr. Mashfiqul Hasan
MD Phase B resident
Department of Endocrinology
Bangabandhu Sheikh Mujib Medical University

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3. Agenda
1. CV risk in DM
2. CV risk management in DM
3. DM management in CVD
4. DM management in acute setting
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4. 1. CV risk in DM
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5. Huge and growing problem
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8. Diabetes
Is considered as
Cardio-vascular risk
equivalent
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10. Insulin resistance is linked to a range of CVD risk
factors
Insulin resistance
Dyslipidaemia
Microalbuminuria
CVD
Vascular
inflammation
Hypertension
Atherosclerosis
Endothelial
dysfunction
Adapted from McFarlane SI, et al. J Clin Endocrinol Metab 2001;86:713–718.
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11. Problem 1
• Stratify according to CVD risk
(highest to lowest)
A. Prior MI, no DM
B. DM, no prior MI
C. No DM, no prior MI
D. Both DM and prior MI
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12. 2. CV risk management in DM
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13. Major focus
Comprehensive CV risk reduction
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14. Treat
cardiovascular risk factors
in diabetic patients
as aggressively as
in non-diabetic patients
with prior myocardial infarction
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15. Blood pressure
• <140/90 mm of Hg in general
• <130/80 mm of Hg if possible
• Lifestyle therapy
• Pharmacological therapy
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16. Dyslipidemia
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17. Anti-platelet agent
• Secondary prevention
• Primary prevention
– Men >50 yr, Women >60 yr
– Additional CV risk factors
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18. Smoking cessation
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19. DECODE: IGT Increases Mortality Risk
Diabetes Epidemiology: Collaborative analysis Of Diagnostic criteria in Europe
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21. Problem-2
• A 56-year-old man with T2DM
• Taking OAD, HbA1C 7.2
• BMI 31.1 kg/m2
• No history of CVD, BP 145/95, non-smoker
• Q. Does he need statin therapy?
• Q. Does he need anti-platelet therapy?
• Q. What is the choice of antihypertensive?
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22. 3. DM management in CVD
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23. Impact of Intensive Therapy for Diabetes:
Summary of Major Clinical Trials
Study Microvasc CVD Mortality
UKPDS      
DCCT /
EDIC*      
ACCORD   
ADVANCE   
VADT   
Long Term Follow-up
Initial Trial
* in T1DM
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24. - HbA1c < 7.0%
- Pre-prandial 4.4-7.2 mmol/l)
- Post-prandial <10.0 mmol/l
- Individualization is key:
 Tighter targets (6.0 - 6.5%) - younger, healthier
 Looser targets (7.5 - 8.0%) - older, comorbidities,
hypoglycemia prone, etc.
- Avoidance of hypoglycemia
Glycemic targets
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25. more
stringent
less
stringent
Patient attitude and
expected treatment efforts highly motivated, adherent,
excellent self-care capacities
less motivated, non-adherent,
poor self-care capacities
Risks potentially associated
with hypoglycemia and
other drug adverse effects
low high
Disease duration
newly diagnosed long-standing
Life expectancy
long short
Important comorbidities
absent severefew / mild
Established vascular
complications absent severefew / mild
Readily available limited
Usually not
modifiable
Potentially
modifiable
HbA1c
7%
PATIENT / DISEASE FEATURES
Approach to the management
of hyperglycemia
Resources and support
system
Figure 1. Modula on of the
intensiveness of glucose
lowering therapy in T2DM
Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0
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27. Healthy eating, weight control, increased physical activity & diabetes education
Metformin
high
low risk
neutral/loss
GI / lactic acidosis
low
If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote
any specific preference - choice dependent on a variety of patient- & disease-specific factors):
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Metformin
+
high
low risk
gain
edema, HF, fxs
low
Thiazolidine-
dione
intermediate
low risk
neutral
rare
high
DPP-4
inhibitor
highest
high risk
gain
hypoglycemia
variable
Insulin (basal)
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Basal Insulin +
Sulfonylurea
+
TZD
DPP-4-i
GLP-1-RA
Insulin§
or
or
or
or
Thiazolidine-
dione
+
SU
DPP-4-i
GLP-1-RA
Insulin§
TZD
DPP-4-i
GLP-1-RA
high
low risk
loss
GI
high
GLP-1 receptor
agonist
Sulfonylurea
high
moderate risk
gain
hypoglycemia
low
SGLT2
inhibitor
intermediate
low risk
loss
GU, dehydration
high
SU
TZD
Insulin§
GLP-1 receptor
agonist
+
SGLT-2
Inhibitor
+
SU
TZD
Insulin§
Metformin
+
Metformin
+
or
or
or
or
SGLT2-i
or
or
or
SGLT2-i
Mono-
therapy
Efficacy*
Hypo risk
Weight
Side effects
Costs
Dual
therapy†
Efficacy*
Hypo risk
Weight
Side effects
Costs
Triple
therapy
or
or
DPP-4
Inhibitor
+
SU
TZD
Insulin§
SGLT2-i
or
or
or
SGLT2-i
or
DPP-4-i
If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote
any specific preference - choice dependent on a variety of patient- & disease-specific factors):
If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add
basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i:
Metformin
+
Combination
injectable
therapy‡
GLP-1-RAMealtime Insulin
Insulin (basal)
+
or
or
or
Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0
Figure 2B. An -hyperglycemic
therapy in T2DM:
Avoidance of weight gain
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28. Adapted Recommendations: When Goal is to Avoid Hypoglycemia
Diabetes Care, Diabetologia. 19 April 201
[Epub ahead of print]

29. ADA-EASD Position Statement: Management of
Hyperglycemia in T2DM
4. OTHER CONSIDERATIONS
• Comorbidities
- Coronary Disease
- Heart Failure
- Renal disease
- Liver dysfunction
- Hypoglycemia
 Metformin: CVD benefit
(UKPDS)
 Avoid hypoglycemia
 ? SUs & ischemic
preconditioning
 ? Pioglitazone &  CVD events
 ? Effects of incretin-based
therapies
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of prin
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30. ADA-EASD Position Statement: Management of
Hyperglycemia in T2DM
4. OTHER CONSIDERATIONS
• Comorbidities
- Coronary Disease
- Heart Failure
- Renal disease
- Liver dysfunction
- Hypoglycemia
 Metformin: May use unless
condition is unstable or severe
 Avoid TZDs
 ? Effects of incretin-based
therapies
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of prin
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31. ADA-EASD Position Statement: Management of
Hyperglycemia in T2DM
4. OTHER CONSIDERATIONS
• Comorbidities
- Coronary Disease
- Heart Failure
- Renal disease
- Liver dysfunction
- Hypoglycemia
 Increased risk of hypoglycemia
 Metformin & lactic acidosis
 US: stop @SCr ≥ 1.5 (1.4
women)
 UK:  dose @GFR <45 &
stop @GFR <30
 Caution with SUs (esp. glyburide)
 DPP-4-i’s – dose adjust for most
 Avoid exenatide if GFR <30
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of prin
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32. ADA-EASD Position Statement: Management of
Hyperglycemia in T2DM
4. OTHER CONSIDERATIONS
• Comorbidities
- Coronary Disease
- Heart Failure
- Renal disease
- Liver dysfunction
- Hypoglycemia
 Most drugs not tested in
advanced liver disease
 Pioglitazone may help steatosis
 Insulin best option if disease
severe
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of prin
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33. ADA-EASD Position Statement: Management of
Hyperglycemia in T2DM
4. OTHER CONSIDERATIONS
• Comorbidities
- Coronary Disease
- Heart Failure
- Renal disease
- Liver dysfunction
- Hypoglycemia
 Emerging concerns regarding
association with increased
mortality
 Proper drug selection in the
hypoglycemia prone
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of prin
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34. Long (Detemir)
Rapid (Lispro, Aspart, Glulisine)
Hours
Long (Glargine)
0 2 4 6 8 10 12 14 16 18 20 22 24
Short (Regular)
Hours after injection
Insulinlevel
(Degludec)
• Therapeutic options: Insulins
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35. 4. DM management in acute setting
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36. Sliding scale insulin (SSI)
in the inpatient hospital setting
Strongly discouraged
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37. Critically ill patients
• Insulin therapy should be initiated for
treatment of persistent hyperglycemia
• starting at a threshold of no greater than
10 mmol/L
• Once insulin therapy is started, a glucose
range of 7.8–10 mmol/L is recommended for
the majority of critically ill patients
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38. Non-critically ill patients
• If treated with insulin, generally premeal
blood glucose targets of 7.8 mmol/L with
random blood glucose 10.0 mmol/L are
reasonable
• A basal plus correction insulin regimen is the
preferred treatment for patients with poor
oral intake
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39. Insulin aspart is a rapid
acting insulin analogue.
Brand name is
NovoRapid®.
Where B 28 position
amino acid proline is
replaced by aspartic acid
through recombinant
DNA technology.
Fig: Structure of Insulin aspart
What is insulin aspart?
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40. Kinetics-Dynamics
Human Actrapid ®
30 mins
1.5 -3.5 hours
7-8 hours
NovoRapid ®
10-20 minutes
1-3 hours
3-5 hours
Onset of action
Peak action
Duration of action
NovoRapid ® has a fasteronset , earlierpeakand sharp returnto baseline
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41. HeinemannLetal.DiabetMed1996;13:683
Insulin aspart has a faster onset, earlier peak and
sharp return to baseline
Insulin aspart (NovoRapid®)
Human Actrapid ®
(0.2 U/kg)
Time (minutes)
Seruminsulin
(pmol/l)(mU/l)
50
25
75
500
400
300
200
100
0
0 60 120 180 240 300 360 420 480 540 600-60
0
48min/414pmol/l
123min/239pmol/l
Doubleblind, cross-over, single dose study in healthy volunteers, N=24
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42. Reduces risk of hypoglycemia
0
0.2
0.4
0.6
0.8
1
1.2
1.4
Total Nocturnal 24:00 – 6:00
Episodesperpatientperyear
NovoRapid ®
Human Actrapid ®
***
Heller et al. Diabetes 2001;50(2):A137
72%
4 months
*** p < 0.005
NovoRapid® reducesthe rate of severenocturnal
hypoglycaemiaby 72%
Double-blind, crossover comparison in T1DMon basal-bolus, Duration 4 mo, N=155
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43. • Improves long term glucose control
– Significantly improved and maintained stable HbA1c levels
over 3 yr compared to Actrapid ® (Amiel S et al, 2001)
• Reduces risk of hypoglycemia
– Only analogue to show a 72% reduction in severe hypo
(Heller S et al, 2001)
– Rapid onset, short duration, sharp return to baseline
(Heinemann L et al, 2001)
• Freedom from meal-time constraints
– Ideal for children and adults with unpredictable meal size
– Offers option of dose adjustment based on meal-size
(Danne T et al, 2003)
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44. Slide no 44
IV use of Insulin aspart in Hospitalized patients
Pre operative
Pre ICU or Pre admission
S.C. NovoRapid
During
Surgery, ICU
or Hospitalization
IV NovoRapid
After surgery
Shift to ward
Just before discharge
S.C. NovoRapid
Same insulin; predictable control; better SC insulin; less loss
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46. Acknowledgements
• Prof. Md. Fariduddin
• Prof. M A Hasanat
• Novo Nordisk
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47. Thank you
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48. Questions?
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