Diabetes and Cardiovascular Disease

Diabetesand

Cardiovascular disease

Dr. Mashfiqul HasanMD Phase B resident

Department of EndocrinologyBangabandhu Sheikh Mujib Medical University

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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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1. CV risk in DM

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Huge and growing problem

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Diabetes

Is considered as

Cardio-vascular risk

equivalent

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Insulin resistance is linked to a range of CVD risk factors

Insulin resistance

Dyslipidaemia

Microalbuminuria

CVD

Vascular

inflammationHypertension

Atherosclerosis

Endothelial

dysfunction

Adapted from McFarlane SI, et al. J Clin Endocrinol Metab 2001;86:713–718.

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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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2. CV risk management in DM

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Major focus

Comprehensive CV risk reduction

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Treat

cardiovascular risk factors

in diabetic patients

as aggressively as

in non-diabetic patients

with prior myocardial infarction

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Blood pressure

• <140/90 mm of Hg in general

• <130/80 mm of Hg if possible

• Lifestyle therapy

• Pharmacological therapy

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Dyslipidemia

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Anti-platelet agent

• Secondary prevention

• Primary prevention

– Men >50 yr, Women >60 yr

– Additional CV risk factors

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Smoking cessation

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DECODE: IGT Increases Mortality Risk

Diabetes Epidemiology: Collaborative analysis Of Diagnostic criteria in Europe

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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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3. DM management in CVD

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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 T1DM23mashfiq-endocrinology-bsmmu

- 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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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 severe few / mild

Established vascular complications absent severe few / mild

Readily available limited

Usually not modifiable

Potentially modifiable

HbA1c7%

PATIENT / DISEASE FEATURES

Approach to the management of hyperglycemia

Resources and support system

Figure1.Modula onoftheintensivenessofglucoseloweringtherapyinT2DM

Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0

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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-RA Mealtime Insulin

Insulin (basal)

+

or

or

or

Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0

Figure2B.An -hyperglycemictherapyinT2DM:Avoidanceofweightgain

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Adapted Recommendations: When Goal is to Avoid HypoglycemiaDiabetes Care, Diabetologia. 19 April 2012

[Epub ahead of print]

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 print]29mashfiq-endocrinology-bsmmu

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 print]30mashfiq-endocrinology-bsmmu

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 <30Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

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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 print]32mashfiq-endocrinology-bsmmu

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 print]33mashfiq-endocrinology-bsmmu

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

Insu

lin le

vel

(Degludec)

• Therapeutic options: Insulins

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4. DM management in acute setting

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Sliding scale insulin (SSI)

in the inpatient hospital setting

Strongly discouraged

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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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Non-critically ill patients

• If treated with insulin, generally premealblood 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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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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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 faster onset , earlier peak and sharp return to baseline

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Heinemann L et al. Diabet Med 1996;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)

Se

rum

in

su

lin

(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

48 min/ 414 pmol/l

123 min/ 239 pmol/l

Doubleblind, cross-over, single dose study in healthy volunteers, N=24

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Reduces risk of hypoglycemia

0

0.2

0.4

0.6

0.8

1

1.2

1.4

Total Nocturnal 24:00 – 6:00

Ep

iso

des p

er

pati

en

t p

er

year

NovoRapid ®

Human Actrapid ®

***

Heller et al. Diabetes 2001;50(2):A137

72%

4 months

*** p < 0.005

NovoRapid® reduces the rate of severe nocturnal hypoglycaemia by 72%

Double-blind, crossover comparison in T1DM on basal-bolus, Duration 4 mo, N=155

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• 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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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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Acknowledgements

• Prof. Md. Fariduddin

• Prof. M A Hasanat

• Novo Nordisk

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Thank you

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Questions?

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