Macrovascular Complications of Diabetes - 1.Cardiovascular Disease 2.Cereberovascular Accident 3.Peripheral Vascular Disease

1. MACROVASCULAR
COMPLICATIONS OF DIABETES
MELLITUS
DR.MONISHA MD(GENERAL MEDICINE)

2. MACROVASCULAR COMPICATIONS ARE
•Cardiovascular disease
•Cerebrovascular disease
•Peripheral Arterial disease

3. RISK FACTORS

4. HYPERGLYCEMIA INDUCED DAMAGE
-increased polyol flux pathway
-production of advanced glycation end products(glyoxal,methylglyoxal,deoxyglucosane
formed from dicarbonyl precursors).
-increased hexosamine pathway
-increased protein kinase C activation
The root cause of all this is due to increased superoxide radicals because of hyperglycemia and
excess fatty acid oxidation in insulin resistance
These ROS cause DNA breaks .PARP repairs it .
NAD+ broken down by PARP to NA and ADR
Polymers of ADR formed which inhibit glyceraldehyde 3 phosphate dehydrogenase which
increases all intermediates above this step

11. IN INSULIN RESISTANCE

12. PATHOGENESIS
• ADIPOCYTE INFLAMMATION & INSULIN RESISTANCE
• REDUCED NITRIC OXIDE AVAILABILITY
• ENHANCED ATHEROSCLEROSIS
• ENHANCED PLATELET ACTIVATION & COAGULATION
Diabetes is artherothrombotic state & all aspects of atherosclerosis are
accentuated in presence of diabetes.

13. ADIPOCYTE INFLAMMATION & INSULIN
RESISTANCE
• Adipocyte is an endocrine organ with capacity to influence insulince
resistance ,inflammatory response & thrombosis.
Free fatty acid activation of macrophage
Interaction between resident macrophage & adipocyte
Fat filled adipocytes

14. Increased amount of IL 6 , C 3 , TNF alpha , PAI – 1
Reduced adiponectin & increased leptin
Insulin resistance

15. REDUCED NITRIC OXIDE BIOAVAILABILITY
• Hyperglycemia , hypertension , dyslipidemia , increased FFA , reduced
adiponectin caused reduced nitric oxide production at transcriptional
level.
• Nitric oxide stimulates vasodilatation by guanyl cyclase
• Reduced nitric oxide increased NF kappa B leucocyte
adhesion molecule , chemokines , cytokines monocytes , vascular
smooth cell migration.
• Diabetes increases vascular reactive oxygen species

16. • Nitric oxide causes reduced adhesion of platelets to endothelium
• Diabetes causes platelet dysfunction & much of morbidity & mortality
of diabetes is related to this thrombotic complication.

17. ENHANCED ATHEROSCLEROSIS

18. Diabetes –
increases E selectin , VCAM 1 , ICAM 1 by endothelium.
Up regulation of monotype chemoattractant Protein 1.
Infiltrated macrophages elaborate cytokines , growth factors , MMP
Promotes plaque expansion and plaque prone to thrombosis & rupture.

19. ENHANCED PLATELET ACTIVATION
Increased PAI – 1 binds to tissue plasminogen activator
Inhibit tPA induced plasmid generation
Venous thrombosis & myocardial infarction

20. Hyperglycemia causes glycation on fibrinogen
Dense structure with thin fibres of fibrin clot
Increased cardiovascular risk

21. CORONARY ARTERY DISEASE
• Studies observe the hazard ratio of cardiovascular mortality risk in
patients with diabetes is similar to that in non diabetic patients with
MI
• Diagnosis of diabetes itself is a risk equivalent to prior MI

25. • Proteinuria is a marker of generalized vascular damage that
predispose to atherosclerosis.
• Therefore persistent proteinuria is a strong predictor of coronary
artery disease.
• In patients with T2 DM higher LDL , lower HDL , higher HbA1c levels ,
systolic BP measurements & history of smoking - associated with risk
of cardiovascular disease.

26. Screening for coronary artery disease in Diabetics
• Resting ECG
• Exercise ECG
• Stress myocardial perfusion imaging
• Stress ecocardiography
• Computed tomography
• Cardiac magnetic resonance imaging
• Catheterization and angiography

27. LIFESTYLE MANAGEMENT
1. Weight reduction
2. Medical nutritional therapy
3. Physical activity
4. Blood pressure
5. Tobacco
6. Antiplatelet drugs
7. Glycemic control

28. CARDIOVASCULAR DISEASE WITH METABOLIC
SYNDROME
Metabolic syndrome based on presence of 3 of the following :
• Abdominal obesity ( waist circumference > 40 inches in men ; > 35
inches in women
• Plama triglyceride > 150mg/dl
• HDL <40 mg in mem < 50 mg in women
• Blood pressure 130/80 mmhg or higher
• Fasting blood glucose > 110mg/ dl or higher.

29. • Cardiovascular mortality increased 2-3 fold in patient with metabolic
syndrome.
• Each percentage point elevation in HbA1c increases cardiovascular
risk by 11 %.

30. DYSLIPIDEMIA IN DIABETES

31. DYSLIPIDEMIA IN DIABETIC PATIENTS
LLD particles in diabetes are smaller & dense triglyceride rich.
More susceptible to oxidation In presence of poor glucose control.
Increased glycation of LDL causes impaired recognition of lipoprotein
by its hepatic receptors increasing its half life.
Increased FFA Flux by insulin resistant adipocytes increases hepatic
VLDL production.

32. Normally INSULIN & lipase mediate uptake of triglyceride derived FFA by striated muscle with
reduced delivery to liver.
In presence of lnsulin resistance this effect is reversed.
According to ADA and American heart association in diabetic individuals without cardiovascular
disease
• LDL <100mg/dl
• HDL >40mg/dl in men and >50 mg/dl in female
• Triglycerides <150g/dl
With known cardiovascular risk LDL value of <70mg/dl recommended
HMG COA REDUCTASE INHIBITORS statins have been incorporated in recent diabetes management
guidelines which significantly reduces major coronary events and revascularisation in patients with
diabetes
Currently statins are accepted effective in reducing cerebrovascular accidents

33. • PCSK9 GENE targets LDL receptor for proteosomal degradation rather
then allowing it to return to the cell surface for another cycle of LDL
Clearence.(EVOLOCUMAB,ALIROCUMAB)
• Fibric acid derivatives lower high triglycerides and raise HDL
gemfibrozil had significant decrease in coronary events and strokes
• ACCORD trial showed combination therapy of statins and fibric acid
would be more useful
• Niacin lack efficacy combined with its side effects of increasing insulin
tolerance

35. HYPERTENSION IN DIABETICS
• Increased duration of diabetes causes increased arterial stiffness and
reduced vasomotor function and loss of nocturnal Bp dip
• Target BP <130/80 mm hg with foremost emphasize on lifestyle
modifications
• ADA recommends ACE inhibitors or ARBS with betablockers/thiazides/CCB
• In patients with type 1 diabetes, hypertension,micro and
macroalbuminuria ACE inhibitors slowed progression of nephropathy
• In patients with type 2 it slowed Progression of macroalbiminuria and
decline in GFR.
• Non hydropyridine calcium channel blockers preferred over dihydroyridine
Agents in diabetics

36. ACUTE CORONARY SYNDROME IN DIABETICS
• Increased risk of heartfailure due to maladaptive remodeling of left
ventricle
• Increased risk of sudden death due to sympathovagal inhibition as a
consequence of autonomic neuropathy
• Increased early reinfarction due to impaired fibrinolysis
• Extensive underlying atherosclerosis
• Changes in myocardial cell metabolism by shift of glucose oxidation to
free fatty acid oxidation with less ATP generation
• Associated cardiomyopathy

37. • Intensive glycemic control improve myocardial cell metabolism and
reverse the impaired fibrinolysis
• ACE inhibitors dramatically reduce infarction size and limit ventricular
remodeling
• Beta blockers dampen the effect of sympathetic overactivity that
arises as a consequence of autonomic neuropathy
• Aspirin cornerstone of primary and secondary prevention which
modulates aggregation of platelets
• Antagonist of P2Y12 subclass – clopidogrel,prasugrel,ticagrelor reduce
rate of ischemia in acute coronary syndrome

38. • Glycoprotein IIb/III a(abciximab,eptifibatide,tirofiban) antagonise
platelet action.The rate of target vessel revascularisation significantly
decreased with additional of this antagonist
• A study showed that CABG showed better outcomes than PTCA and
reduced 5 year mortality

39. CARDIOMYOPATHY IN DIABETES

40. CARDIOMYOPATHY IN DIABETES MELLITUS
• Diabetes associated with fourfold increase in risk of CCF
FACTORS CONTRIBUTING
• Diabetes induced cardiomyocyte dysfunction due to altered substrate
utilisation
• Impaired microvascular perfusion because of defective endothelial
function
• Increased collagen deposition with fibrosis due to increased
activation of RAAS and formation of AGEs
• Maladaptive remodeling after MI

41. • Evidence of silent myocardial infarction is found in 40 percent of
patients with diabetes who present with clinically apparent infarct
and unrecognized regional and global ventricular dysfunction
• On cellular level both hyperglycemia and insulin resistance depress
myocardial GLUT4 levels as a result metabolism shifts from glycolysis
to FFA oxidation thereby reducing ATP generation a major source
during ischemic conditions
• The combination of ARB(valsartan) and a nephrilysin
inhibitor(sacubitril)proved superior to ACE Inhibitor in patients with
reduced ejection fraction

42. CEREBROVASCULAR DISEASE
• Strokes can be either is ischemic or hemorrhagic
• Ischemic strokes are classified as
1. Large artery atherosclerosis
2. Cardioembolism
3. Lacunar strokes
4. Other determined etiology
5. Undetermined etiology
Patients with diabetes are more prone for lacunar infarcts

43. Risk of ischemic stroke in diabetic patients is increased by 1.5-4 times
Diabetics of more than 65 yrs have 12 fold increased risk than non
diabetics
17 percent increase in risk of stroke with each 1% rise in HbA1C
Risk factors for stroke in Diabetes
• Diabetic retinopathy
• Hyperuricemia
• Proteinuria >300mg/dl
• Concomitant hypertension

44. An elevated blood sugar can be seen in more than 40 percent of
patients with ischemic stroke especially in diabetics
Normally glucose metabolized to pyruvate
In ischemic brain pyruvate to lactate
accumulation of lactate and intracellular acidosis
accumulation of intracellular calcium
Glutamate dependent excitotoxicity and cell death

45. • The current standard of care of patients with acute ischemic stroke is
thrombolysis with iv recombinant tissue plasminogen activator
• Hyperglycemia is one of the important risk factor for developing
subsequent ICH
• In acute ischemic stroke blood sugar maintained below 180 mg/dl
with insulin.High blood glucose will impair brain plasticity and
functional recovery