Cardio Diabetes_2017 book

278 Diabetes and Genetalia

Diabetes and Genetalia

Dr. M. Balasubramanian, MD, DDVL,

Past IMA State President,
Retd.Deputy Director, TANSACS

INTRODUCTION third the size of Coronary artery. Hence if ED is noted
and reported and remedial Life Style Changes are im-
It was said ‘He who knows Syphilis knows Medi- plemented,impending cardiac arrest can be certainly
cine’,because Syphilis affects not only the generals averted.
but each and every structure in the body except the
ovary and mimics many diseases in the field of Medi- With more and more new Diabetics in younger age
cine and Surgery. Then the saying shifted to Diabetes group,  genital manifestations cannot be sidelined
due to decrease in number and severity of Syphilis and have to taken care of.
after the discover of Penicillin.
Than only we can proudly say ‘He who knows Dia-
Diabetes is a life style disease increasing in number betes knows Medicine.
every year and likely to fetch our India the dubious
distinction of Diabetic Capital of the World in another IMA CGP has been conducting Fellowship Certificate
fee years. in Sexual Medicine and 9th batch is going on.

Diabetes is known to affect many organs and sys-
tems. But little is known or given least importance
regarding its manifestations over genital organ in
both the sexes.

Even though Polyurea. Polydipsia or Polyphagia are
the three cardinal signs of Diabetes,it is often diag-
nosed

It is seldom realised and reported that early sign
and symptom of Diabetes is over the genitals. When
blood sugar crosses 160 or 180 mg%, sugar is begin
to be excreted through urine. This glycosuria pave
way for growth of Candida albicans dormant in every-
body’s body leading to micro fissures leading to the
symptom of burning sensations over the genitals af-
ter coitus or sign of Candidiasis with macro fissures
over prepucial edges. In woman it presents with thick
Curdy white vaginal discharge with itching over the
vulva. It is proved beyond doubt the Venereologist
detect new cases of Diabetes clinically than any oth-
er specialist who detect only on routine screening.

Yet another  early symptom of Diabetes is Erectile
dysfunction.Endothelial dysfunction is the basic pa-
thology similar to Cardiac Infarction.Erectile dysfunc-
tion is early to occur because Penile artery is one

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Cardio Diabetes Medicine 2017 279

Diabetic Kidney Disease: When To Refer To A
Nephrologist & Why?

Dr. Pritam Gupta,MD

(HOD Med Sunder Lal Jain Hospital & Sr. Consultant Fortis Hospital,
Shalimar Bagh, Delhi)

Dr. Mudit Gupta, DM (Nephro),

Sr.Consultant Sunder Lal Jain Hospital & Sant Parmanand Hospital,Delhi

Introduction: M.K. Mani from Chennai done in a Hamlet of rural
population covering 21,062 subjects detected diabe-
The incidence and prevalence of diabetes mellitus tes in 3.64% and CKD up to stage III in 0.68% popula-
(DM) continue to grow markedly throughout the tion. SEEK study which was started in 2006, covering
world, primarily due to the increase in T2DM. Because 21 centers with 53 community camps to include rural,
of better available treatment options, proportion of semi-rural, semi-urban and urban communities from
diabetic individuals who develop chronic kidney widely spread over in India, reported diabetes as a
disease (CKD) have reduced significantly.1Although main cause of CKD.
chronic kidney disease attributable to diabetes is re-
ferred to as DKD, but people with diabetes may have Diabetic Kidney disease (DKD)
other etiologies of CKD. Therefore DKD is defined as
a microvascular complication of diabetes marked by The term “diabetic kidney” has recently been pro-
albuminuria and a deteriorating course from normal posed to encompass the various lesions, involving
renal function to ESRD. Notably, DKD remains one of all kidney structures that characterize protean kidney
the most frequent complications of both types of dia- damage in patients with diabetes. The classic term
betes, and diabetes is the leading cause of end-stage “diabetic nephropathy” points to the presence of a
renal disease (ESRD), accounting for approximately single, well defined, and identifiable kidney disease.
50% of cases in the developed world.2 Because of the complexity and heterogeneity of re-
nal impairment in diabetic patients, the classic term
Epidemiology: has been increasingly replaced by the more generic
term “diabetic kidney disease” which is reminiscent
Globally, an estimated 422 million adults were suf- of the term “chronic kidney disease”.
fering from diabetes in 2014. The global prevalence
of diabetes has nearly doubled since 1980, rising Non Diabetic Kidney disease (NDKD)
from 4.7% to 8.5%. This reflects an increase in asso-
ciated risk factors such as obesity, dyslipidemia,and Type 2 DM often experience diabetic nephropathy
smoking.3 Diabetes is fastly gaining the status of a which is now referred as Diabetic kidney disease but
potential epidemic in India with more than 62 million they can also develop other renal diseases, patholog-
diabetic individuals and is being considered as the ically unrelated to diabetes and are known as non-di-
capital of diabetes in the world. By 2030, it is predict- abetic Kidney disease (NDKD).The clinical clues for
ed that diabetes mellitus may afflict up to 79.4 million NDKD in Type 2 DM patients are (i) Short duration of
individuals in India. Diabetes is the leading cause of diabetes, (ii) Rapid loss of renal function, (iii) Heavy
ESRD affecting 25% to 40% of patients with T1DM and proteinuria with normal renal function, (iv) Significant
5% to 40% of patients with T2DM.The Chennai urban renal dysfunction with minimal/ normoalbuminuria,
Rural Epidemiological study (CURES – part I 2003) (v) Active urinary sediment, (vi) Gross hematuria and
conducted by V. Mohan which covered 50,000 sub- (vii) Absence of retinopathy. Renal biopsy is often re-
jects revealed that 16% of the subject above the age quired for precise diagnosis of NDKD.
of 20 Years were affected by Diabetes.4 A study of

Cardio Diabetes Medicine

280 Diabetic Kidney Disease:
When To Refer To A Nephrologist & Why?

Renal Retinal relationship both primary care providers and for nephrologists.
This challenge increases when patients are referred
The renal-retinal relationship is well established for late to a nephrologist, that is, when they require ur-
the clinical diagnosis of diabetic kidney disease in gent dialysis. Delayed referral leads to emergency
Type 1 DM. However, renal-retinal relationship re- dialysis with higher morbidity, mortality and exces-
mains poor in predicting DKD in Type 2 DM. Biopsy sive cost.
proven DKD have been reported to occur in protein-
uric Type 2 diabetic patient in absence of retinop- Recent studies, have found that it is not uncommon
athy. It means that absence of retinopathy cannot for CKD patients to be examined by a nephrologist
exclude the presence of diabetic kidney disease. The for the first time only one month before starting di-
presence of diabetic retinopathy suggests the con- alysis. Many patients with chronic kidney disease
currence of DKD, but does not exclude non diabetic (CKD) are seen by primary care physicians who may
kidney disease. Early diagnosis of NDKD is crucial not be aware of indications or benefits of timely
as appropriate therapy could prolong renal survival in nephrologist referral. Late referral to a nephrologist
this patient population. It is important to mention that may lead to suboptimal pre-end stage renal disease
40% to 60% of ESRD in diabetic patients is associat- care and greater mortality. Late evaluation of patients
ed with non-diabetic primary renal diseases. with CKD by a nephrologist, especially close to the
time of starting dialysis, is associated with subopti-
Pathological features of DKD mal pre-ESRD management and increased mortality
risk . A survey of primary care physicians who made
The main glomerular renal lesions in type 1 diabe- late referrals showed that approximately 90% of the
tes include a nodular, classical Kimmelstiel-Wil- physicians felt they did not receive adequate training
son lesion, a diffuse pattern, and the presence of regarding timing or indications for referral of patients
non-specific exudative lesions. Today, the accumula- with CKD.In 2002, the National Kidney Foundation
tion of extracellular matrix is considered an indication (NKF) developed the Kidney Disease Outcomes
of nephropathological changes. This accumulation Quality Initiative (KDOQI) clinical practice guidelines
may lead to mesangial expansion and reduction of to facilitate primary care physician management of
filtration surface area, which is further disrupted by CKD by early detection, formulation of an action plan
the thickening of glomerular basement membranes. for each stage of CKD, monitoring of CKD progres-
Concomitant changes at the arteriolar level and in the sion, assessment of complications, and timely refer-
renal interstitium contribute to the overall functional ral to a nephrologist.
impairment. The recent pathologic classification by
Tervaert9 and the Renal Pathology Society does not KDIGO Guidelines for Referral
differentiate between type 1 and T2DM, but provides
a comprehensive effort to classify renal lesions from Indication for referral to specialist kidney care serves
the mildest to the worst ones. for people of CKD

Pathologic classification 1. Acute Kidney injury or abrupt sustained fall in
GFR
Class 1: Isolated glomerular basement membrane
thickening and mild, non-specific changes, observ- 2. GFR <30ml/min/1.73m2 (Categories) G4-G5)
able by light microscopy, at an extent at which they
may not be applicable to the criteria of the other 3. Persistent albumineria (ACR≥ 300mg/gm)
classes.
4. Progression of CKD
Class 2: Mesangial expansion, classified as mild or
severe, but without nodular sclerosis or global glo- 5. Urinary red cell casts, RBC more than 20 per HPF
merulosclerosis in more than 50% of glomeruli (class sustained & not readily explained.
2a: mild; class 2b: severe).
6. CKD and hypertension refractory to treatment
Class 3: Presence of nodular sclerosis in at least one with 4 or more anti hypertensive agents.
glomerulus (Kimmelstiel-Wilson), without changes as
described in class 4. 7. Persistent abnormalities of serum potassium.

Class 4: Advanced diabetic glomerulosclerosis involv- Timing of referral of patients with CKD by their prima-
ing more than 50% of glomeruli. ry care physician to the nephrologist affects patients’
prognosis and clinical outcomes.11 Patients that are
Nephrology Referral evaluated by a nephrologist less than four months
prior to dialysis would be classified as a late referral;
Caring for patients with CKD is a great challenge for four to twelve months prior to dialysis as intermedi-

GCDC 2017

Cardio Diabetes Medicine 2017 281

ate, and over twelve months as an early referral. Late phosphate binders calcium based or non calcium
referral of patients with CKD has numerous serious based.
consequences, including an increased mortality risk
(relative risk 1.68 at 1 yr), increased morbidity with 6. Referral to a team consisting of a nephrologist,
lower use of antihypertensives, suboptimal manage- renal dietitian, dialysis nurse, social worker and
ment of bone and mineral disorders, lower serum al- financial counselor allows time to establish the
bumin (malnutrition), more use of temporary vascular best treatment modality for the patient, develop
access, longer hospital stay, and reduced access to financial support if needed and to allay the fears
renal transplantation. The reasons for late referral of both patient and family.”
may be patient related or physician related. Psycho-
logic factors such as denial of the need for dialysis, 7. Prevention of recurrent infections.
advanced age, and low socioeconomic status with
poor access to care may lead to late referral. 8. Education to the patients and attendants regard-
ing early transplant.
Frequently the primary care provider will make the
diagnosis of chronic kidney disease. Referral to a 9. To prevent emergency dialysis which is associat-
nephrologist or other specialist for consultation or ed with poor outcome due to following reasons?
co-management should be made after diagnosis
under the following circumstances: a clinical action -- jeopardizes the dialysis modality choice
plan cannot be prepared based on the stage of the
disease, the prescribed evaluation of the patient can- -- endangers ability to maintain prolonged vas-
not be carried out, or the recommended treatment cular access
cannot be carried out. These activities may not be
possible either because the appropriate tools are not -- precludes psychological preparation of pa-
available or because the primary care physician does tients and family
not have the time or information needed to do so. In
general, patients with GFR <30 ml/min/1.73 m2 (CKD -- Frequently necessitates hospitalization for a
Stages 4-5) should be referred to a nephrologist. In catastrophic complex illness.
case any I/V contrast has to be used for CT Scan/
MRA/Coronary interventions, the nephrologist opin- -- Mortality associated with acute dialysis can be
ion should be considered. as high as 25%

Early referral of CKD patients offers Conclusions
following advantages:
Ideally, after referral to the nephrologist for consul-
1. A diligent search may reveal a potentially revers- tation, the patient will be referred back to his/ her
ible cause of renal failure. primary care physician (PCP) for further care. The
nephrologist should then develop a long-term man-
2. A number of measures may be implemented to agement plan in collaboration with the PCP to assist
preserve the remaining renal function, e.g., good in optimizing the patient’s care until there is further
control of blood pressure, glucose control in di- progression toward end-stage renal failure. In con-
abetics, nutritional guidance, and avoidance of clusion, the studies support that chronic kidney dis-
nephrotoxic drugs. ease patients fair better as their disease progress-
es toward end stage failure if they are referred to
3. Upper extremity vessels may be preserved for nephrologists for evaluation and co-management of
placement of a native arterio-venous fistula, their care – ideally twelve months prior to the initiation
which is the most reliable type of vascular ac- of renal replacement therapy.
cess. Dialysis grafts and catheters are sub-opti-
mal because of recurrent thrombosis and infec- References
tion. In addition, central venous catheters may
irreversibly damage proximal veins precluding 1. ME Molitch et al.: Diabetic kidney disease: a KDIGO report, Kidney
future use of that extremity for vascular access. International advance online publication, 30 April 2014

4. Treatment of anemia with erythropoietin may sig- 2. Diabetes Care 2014;37:2864–2883
nificantly improve life quality.
3. Global report on Diabetes by WHO 2016
5. Secondary hyperthyroidism may be treated with
4. V. Mohan - Prevalence of Diabetes and Hypertension in South Indian
population – The Chennai Urban Rural Epidemiology study (CURES).
The Asian journal of Diabetology 2003;5:29-30.

5. Ref: Mani MK – Prevention of Chronic renal failure at the community
level. Kidney Int 2003;83:86-89)

6. Rajapurkar.M, Dabhi M, Burden of disease-prevalence and incidence of
renal disease in India. Clinical Nephropathy 2010;74:9-12

Cardio Diabetes Medicine

282 Cardio Diabetes Medicine 2017

Role of Nerve Conduction
Study in Diabetic Patients

Dr. B. Kannan

MD., DM (Neuro), Consultant Neurologist,
Sundaram Arulrhaj Hospitals, Tuticorin

Senior Assistant Professor, Thoothukudi Medical College Hospital, Tamil Nadu

Dr. Princy John P, DNB Resident, Internal Medicine

ABSTRACT have been excluded. A more detailed definition of
Diabetic neuropathy was previously agreed upon at
-- Peripheral Neuropathy is one of the commonest the San Antonio Consensus Conference:
complication in Diabetic patients.
“Diabetic neuropathy is a descriptive term meaning
-- Nerve Conduction Study is useful to assess in- a demonstrable disorder, either clinically evident or
volvement of Neuropathy in Diabetic patients es- subclinical, that occurs in the setting of diabetes mel-
pecially Large fibre. litus without other causes for peripheral neuropathy.
The neuropathic disorder includes manifestations in
-- In Diabetic patients Nerve Conduction studies pre- the somatic and/or autonomic parts of the peripheral
dominantly will show axonal type of Peripheral nervous system”
Neuropathy.
Epidemiology
Introduction
-- Occurs in Type I and Type II Diabetes Mellitus
Peripheral Neuropathy is inflammation and degener-
ation of the peripheral nerves and the cranial nerves -- Occurs in 42% of Type II Diabetes Mellitus
resulting in impairment of the conductivity of these
nerves. Peripheral neuropathy may be classified: -- Onset within 10 years of disease

-- According to the number and distribution of nerves -- Higher risk with higher Glycosylated Hemoglobin
affected (mononeuropathy, mononeuritis multi-
plex or polyneuropathy) What causes Diabetic Neuropathy?

-- The type of nerve cell predominantly affected (mo- • Metabolic factors - such as high blood glucose,
tor, sensory, autonomic) or long duration of diabetes, abnormal blood fat lev-
els, and possibly low levels of insulin
-- The process affecting the nerves; e.g., inflamma-
tion (neuritis), compression(compressionneuropa- • Neurovascular factors, leading to damage to the
thy chemotherapy(chemotherapy-induced periph- blood vessels that carry oxygen and nutrients to
eral neuropathy). nerves

Etiology can be Genetic diseases, Metabolic, e n - • Autoimmune factors that cause inflammation in
nerves
docrine diseases, Toxic causes, Inflammatory
• Mechanical injury to nerves
diseases,Vitamin deficiency ,Physical trauma,Che-
• Lifestyle factors, such as smoking or alcohol use .
motherapy or Other causes including, electric shock,
Classification of Diabetic Neuropathy
HIV, malignant disease, radiation, shingles (Herpes
• Generalized Symmetrical Polyneuropathies
zoster a viral infection).
• Distal sensory or sensorimotor polyneuropathy
People with diabetes have a high risk of neuropathy.
Diabetic Neuropathy can be defined as the presence
of symptoms and/or signs of peripheral nerve dys-
function in people with diabetes after other causes

GCDC 2017

Role of Nerve Conduction Study 283
in Diabetic Patients

• Small-fiber neuropathy Treatment related Neuropathy of ketoaci-
• Autonomic neuropathy dosis
• Large-fiber sensory neuropathy Neuropathy of chronic
renal failure
Focal and Asymmetrical Neuropathies Neuropathy associated
with large vessel ischemia
• Cranial neuropathy (single or multiple) Insulin neuritis Hyperinsu-
• Truncal neuropathy (thoracic radiculopathy) lin neuropathy
• Limb mononeuropathy (single or multiple)
• Proximal motor neuropathy (lumbosacral radiculo- Features of Diabetic Neuropathy

plexopathy, amyotrophy) • Common complication affecting up to 50% pa-
tients with Diabetes mellitus.
Figure 1: Schematic diagram showing type of diabetic
neuropathy. a) Distal symmetrical peripheral neuropahy. • Frequently asymptomatic
b) proximal neuropathy c) cranial and truncal neuropathy
• Requires careful examination/assessment to de-
d) mononeuropathy multiplex tect .

Combinations : • The dermatological assessment should initially
include a global inspection,(interdigitally also), for
• Polyradiculo neuropathy Diabetic neuropathic ca- the presence of ulceration or areas of abnormal
chexia erythema. The presence of callus (particularly with
haemorrhage), nail dystrophy, ingrown toe nail or
Pathophysiological types paronychia should be recorded, Focal or global
skin temperature differences between one foot
Presumed Underlying Subtype of Neuropathy and the other may be predictive of either vascular
Pathophysiology disease or Cellulitis associated with or without ul-
Metabolic-microvascu- DPN cer. Local Skin temperature can be judged crudely
lar-hypoxic DAN by back of the hand otherwise Laser Thermometer
Inflammatory immune is ideal and more precise.Should be examined for
DLRPN Peripheral nerve thickening, muscle tenderness
ompression and repetitive DTRN whether localization of pain possible or not. Small
injury DCRPN muscle wasting and deformity should be exam-
ined for.
Complications of diabetes Cranial neuropathies Pain-
ful neuropathy with weight • Foot deformities lead to high pressure areas lead-
loss, “diabetic cachexia” ing to diabetic foot ulceration. The musculoskele-
tal assessment should include evaluation for any
CIDP in DM gross foot deformity. Rigid deformities are defined
Median neuropathy at the as any contractures that cannot easily be manually
wrist reduced and are most frequently found in the dig-
Ulnar neuropathy at the its. Common forefoot deformities that are known
elbow to increase plantar pressures and are associated
Peroneal neuropathy at with skin breakdown include claw toe or hammer
the fibular head toe. An important and often overlooked or misdi-
agnosed condition is Charcot arthropathy. This oc-
curs in the neuropathic foot and most often affects
the mid foot. This may present as a unilateral red,
hot, swollen, flat foot with profound deformity1.
A rocker-bottom deformity secondary to Charcot
arthropathy can cause excessive pressure at the
plantar mid foot, increasing risk for ulceration at
that site. A patient with suspected Charcot arthrop-
athy should be immediately referred to a specialist
for further assessment and care.

• Affects quality of life (pain, depression)

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284 Cardio Diabetes Medicine 2017

• Patients with Diabetic Neuropathy are 15 times • Painless or silent myocardial infarction
more likely to have Lower limb amputation
Mononeuropathy
• Foot problems are the commonest reason for
in-patient admission In diabetic patients, nerve entrapment is commoner
than nerve infarction. The entrapment neuropathies
Diabetic Sensory Motor Neuropathy have insidious onset, have characteristic electrodi-
agnostic features such as conduction block or seg-
• Most common Diabetic Neuropathy ,three- fourth mental nerve conduction slowing in the entrapped
of all Diabetic Neuropathy. segment of the nerve. Carpal tunnel syndrome is
three times more common in diabetic patients than
• Sensory predominant, autonomic correlate with the normal population. The other entrapment neu-
severity ropathies in diabetic patients are ulnar, radial, lateral
femoral cutaneous nerve of thigh, peroneal and me-
• Minor involvement of distal muscles of lower ex- dial and lateral planter nerves.
tremities.
Cranial neuropathy
• Sensorystocking-glove distribution
Cranial neuropathy in diabetic patients, most com-
• Length-dependent pattern. monly involve the oculomotor nerve followed by
trochlear and facial nerve in order of frequency. Third
• Advanced- sensation impaired over chest & abdo- nerve palsy with pupillary sparing is the hallmark of
men - wedge-shaped area diabetic oculomotor palsy and is attributed to nerve
infarction. The pupillary fibres are peripherally locat-
Large-fiber neuropathy ed; therefore escape in diabetic oculomotor palsy.

• Often asymptomatic, sensory deficit on examina- Multiple neuropathies
tion
Multiple neuropathies refer to the involvement of two
• Painless paresthesias beginning at the toes and or more nerves. As in mononeuropathy the onset is
feet, abrupt in one nerve and occurs earlier than the other
nerves, which are involved sequentially or irregularly.
• Impaired vibration & Joint position sense. Nerve infarctions occur because of occlusion of vasa
nervosum and should be differentiated from system-
• Diminished reflexes. ic vasculitis.

• Ataxia secondary to sensory deafferentation. Diabetic Amyotrophy

Small-fiber neuropathy Unilateral severe pain in the lower back, hip, and an-
terior thigh heralds onset
• Deep, burning, stinging, aching pain ;allodynia to
light touch. Within days to weeks, weakness of proximal and,
to a lesser extent, distal lower-extremity muscles
• Pain & temperature impaired, relative preservation (iliopsoas, gluteus, thigh adductor, quadriceps, ham-
of vibration, Joint Position sense and Deep tendon string, and anterior tibialis).
reflex.
Opposite leg affected after days to months.
• Often accompanied by autonomic neuropathy
Reduced or absent knee and ankle jerks.
• May even develop soon after onset of Impaired
Glucose tolerance. The role of Nerve Conduction studies in
Diabetes mellitus
Autonomic Neuropathy
The American Academy of Neurology recommends
• Correlates with severity of somatic neuropathy that Diabetic Neuropathy is diagnosed in presence of
Subclinical impairment Cardiovascular system , somatic or autonomic neuropathy when other causes
Gastrointestinal system , Genitourinary system of neuropathy have been excluded.About 10% of dia-
dysfunction betic patients may have other causes of neuropathy.
Diabetic Neuropathy cannot be diagnosed without
• Orthostatic hypotension, resting tachycardia, di-
minished heart-rate response to respiration

• Vagal denervation of heart- high resting pulse &
loss of sinus arrhythmia.

GCDC 2017

Role of Nerve Conduction Study 285
in Diabetic Patients

careful examination, because Diabetic Neuropathy done.
may be asymptomatic in a number of patients. At
least one of each of the five criteria is needed: symp- • In(Entrapement) mononeuropathy specific nerve
toms, signs, electrodiagnostic tests, quantitative sen- is studied and NCS shows reduction in segmen-
sory, and autonomic testing. tal conduction velocity and conduction block.

Motor nerve conduction, F response and sensory • For cranial neuropathies
nerve conduction studies are commonly analysed in
routine Nerve conduction study. Motor nerve conduc- • 1. Facial nerve conduction- Facial Neuropathy
tion studies are affected in a large fibre neuropathies.
The nerve conduction changes are non‐specific and • 2. Blink reflex- Trigeminal Neuropathy
key to the diagnosis lies in excluding other causes or
those superimposed on Diabetic Neuropathy. • 3. Visual evoked potential- Optic Neuropathy

Entrapment neuropathies are common in diabetic • 4. BERA and VEMP to study Vestibulopathy
patients and result in unilateral Nerve conduction
velocity changes, especially across the entrapped • 5. SSEP to study posterior column- Vitamin
segment of the nerve. The commonest abnormality B12 deficiency
in diabetes is reduction in the amplitude of motor
or sensory action potentials because of axonopathy. Advantages of Nerve conduction studies

Pronounced slowing of Nerve conduction velocity -- Easily tolerated, safe
suggests demyelinating neuropathy, which is rare-
ly associated with diabetes; therefore pronounced -- Very sensitive to axonal loss
slowing of Nerve conduction velocity in a diabetic pa-
tients should prompt investigations for an alternative -- Very specific for demyelinating disease which is
diagnosis. However, the likelihood of CIDP occurring rare in Diabetes.
in diabetic patients is 11 times higher than the normal
population.The Nerve conduction velocity is gradually Limitations:
diminished in Diabetes neuropathy, with estimates of
a loss of about 0.5 m/s/y. -- Routine motor and sensory conduction velocity
and latency measurements are from the largest
NCS findings in Diabetic Neuropathy and fastest fibers.

1. In Diabetic Neuropathy evoked nerve action po- -- Large-diameter fibers have the most myelin and
tential (CMap, SNap) amplitude are reduced (Ax- the least electrical resistance, both of which result
onal). in faster conduction velocities.

2. NCS abnormalities more common in sensory -- Thus, early stage of DSMPN and also neuropathies
than motor fibres , in the legs more than in the that preferentially affect only small fibers may not
arms, and in the distal more often than proximal reveal any abnormalities on NCSs.
nerve segments .
-- When in doubt, always think about technical fac-
3. Nerve conduction velocities are slower in the tors.
group than in healthy subjects but not upto the
criteria for demyelinating neuropathy. If NCS -- When in doubt, reexamine the patient.
shows predominantly demyelinating pattern then
diagnosis of Diabetic Neuropathy is to be ques- -- Findings should be reported in the context of the
tioned. clinical symptoms and the referring diagnosis.

4. Thus, early stage of DSMPN and also neuropa- -- When in doubt, do not overcall a diagnosis.
thies that preferentially affect only small fibers
may not reveal any abnormalities on routine -- Always think about the clinical-electrophysiologic
NCSs correlation.

Special NCS Conclusion

• For small fibre neuropathy Sympathetic skin Diabetic neuropathy has been defined as presence of
response test and other autonomic test will be symptoms and signs of peripheral nerve dysfunction
in diabetics after exclusion of other causes, which
may range from hereditary, traumatic, compressive,
metabolic, toxic, nutritional, infectious, immune me-
diated, neoplastic, and secondary to other systemic
illnesses. Since the manifestations of diabetic neu-
ropathy closely mimic chronic inflammatory demy-

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286 Cardio Diabetes Medicine 2017

elinating polyneuropathy, alcoholic neuropathy, and
other endocrine neuropathies, hence, before label-
ling diabetic neuropathy it is mandatory to exclude all
other causes of peripheral nerve dysfunction. Nerve
conduction studies are frequently used to assess the
presence of severity of peripheral nerve involvement
in patients with diabetes. They are sensitive, specif-
ic, reproducible, and easily standardised. Studies are
most commonly performed on upper and lower limbs
on motor and sensory nerves.

References

1. ALKakrani, VS Gokhale, Karan V Vohra Clinical And Nerve conduction
study correlation in patients of Diabetic Neuropathy JAPI January 2014,
Vol 62 .

2. D. England, MD, G. S. Gronseth, MD, G. Franklin, MD, MPH, et al.
Report of the American Academy of Neurology, the American Association
of Electrodiagnostic Medicine, and the American Academy of Physical
Medicine and Rehabilitation Neurology January 25, 2005 vol. 64 no.
2 199-207

3. V Bansal, J Kalita, and U K MisraDiabetic neuropathy Postgrad Med J.
2006 Feb; 82(964): 95–100.

4. Christel Tran, Jacques Philipp, François Ochsner et al Acute painful di-
abetic neuropathy: an uncommon,remittent type of acute distal small
fibre neuropathy Swiss Med Wkly. 2015;145:w14131

5. Holli A. Horak, MD Basic Nerve Conduction Studies American Associa-
tion of Neuromuscular &Electrodiagnostic Medicine August 2015

GCDC 2017

Cardio Diabetes Medicine 2017 287

South Asians With PCOS -
Metabolic Risk in Future Generation

Dr. Aarathy Kannan, MD, Dip.Diab

Director, Physician and Diabetologist
Sundaram Arulrhaj Hospitals, Tuticorin

Dr. Kiran Palsania & Dr. Bhubaneshwar

DNB resident (internal medicine)

Background pounded by fertility issues later on. The downstream
risks of PCOS caused by insulin resistance are an
Polycystic ovary syndrome (PCOS) is the most com- even greater threat to health:
mon endocrinological problem affecting women with
a prevalence estimated at 4-25% depending on the • Risk of diabetes is over seven times someone
diagnostic criteria used Patients with PCOS demon- without PCOS
strate a combination of characteristics which may in-
clude anovulation, oligo or amenorrhoea, hirsuitism, • Increased risk of heart disease with more exten-
acne, evidence of increased serum androgen levels sive atherosclerosis of blood vessels
and morphological changes in the ovary evident
on ultrasonography. Diagnostically, current practice • High blood pressure
uses criteria agreed in Rotterdam 2003 Approximate-
ly 50% of PCOS patients are obese ; a much higher • Increased risk of metabolic syndrome
prevalence than the general population. There is also
a metabolic element to the condition in the form of PCOS IN SOUTH ASIANS:-
insulin resistance that may result in long-term mor-
bidity. South Asian refers to those persons who origi-
nate from the Indian subcontinent (India, Pakistan,
PCOS Symptoms and Diagnosis Sri Lanka, Bangladesh and Nepal) In a communi-
ty-based study in the United Kingdom (UK), it was
Blood testing and diagnostic imaging are confirma- found that polycystic ovaries (PCO) were particularly
tory, but the diagnosis of PCOS is made primarily by common among women of South Asian origin (52%)
symptoms, including one or more of the following: , compared to the prevalence of PCO observed in
a predominately Caucasian population (22%) . The
• Irregular periods South Asian population, in general, also exhibit a
higher prevalence of insulin resistance and type 2
• Evidence of excess male hormones (androgens), diabetes which may increase long term morbidity
which produce symptoms like acne, excess facial among those with PCOS. Recent research indicated
and body hair, and hair loss over the scalp (alo- higher insulin concentrations and lower insulin sensi-
pecia) tivity in South Asian women with PCOS compared to
Caucasian women with PCOS This research also con-
• Obesity cluded that South Asians presenting with anovular
PCOS were significantly younger, had more severe
• Acanthosis-Nigricans, which is a rash consisting hirsuitism and a higher prevalence of acanthosis ni-
of dark brown to black colored velvety or thick tex- gricans than their Caucasian counterparts.
tured skin lesions found in body skin folds (back
or side of neck, armpits, groin, etc.) Health-related quality of life (HRQoL), is a concept
used to describe the physical, social and emotional
 The immediate symptoms of PCOS can be devastat- effects of a disease and its associated treatments .
ing to teenagers and young women.  Obesity, acne, Research has shown a reduction in the HRQoL of
and facial hair severely impact body image, particu- women with PCOS compared with healthy controls
larly during adolescent years, which is further com-

Cardio Diabetes Medicine

288 South Asians With PCOS -
Metabolic Risk in Future Generation

Comparisons with other medical conditions and gy- Hypertension in PCOS
naecological populations have also yielded partic-
ularly low scores on psychological well-being and In South Asians,Interestingly, their larger waist cir-
quality of life for women with PCOS cumference is linked to greater IR but not hypertri-
glyceridemia. We recommend a study of pregnan-
Overall, there has been a great paucity of research cy-induced hypertension in women with PCOS from
comparing the influence of ethnicity or cultural back- differing ethnic origins. This is likely to shed more
ground on HRQoL in women with PCOS. Two studies light on the less understood long-term cardiovascular
have tentatively explored this relationship. However, risks of PCOS.
this was inter-country research and the impact of cul-
tural, social and economic differences between the Metabolic risks & Hyperandrogenism of
two countries is unexplained. Twenty percent of the PCOS
world’s population are South Asian. 
The relationship between HA and metabolic pheno-
The metabolic phenotypic differences of PCOS ob- type also shows ethnic variation. Yet, their hyperan-
served in Asians include: drogenemia is independently associated with a five-
fold risk of developing T2DM. However, the direct
• Indigenous south Asians, at a younger age and relationship between metabolic problems and HA
with a lower BMI (26 kg/m2) have greater meta- was not mirrored in the cohort of indigenous south
bolic derangement than older, obese white cau- Asians their metabolic problems being similar among
casians; their central obesity rather than BMI cor- all phenotypic subgroups of PCOS with and without
relating with metabolic manifestations; HA. In fact, their degree of obesity was noted to
be related to the occurrence of oligo-amenorrhea, .
• However, they have the highest prevalence of women with obesity, where obesity and metabolic
MetS (50%) problems do not correlate in a linear fashion with HA.

• Indigenous Thai women with PCOS (mean BMI Such variations based on ethnicity in the susceptibil-
of 27 kg/m2) have similar prevalence of MetS to ity of PCOS to metabolic derangement that is seem-
south Asians at a slightly older age. ingly independent of the HA of PCOS must be noted,
in that the less apparent hirsutism must not discour-
These highlight that central obesity rather than BMI age the practitioner from suspecting PCOS. There-
(based on standard cutoff of 30 kg/m2) affects the fore, utilizing an ethnic-appropriate cutoff level for FG
metabolic issues of PCOS in Asians; thus the need to and diagnostic definition of PCOS must be chosen
measure waist circumference rather than BMI alone. in order to optimally benefit individual patients of a
given population, as well as for comparison of data
Low SHBG in PCOS from different geographic regions and self-identified
ethnicities.
Sex hormone-binding globulin (SHBG) is significantly
lower in affected south Asians compared with their Ethnicity is a factor that determines the degree of
white European counterparts. Since SHBG is lowered hyperandrogenism and warrants measuring plasma
by hyperinsulinemia and considered a surrogate androgens, having defined the cutoff based on eth-
marker of IR,. Therefore, it is logical to encourage life- nically matched normal women (women unaffected
style modification and weight reduction upon diag- by PCOS). The degree of obesity must also be tak-
nosis of PCOS in these ethnic groups, even though en into account, along with its impact on androgen
they have a ‘lower’ BMI. metabolism. This aspect needs further elucidation, in
particular among differing ethnic groups.
Acanthosis Nigricans & Family History of Diabetes
in PCOS Psychosocial Impact of PCOS

A common clinical sign of IR is acanthosis nigricans. PCOS causes significant psychological distress and
A large cohort of Sri Lankan women with PCOS re- leads to poor health-related Quality of Life in wom-
vealed acanthosis nigricans as an important predictor en due to their physical, reproductive and metabolic
of the MetS-complicating PCOS. This supports the effects. While western women have poor QoL due to
recommendation to adopt a policy of training primary obesity, it is different in others, with the main cause
healthcare givers in Asia, on the need to evaluate being infertility and hirsutism among Arab wom-
young woman complaining of irregular menses and en and hirsutism in south Asians. The likely cause
HA with or without infertility for PCOS, which must may be sociocultural factors, with obesity being per-
also be perceived as a long-term metabolic risk.

GCDC 2017

Cardio Diabetes Medicine 2017 289

ceived as a sign of prosperity rather than a negative to improved ethnic-specific clinical practice both
impact on health in some cultures. Hence, the impact for migrant and indigenous groups of affected
of PCOS on psychological issues based on the ethnic women; this takes into account sociocultural is-
background must be taken into account. sues that vary based on one’s ethnic background.

Summary & Conclusion 10. A greater awareness of this aspect among clini-
cians practicing in different settings with varying
1. Central obesity rather than BMI (based on stan- resources would enhance the quality of care and
dard cutoff of 30 kg/m2) affects the metabolic a more holistic approach to managing PCOS in
issues of PCOS in Asians; thus the need to mea- women by adopting a life-cycle approach to the
sure waist circumference rather than BMI alone. problem.

2. South Asians presenting with anovular PCOS References
were significantly younger, had more severe hir-
suitism and a higher prevalence of acanthosis 1. Hart R, Hickey M, Franks S. Definitions, prevalence and symptoms of
nigricans than their Caucasian counterparts. Polycystic ovaries and Polycystic ovary syndrome. Best Pract Res Clin Ob-
stet Gynaecol. 2004;18:671–683. doi: 10.1016/j.bpobgyn.2004.05.001.
3. The chief clinical features of PCOS – reproductive
and hyperandrogenic effects – are closely inter- 2. Homberg R. What is polycystic ovarian syndrome? - A proposal for a
woven with the insulin resistance that is its cen- consensus on the definition and diagnosis of polycystic ovarian syndrome.
tral metabolic problem. The clinical heterogeneity Hum Reprod. 2002;17:2495–2499. doi: 10.1093/humrep/17.10.2495.]
of its presentation has led to much debate and
deliberation on a more pragmatic approach to the 3. Balen A, Michelmore K. What is polycystic ovary syndrome? Are nation-
diagnosis of PCOS. al views important? Hum Reprod. 2002;17:2219–2227. doi: 10.1093/
humrep/17.9.2219.
4. In parallel, there is ethnic-based geographic vari-
ation in the prevalence, complications and out- 4. Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group.
comes of the main metabolic problems of PCOS Revised 2003 consensus on diagnostic criteria and long-term health risks
and its inherent hyperinsulinemia, Type 2diabe- related to polycysticovary syndrome (PCOS) Hum Reprod. 2004;19:41–
tes mellitus and hypertension. 7. doi: 10.1093/humrep/deh098.

5. PCOS, an ill defined symptom complex needs 5. Gambineri A, Pelusi C, Vicennati V, Pagotto U, Pasquali R. Obesity and the
its due attention. As ethnicity plays an important polycystic ovary syndrome. International Journal of Obesity and Related
role in this symptom complex, there is a greater Metabolic Disorders. 2002;26:883–896. doi: 10.1038/sj.ijo.0801994.
need to know the characteristics of the same in
different populations.

6. Women presenting with oligomenorrhea should
be further investigated for PCOS and treated ac-
cordingly.

7. There are report of lower response to advance fer-
tility treatment among asian women with PCOS
that require further study to determine whether
this is due to lower ovarian volume or linked to
greater insulin resistance.

8. Overall occurrence of a single or couple of fea-
tures is less common as compared to that of
multiple characters. This is suggestive of a chain
of pathological and hormonal reactions. Timely
therapeutic intervention can halt this ongoing
process. Nevertheless, complaint related to a
single feature should not be neglected.

9. Knowledge on the etiology of PCOS will be fur-
ther improved by in-depth study of phenotypic
and genotypic differences of PCOS in specific
ethnic groups the world over. This in turn will lead

Cardio Diabetes Medicine

290 Cardio Diabetes Medicine 2017

Hypertension in Elderly Population

Prof. Dr. Jyotirmoy Pal,

Professor, Dept of Medicine, RG Kar Medical College

Subhadeep Gupta, Amlan Kusum Datta, Manidipa Majumdar

Post Graduate Trainee, Dept of Medicine, RG Kar Medical College

Introduction: Consequences of decreased vascular compliance
are Relative increase in systolic pressure, Increase
Hypertension is a very important public health prob- in pulse pressure (SBP – DBP),Decreased Diastolic
lem all over the world. It follows iceberg pattern where blood pressure, Lower intravascular volume . De-
unknown number of cases far exceeds known cas- creased Baroreceptor Sensitivity results in Increased
es. Hypertension is a threat to life at all ages and in BP variability, Impaired BP homeostasis with Early
both sexes. Prevalence of hypertension is increasing morning BP surge, Postural (orthostatic) hypoten-
alarmingly in developing countries and is now one of sion, Post-prandial hypotension, Orthostatic Hyper-
the leading causes of morbidity and mortality among tension. Two thirds of older hypertensives are sodium
the elderly. Prevalence of hypertension in India in the sensitive. This is because decreased GFR, increased
last three decades has increased manifold, approx- proximal tubular reabsorption, decreased produc-
imately by about 30 times among urban residents tion of natriuretic factors. Neurohumoral Changes
whereas about 10 times among rural residents. Av- are in form of Decreased Beta receptor sensitivity,
erage life span all over the globe has been increas- Increased Nor-epinephrine , Increased Renin activity,
ing. In the year of 1961, Indian elderly were 5.63%, Increased Aldosterone activity.
numbering around 24.7 million whereas in 2001, it
has risen to 7.4%(76.6 million). By considering cur- BP Measurement:
rent demographic trend it is projected that in middle
of this century geriatric population will go up to 324 For measuring blood pressure, patient should have
million i.e. four times of the current aged population. taken rest for 5 minutes and he should not have
Increase in hypertension prevalence in elderly is due taken caffeine or tobacco in last 30 minutes .Patient
to changes in arterial structure and function accom- should be made to seat with support behind his
panying aging process. Subjects with uncontrolled back and legs should remain uncrossed with arm at
or poorly controlled hypertension are known to have heart level. The use of android sphygmomanometer
higher risk of developing coronary artery disease is now-a-days recommended by WHO.
(CAD), congestive heart failure, Cerebro Vascular dis-
ease and stroke. The elderly population in India is Radial artery should be palpated during initial cuff
second largest in the world. According to 2011 censes inflation which help in determining the level of sys-
8.1% are of the age 60 years and above. tolic BP and rules out presence of auscultatory gap
which if not done, can underestimate SBP or overes-
Physiological changes in Old Age: timate DBP. Auscultatory gap is commomly seen in
elderly, female sex, increased arterial stiffness, and
• Decreased vascular compliance atherosclerosis.

• Decreased baro receptor sensitivity If the pulse less radial or brachial artery can be pal-
pated after occlusion by the cuff, pseudo hyperten-
• Increased Salt-sensitivity of blood pressure sion should be suspected. Lack of understanding of
this entity can falsely over- diagnose hypertension
• Increased total and central adiposity and injudicious use of anti hypertensive drugs.

• Neuro-humoral Changes in aging

GCDC 2017

Hypertension in Elderly Population 291

Bell of the stethoscope should be lightly applied over Evaluation:
the brachial artery for auscultation because Korot-
koff sounds are low pitched (9). BP measurements FBS,PPBS, lipid profile, complete blood count, uri-
are recorded to the nearest 2 mmHg. Three measure- nalysis with microscopic examination, and electro-
ments should be done and average of the last two cardiogram are reasonable for an initial evaluation.
measurements should be taken as the value for that
visit. Three visits with six measurements should be Treatment Issues in Elderly
taken to diagnose systemic hypertension .
-- Antihypertensive drugs are strongly advocated in
White coat hypertension is more commonly seen in elderly , though most datas are on patients with
elderly –Home monitoring and ABPM have got ad- age < 80 yrs .
vantage in this population. Ambulatory (24 hour) BP
monitoring can detect dipper, non-dipper, early morn- -- HYVET trial demonstrated clear benefit if used
ing surge pattern-which is associated with severe CV above age > 80 yrs of age.
events.
Goal to be achieved :
Clinical Issues
Below 80 yr target BP 140/80 is desirable , but above
• White Coat Hypertension 80 yr, SBP 140-45 is desirable.

• Labile Hypertension In elderly BP lowering below 130/ 70 mm Hg not de-
sirable due to increased incidence of orthostatic fall.
• Pseudo hypertension
As per JNC 8,
• Postural hypotension
“In the general population aged 60 years or older,
• Secondary Hypertension initiate pharmacologic treatment to lower BP at sys-
tolic blood pressure (SBP) of 150 mm Hg or higher or
• Resistant hypertension diastolic blood pressure (DBP) of 90 mm Hg or higher
and treat to a goal SBP lower than 150 mm Hg and
• Polypharmacy and drug interaction goal DBP lower than 90 mm Hg.

• Nonadherence (Recommendation : grade A)

Measuring only office BP may give erroneous result In the general population aged 60 years or older, if
in BP due to white coat hypertension.For that pur- pharmacologic treatment for high BP results in low-
pose,24 Hrs ABPM should be considered. There is er achieved SBP (for example, <140 mm Hg) and
Fluctuation in BP from day to day, hour to hour due to treatment is not associated with adverse effects on
arterial stiffness and decreased windkessel effect of health or quality of life, treatment does not need to
aorta. Higher prevalence of Atherosclerosis gives rise be adjusted.
to a substantial portion of patients with pseudo-hy-
pertension. Loss of autonomic tones, baroreceptor (Recommendation: grade E)”
sensitivity gives rise to postural hypotension and
post prandial hyotension. After a high-carbohydrate Treatment issues:
meal, supine BP declines, and heart rate increases
without an increase in plasma norepinephrine levels . Non Pharmacological treatment:

Secondary hypertension should be suspected if there Lifestyle changes particularly weight loss, avoidance
is sudden surge of SBP and DBP, particularly DBP, of sedentary lifestyle, reduced sodium intake are
occurrence of Malignant hypertension, presence of beneficial in controlling BP in elderly hypertensive.
resistant hypertension.Common secondary causes of However these changes have to be in moderation, as
hypertension are chronic kidney disease, reno-vas- they should not compromise with the quality-of-life
cular hypertension, Obstructive Sleep Apnoea, Hy- in the elderly as IHD, cardiac failure, renal failure,
pothyroidism. Resistant Hypertension is seen due to peripheral vascular disease and orthopedic problems
arterial stiffness, Higher baseline BP , Co-morbidities, are also co-existent in this population.
increase salt intake, sedentary lifestyle, nicotine, al-
cohol intake,Poor compliance, Volume overload, Pharmacological Treatment:
NSAID use.
What guidelines say

As per ACC/AHA 2011 ,

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292 Cardio Diabetes Medicine 2017

“The initial antihypertensive drug should be started at Individual class of drugs:
the lowest dose and gradually increased depending
on the BP response to the maximum tolerated dose. A. Diuretics:
If the anti hypertensive response to the initial drug is
inadequate after reaching full dose (not necessarily Decrease blood volume, decrease peripheral resis-
maximum recommended dose), a second drug from tance and so BP.They are Very effective in elderly
another class should be added, provided the initial with stiff peripheral artery. But at the same time caus-
drug is tolerated. If the person is having no thera- es increase of age related physiological changes and
peutic response or significant adverse effects, a drug further depletion of blood volume, increase postural
from another class should be substituted. If a diuretic hypotension. Electrolyte imbalance causing more ar-
is not the initial drug, it is usually indicated as the rhythmia. Impaired glucose tolerance, hyperuricae-
second drug. If the antihyperten- sive response is mia, hypokalaemia. hypomagnesimia .But thiazide
inadequate after reaching the full dose of 2 classes diuretics maintain BMD and increase blood Calcium
of drugs, a third drug from another class should be level. Loop diuretics decrease blood Ca level.
added. When the BP is 20/10 mm Hg above goal,
drug therapy should generally be initiated with 2 an- B. Ca Channel blocker:
tihypertensive drugs, 1 of which should be a thiazide
diuretic; however, in the elderly, treatment must be It is effective in elder population because of increased
individualized .’’ vascular stiffness ,decreased vascular compliance ,
diastolic dysfunction . Adverse effects are postural
As per JNC 8, hypotension, ankle edema, headache. These are ef-
fective in preventing dementia.
“In the general nonblack population, including those
with diabetes, initial antihypertensive treatment C. ACEI and ARBs:
should include a thiazide-type diuretic, calcium chan-
nel blocker (CCB), angiotensin-converting enzyme in- Reduce peripheral resistance without reflex stimula-
hibitor (ACEI), or angiotensin receptor blocker (ARB). tion of HR and contractility.

Moderate Recommendation Grade B Indications are HTN with HF / DM /Nephropathy/
Post AMI/ Angina and also effective in preventing
In the general black population, including those with dementia.
diabetes, initial antihypertensive treatment should in-
clude a thiazide-type diuretic or CCB. D. Beta Blocker:

For general black population: Moderate Recommen- They are not used as first choice but used when Hy-
dation – Grade B pertension associated with arrhythmias, Post AMI ,
Heart Failure, hyperthyroidism, essential tremor, anx-
For black patients with diabetes: Weak Recommen- iety neurosis, preoperative hypertension.
dation – Grade C”
Adherence is most important issue in eldely hyper-
As per Indian Hypertension Guidelines-III, tension. Frequent non-adherence and non-control
of BP occur due to dementia, Low socio-economic
Elderly hypertensives should be started with Calcium condition, isolation, Cost, Side effects, Treating com-
Channel blocker or Diuretic. plications and all these issues are to be addressed
while dealing a older hypertensive.

Summary of all guidelines: References:

-- Start with small dose 1. Puspanjali S, TP Sherin Raj. Demography of aging in India. Indian Journal
of Gerontology 2005;19:327-42.
-- Increase gradually with monitoring
2. Franlin SS, Jacobs MJ, Wong ND, L’Italian GL, Lapuerta P. Predominance
-- Add next drug if not controlled of isolated systolic hypertension among middle age and elderly US hyper-
tensives analysis based on National Health and Nutrition Examination
-- Observe side effects and drug interaction , non- Survey(NHANES) III. Hypertension 2001;37:869-74.
compliance
3. Franklin SS, Khan SA, Wong ND, Larson MG, levy D. Is pulse pressure
-- Choice of drug according to concomitant diseases more important than systolic blood pressure in predicting coronary heart
and other duugs. disease event. Circulation 1999;100:354-60.

-- Ordinarily ca- channel blockers and diuretcs are 4. Dalal PM. Hypertension – A report on community survey for casual hy-
1st line of choice. pertension in old Bombay. Ed H Jhala Bombay Sir HN Hospital 1980.

5. Reaven GM. Insulin resistance, hyper-insulinemia and hyper-triglyceridemia
in the etiology clinical course of hypertension. Am J Med 1991;90:7S-12S.

GCDC 2017

Hypertension in Elderly Population 293

6. Mohan JC. Prevalence, awareness, treatment and control and risk factors 24. SRS Statistical Report 2011: SRS Statistical Report Tables. Available at:
of hypertension in India and its neighborhood: Newer data and older per- http://www.censusindia.gov.in/vital_statistics/SRS_Report/12S RS%20Sta-
spective. Indian Heart J 2006;58:7-9. tistical%20Report%20Table%20-%2020111.pdf [Accessed on Septem-
ber 15, 2013].
7. Anderson GH, Blackman N, Streeten DH. The effect of age on prevalence
of secondary forms of hypertension in 4429 consecutively referred patients.
J Hyperns 1994;12:609-15.

8. Chobanian AV, Bakris GL, Black HL. Seventh report of the Joint National
Committee on Prevention, Detection, Evaluation, and Treatment of High
Blood Pressure. Hypertension 2003;42:1206-52.

9. National High Blood Pressure Education Program Working Group. Report
on Hypertension in the elderly.Hypertension 1994;23:275-85.

10. Psaty BM, Lumley T, Furberg CD, et al. Health outcomes associated with
various anti-hypertensive therapies used as first line agents: a network
meta-analysis. JAMA 2003;289:2534-44.

11. Major outcomes in high risk hypertensive patients randomized to angioten-
sin converting enzyme inhibitor or calcium channel blocker vs diuretic. The
Antihypertensive and Lipid-Lowering Treatment to prevent Heart Attack
Trial (ALLHAT). JAMA 2002; 288:2981-97.

12. Staessen JA, Fagard R. Thijs L, et al. Randomised double blind comparison
of placebo and active treatment for older patients with isolated systolic
hypertension. The Systolic Hypertension in Europe (Syst-Eur) Trial Inves-
tigators. Lancet 1997; 350:757-64.

13. SHEP Cooperative Research Group. Prevention of stroke by antihyperten-
sive drug treatment in older persons with isolated systolic hypertension.
JAMA 1996;265:3255-64.

14. Schiffrin EL. Effects of antihypertensive drugs on vascular remodeling: do
they predict outcome in response to antihypertensive therapy? Curr Opin
Nephrol Hypertens 2001;10:617-24.

15. Yusuf S, Sleight P, Progue J. Effects of angiotensin converter inhibitor ,
ramipril, on cardiovascular events in high risk patients. The out comes Pre-
vention Evaluation Study Investigators. N Engl J Med 2000; 342:145-53.

16. Linholm LH, Ibsen H, Dahlof B, et al. Cardiovascular morbidity and mor-
tality in patients with diabetes in the losartan intervention for End point
reduction in hypertension study (LIFE): a randomized trial against atenolol.
Lancet 2002;359:1004-10.

17. Dahlof B, Lindholm LH, Hansson L, Schersten B, Ekbom T, Wester PO.
Morbidity and mortality in the Swedish Trail in Old patients with hyper-
tension. Lancet 1991;338:315-9.

18. Frishman WH, Landau A, Cretkovic A. Combination drug therapy with
calcium-channel blockers in the treatment of systemic hypertension. J
Clin Pharmacol 1993;33:752-5

19. Madhukumar S, Gaikwad V, Sudeepa D. An Epidemiological study of Hy-
pertension and its risk factors in Rural Population of Bangalore Rural
District. Al Ameen J Med Sci. 2012; 5(3):264-70.

20. Pradeepa R, Mohan V. Hypertension and pre hypertension in developing
countries. Indian J Med Res 2008; 128:688-90.

21. Hafez G, Bagchi K, Mahaini R. Caring for the elderly: A report on the
status of care for the elderly in the Eastern Mediterranean Region. East
Mediterr Health J. 2000; 6(4):636-43.

22. Aronow WS, Fleg JL, Pepine CJ, Artinian NT, Bakris G, Brown AS, et al.
ACCF/AHA 2011 Expert Consensus Document on Hypertension in the
Elderly. A Report of the American College of Cardiology Foundation Task
Force on Clinical Expert Consensus Documents. J Am Coll Cardiol. 2011;
57(20):2037-114.

23. World health organization: World Health Day. Available at: http://www.
who.int/world-healthday/previous/en/index.html [Accessed on September
15, 2013].

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294 Cardio Diabetes Medicine 2017

CVD in Diabetes -
Is It Only Macrovascular?

Dr. Arulprakash,

MD., MRCP(UK).,FRCP(London)
Endocrinologist, Indra Diabetes Centre, Tuticorin, Tamil Nadu

Introduction: complications progress, despite intensive glycaemic
control, in patients with DM. Hyperglycemia triggers
CVD account for most morbidity and mortality in the production of ROS in vascular cells through en-
patients with diabetes mellitus. Diabetic subjects zymatic (protein kinase C and the reduced form of
are known to have a two to four times increased nicotinamide adenine dinucleotide phosphate [NA-
CAD risk, and CAD has been reported to occur two DPH] oxidases) and nonenzymatic sources of oxi-
to three decades earlier in diabetic subjects as op- dant stress (e.g., the formation of advanced glycation
posed to their nondiabetic counterparts.Diabetes end products, AGEs).As oxidative stress increases,
causes microvascular diseases, such as nephropa- the eNOS cofactor tetrahydrobiopterin becomes oxi-
thy, neuropathy, and retinopathy, and macrovascular dized and uncouples eNOS, which cause the enzyme
disease (e.g., atherosclerosis). Atherosclerosis of the to produce superoxide anion instead of NOSuperox-
coronary, cerebral, and peripheral arteries accounts ide anion quenches NO in a diffusion-limited reac-
for approximately 80 percent of mortality and for 75 tion to produce peroxynitrite. Peroxynitrite inhibits
percent of hospitalizations in persons with diabetes. prostacyclin synthase and endothelium-dependent
hyperpolarizing factor activity. Similar to the effects
As type 2 diabetes shares several risk factors in com- of hyperglycemia, free fatty acids activate intracel-
mon with coronary artery disease (CAD), such as age, lular enzymatic oxidant sources, including protein
hypertension, dyslipidemia, obesity, physical inactiv- kinase C, NADPH oxidases, and eNOS, yielding
ity, and stress, an increase in the prevalence of dia- analogous increases in superoxide anion.The excess
betes indirectly implicates an escalating risk of CAD. adipose tissue that usually accompanies type 2 dia-
betes mellitus releases excess fatty acids. Free fatty
Diabetes and Endothelial dysfunction: acids attenuate prostacyclin bioavailability by inhib-
iting prostacyclin synthase. Moreover, free fatty ac-
Diabetes causes metabolic abnormalities, including ids interfere with intracellular signaling pathways to
hyperglycemia, dyslipidemia, and insulin resistance, cause not only muscle and visceral insulin resistance
that disrupt normal arterial function and render arter- but also vascular insulin resistance. In diabetes, hy-
ies susceptible to atherosclerosis. It specifically alters perglycemia and increased free fatty acids increase
the function of vascular endothelium and smooth the concentration in the cell of the metabolite dia-
muscle cells, as well as platelets, in ways that pro- cylglycerol. Diacylglycerol , in turn, activates a family
mote atherogenesis. Diabetes impairs the vasodila- of enzymes known as protein kinase C (PKC), that
tor function of endothelial cells and decreases the perform key regulatory functions by phosphorylating
bioavailability of nitric oxide (NO).Hyperglycemia de- proteins important in metabolic control. Activation of
creases NO production from endothelial nitric oxide PKC can inhibit the expression of eNOS, augment
synthase (eNOS) and increases its degradation via cytokine-induced tissue factor gene expression and
generation of reactive oxygen species (ROS). Recent procoagulant activity in human endothelial cells,
evidence suggests that hyperglycaemia-induced ROS and increase the production of proinflammatory cy-
generation is involved in the persistence of vascular tokines, proliferation of vascular wall cells, and pro-
dysfunction despite normalization of glucose levels. duction of extracellular matrix macromolecules that
This phenomenon has been called ’metabolic mem-
ory’ and may explain why macro- and microvascular

GCDC 2017

CVD in Diabetes- Is It Only Macrovascular? 295

accumulate Diabetes also disturbs vascular function
through nonenzymatic glycation of macromolecules.

In states of hyperglycemia and increased oxida-
tive stress, many proteins and even lipids undergo
nonenzymatic glycation. Glycated proteins can form
structures known as AGEs that cause the macromol-
ecule to take on a brown hue, similar to burnt sugar.
AGEs accumulate in the vessel wall and appear to
contribute to the pathobiology of complications of
diabetes, notably the accelerated vascular disease
characteristic of this conditionduring atherosclerotic
lesion formation.Phospholipids and apolipoproteins
can form AGEs and AGE-modified proteins can ac-
cumulate in diabetic subjects. The presence of gly-
cated forms of low-density lipoproteins (LDLs) can
engender an immune response and contribute to
macrovascular disease. AGE-modified LDL apopro-
tein and LDL lipid levels increase in diabetic subjects
compared with nondiabetics.Increased AGE produc-
tion is associated with reduced nitric oxide bioavail-
ability through impairment of eNOS transcription and
activity, production of oxygen-derived free radicals,
and activation of NF-kBDiabetes impairs vascular
smooth muscle function and augments the produc-
tion of vasoconstrictor mediators, angiotensin II and
vasoconstrictor prostanoids, including endothelin-1,
which causes vascular smooth muscle growth and
inflammation. However, most diabetics have periph-
eral autonomic impairment at the time of diagnosis,
and vascular beds regulated by these nerves have
decreased arterial resistance. Similar to endotheli-
al cells, diabetes activates atherogenicmechanisms
within vascular smooth muscle cells, including pro-
tein kinase C, RAGE, NF-kB and the production of
oxidative stress.Diabetes heightens vascular smooth
muscle cell migration in atherosclerotic lesions.

Advanced atherosclerotic lesions have fewer vas-
cular smooth muscle cells in diabetic patients than
nondiabetic patients, possibly resulting in decreased
resiliency of the fibrous cap and thereby increasing
the risk of rupture and luminal thrombi.

To sum up the interconnection between Type 2 DM
and CVD, various genetic and environmental play up
ending in Macrovascular complication namely ath-
erosclerosis through various steps namely endothe-
lial dysfunction. It gives room for the plaque rupture
and then activation of clotting system resulting in
thrombus formation. So we can conclude that CVD
is only a macrovascular complication of Type 2 DM

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296 Cardio Diabetes Medicine 2017

Double Trouble -
Diabetes and Heart Disease (CAD)

Dr Preetam Arthur,

MD, FRCP,HOD OF MEDICINE,SRMC.CHENNAI

Dr. Harshavardhan TS, MD

1. Diabetes and Cardiovascular disease – and 48 years for men and women respectively with
epidemiology: diabetes. This was 15 years (mean) younger than that
of the non-diabetic population. Currently the Nation-
There is sufficient evidence to show that patients al cholesterol education programme from the United
with type 1 or type 2 diabetes mellitus are at a higher States of America and guidelines from Europe desig-
risk for cardiovascular disease than the normal pop- nate diabetes to be a coronary heart disease equiva-
ulation. These include coronary artery disease(CAD), lent, highlighting the highest risk category.
peripheral vascular disease, stroke, cardiomyopathy
and congestive cardiac failure. The public health sig- B. Extent of disease:
nificance of this association is emphasised in re-
cent times due to the ‘diabetic epidemic’. With better Studies have shown that the extent of coronary ar-
treatment options, more people are living longer with tery disease is more among diabetics in comparison
diabetes and this population is at a higher risk for to non diabetics. Multi vessel disease was more in
cardiovascular disease due to advancing age. More- patients with an acute myocardial infarction with dia-
over, lower levels of physical activity and lifestyle betes mellitus than in non diabetics (66% versus 46%)
variations have seen the rise of obesity and diabetes in the Thrombolysis and Angioplasty in myocardial
among younger populations, putting them at a higher infarction study. Even in asymptomatic patients this
risk for cardiovascular disease as well. difference has been observed.

2. The effect of diabetes on cardiovascular C. Pattern of cardiovascular disease:
disease:
Diabetes has been shown to be associated with as-
A. The strength of association ymptomatic vascular thrombogenesis, stable coro-
nary artery disease, acute coronary syndromes, silent
Diabetes mellitus has been recognised as an inde- ischemia and cardiomyopathy.
pendent risk factor for cardiovascular disease in mul-
tiple prospective studies including the Framingham, Acute myocardial infarction:
San Antonio and the Honolulu heart studies. In the
Framingham heart study the presence of diabetes Studies from Finland and the Atherosclerosis risk in
mellitus doubled the age adjusted risk for cardiovas- Communities (ARIC) study from the United States
cular disease in men and tripled it in women. Diabe- have established higher rates of acute myocardial
tes was identified as a major independent risk factor infarction(MI) in patients with diabetes in comparison
even after adjusting for advancing age, hypertension, to non diabetics. In the ARIC study the event rate of
hypercholesterolemia , left ventricular hypertrophy cardiac deaths or non fatal MI was higher in patients
and smoking. A large database based retrospective with diabetes alone (10.8%) and diabetes and prior MI
cohort study from Canada demonstrated that the (32.2%) compared to no diabetes and no MI (3.9%).
age of transition to a higher risk of cardiovascular Diabetics are also prone to higher rates of post in-
disease was much lower in diabetics than non dia- farction angina and heart failure. (1) (2) The mortality
betics. This transition to a high risk category (10 year at 1 year post MI in diabetics has been shown to be
event rate of more than 20 %) occurred at 41 years as high as 50% in some studies. The reason for this
higher occurrence has been explained by the propen-

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Double Trouble - Diabetes and Heart Disease (CAD) 297

sity to increased coagulability. Diabetics have higher also been observed in patients with diabetes based
rates of platelet activation, and increased levels of on Doppler studies. Interstitial fibrosis with increased
tissue plasminogen activator inhibitor type 1, leading collagen deposition has been postulated as contrib-
to accelerated thrombus formation and reduced ly- uting to the altered mechanics. The prevalence of
sis of clot. Moreover, proteinuria due to diabetic ne- heart failure, especially heart failure with preserved
phropathy can reduce the levels of protein C and an- ejection fraction(16-31%) is higher among diabetics
ti-thrombin III, furthering the pro-coagulant state. (3) than the general population (4-6%). Thus diabetes
per se independently influences cardiac structure
Silent Ischemia and function by promoting hypertrophy and fibrosis.

Some diabetics may have a blunted pain response
to ischemia, which may result in atypical symptoms.
This may result in silent ischemic insult to the cardiac
musculature and eventually, silent infarction. Silent
ischemia is far more prevalent in patients with DM
(10%-20%) than those without DM (1%-4%) and may
have a male predilection. Silent Myocardial infarction
may contribute to the higher rates of morbidity and
mortality in cardiovascular disease among diabetics.
Silent ischemia is partly explained by the autonom-
ic neuropathy seen in diabetes. The astute clinician
therefore, must have a low threshold for suspecting
cardiac ischemia in a diabetic patient with atypical
symptoms and early evaluation is prudent.

Asymptomatic disease: D. Diabetes as a risk factor for cardiovascular disease:

People with diabetes have higher rates of asymptom- There are multiple identified risk factors for coronary
atic disease (11 to 60%). This has been studied based artery disease amongst which diabetes is an import-
on the presence of coronary artery calcification (CAC) ant modifiable factor. The cardiovascular risk identi-
on electron beam CT scanning and by inducible silent fied with that of diabetes has been compared with
ischemia on stress imaging. The American Diabetes the cardiovascular associated with a prior myocardial
association (ADA) and European guidelines, howev- infarction. Diabetics have a greater burden of other
er, do not recommend routine screening for coronary atherogenic risk factors than nondiabetics, including
artery disease in asymptomatic patients as outcomes hypertension, obesity, increased total to HDL choles-
are not improved as long as cardiovascular risk fac- terol ratio, hypertriglyceridemia, and elevated plasma
tors are controlled. (4) fibrinogen. The CAD risk in diabetics varies widely
with the intensity of these risk factors
Diabetic Cardiomyopathy:
E. Cardiovascular Risk and targeted reduction in di-
Diabetes affects the heart in more ways than just cor- abetes:
onary atherosclerosis and the effects of associated
systemic hypertension. Diabetics tend to have great- In patients with diabetes, multiple risk factors that
er cardiac muscle mass, especially of the left ventri- predispose to coronary artery disease have been
cle. One multi-ethnic study showed that the likeli- identified. These include both traditional and non-tra-
hood of having a left ventricular mass exceeding 75th ditional risk factors.
percentile was greater in type 2 diabetics even after
adjusting for other factors. This has been attributed
to higher levels of leptin and resistin which contrib-
ute to hypertrophic effects on the cardiac myocytes.
Studies have shown that 40-75% of diabetics with no
overt signs of coronary artery disease have diastolic
dysfunction. This finding has been explained based
on triglyceride accumulation in cardiac myocytes in
diabetes, which results in lipotoxicity and altered
calcium metabolism. Subtle systolic dysfunction has

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298 Cardio Diabetes Medicine 2017

Table 1 9% in all-cause mortality (p = 0.02) and of 21% in in-
cidence of major vascular events (p < 0.0001) per
Traditional Nontraditonal each mmol/l of reduction in LDL-c. Besides that there
Dysplidemia Insulin resistance and Hyper- are also significant reductions in acute myocardial in-
insulinemia farction (AMI) (p < 0.0001), coronary revascularization
Hypertension Postprandial Hyperglycemia (p < 0.0001) and stroke (p < 0.0002). (6) (7) Thus the
Obesity Glucose Varibility evidence supporting the role of statins in risk reduc-
Abdonimal Obesity Microalbuminuria tion is strong and various guidelines advocate the
Physical Exercise Haeatological Factors initiation of statins in patients with diabetes based
Cigarette Smoking Thrombogenic Factors on cardiovascular risk.
Inflammation C-reactive pro-
tein Proteinuria
Homocyste and vitamins
Erectivel dysfunciton Microalbuminuria, one of the earliest markers of di-
Genetics and Epigenetics abetic nephropathy, has been shown to be associ-
ated with a greater risk for cardiovascular disease
Role of select risk factors: and death. The HOPE ( Heart outcomes Prevention
Evaluation) trial and the LIFE study showed that the
Glycemic control: The role of glycemic control in mi- risk of an adverse cardiovascular event increased
crovascular complications of diabetes mellitus has progressively with increased absolute levels of micro-
been demonstrated in large prospective trials in albuminuria. Annual cardiovascular death rates also
both type 1 and type 2 diabetes mellitus. However increase with worsening diabetic nephropathy. (7)
the same has not been conclusive for macrovascu- (8)The existence of microalbuminura in people with
lar complications. A meta-analysis of 13 prospective T2DM is an important early sign that should alert us
studies showed the relative risk for any cardiovascu- to the onset of a systemic endothelial disease, and
lar event was 1.18 (CI 1.10-1.26) for every percentage associated target organ damage to the heart, the
point increase in hba1c. (5) However multiple ran- brain and the kidney.
domised controlled trials conducted till date in type
2 diabetes mellitus (ACCORD, ADVANCE, Veteran Smoking: Active smoking is associated with a high
affairs study) have not shown benefit of glycemic risk of total mortality and cardiovascular events
control in cardiovascular end points. among patients with diabetes, while smoking cessa-
tion is associated with a reduced risk in total mor-
Systemic Hypertension: In both type 1 and 2 diabetes, tality and cardiovascular events in patients with di-
hypertension is a major risk factor for cardiovascu- abetes. Benefit of smoking cessation is more when
lar events and microvascular complications. A me- stopped early.
ta-analysis of forty studies, including 100,354 adults
with type 2 diabetes mellitus, observed that for each Physical activity : Multiple observational studies have
10-mmHg lowering in systolic blood pressure there shown the beneficial effects of physical activity on
was a significant lowering in risk for many outcomes diabetes and related cardiovascular disease. The
such as: mortality (RR: 0.87; 95% CI 0.78–0.96); car- findings of MRFIT study provide evidence for better
diovascular events (RR: 0.89 [95% CI 0.83–0.95], coro- glycemic control and cardiovascular outcomes with
nary heart disease (RR: 0.88 [95% CI 0.80–0.98]) and exercise. Current recommendations are to advise
stroke (RR, 0.73 [95% CI 0.64–0.83]). The ADA recom- atleast 150 minutes of moderate intensity or 75 min-
mends a target blood pressure goal of 140 mm hg utes of vigorous intensity aerobic exercise in a week.
systolic and 90 mm Hg diastolic blood pressure. (6)
3. Therapeutic implications in diabetes and
Dyslipidemia: Dyslipidemia, especially raised LDL- cardiovascular disease:
holesterol (LDL-c) is one of the most important re-
versible risk factors for cardiovascular morbidity and This section examines the relationship of drugs used
mortality. Patients with diabetes tend to have a high- in diabetes and their effect on cardiovascular disease.
er proportion of LDL particles that are smaller and
denser, are more susceptible to oxidation, and may Thiazolidinediones-: Rosiglitazone is infamous for its
thereby increase the risk of cardiovascular events. In association with adverse cardiovascular risk based on
diabetics, statins promote a proportional reduction of a meta-analysis of trials featuring this drug, though
the interpretations of the data have been debated
extensively.

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Double Trouble - Diabetes and Heart Disease (CAD) 299

Pioglitazone is also a member of the thiazolidinedi- has potential benefits on cardiovascular outcomes
one group which is extensively used in clinical prac- in patients with diabetes. However the potential
tice. In the Prospective Pioglitazone Clinical Trial in for precipitating lactic acidosis in patients receiv-
Macrovascular Events (PRO-active) , treatment with ing Metformin and having concomitant heart or re-
pioglitazone produced a non-significant reduced risk nal dysfunction is well recognised. Metformin must
of coronary and peripheral vascular events (hazard therefore be avoided in patients with acute coronary
ratio [HR], 0.90; 95% CI, 0.80 to 1.02; P=0.10). In ad- syndromes and patients with unstable or acute heart
dition, a meta-analysis of CV outcome from 19 ran- failure which pose risk of hypoperfusion and hypox-
domized clinical trials, with a total of 16,390 diabetic emia. Stable compensated heart failure is however,
patients, showed that pioglitazone was associated not considered a contraindication to the use of met-
with a significantly lower risk of the composite of formin. It may also be prudent to avoid the use of
death, myocardial infarction, and stroke (HR, 0.82; metformin prior to and immediately after the admin-
95% CI, 0.72 to 0.94; P=0.005). (10) However there is istration of contrast agents in the setting of coronary
a concern on serious risk of worsening heart failure angiography, though the evidence for this recom-
that was demonstrated in both the PROactive trial mendation is not strong.
and the meta-analysis on use of pioglitazone. How-
ever this did not translate into increased mortality in Insulin: Glycemic control with insulin has shown car-
these studies. Caution is advised in using pioglita- diovascular benefit in type 1 diabetics ( DCCT/EDIC
zone in patients with heart failure. trials).The true effect in type 2 diabetics is unclear.
However Insulin promotes weight gain that may ac-
DPP-4 Inhibitors: The SAVOR-TIMI 53, EXAMINE & centuate the disordered body habitus in type 2 di-
TECOS trials have examined dipeptidyl peptidase 4 abetics and this may be counterproductive to the
(DPP-4) inhibitors and their effect on cardiovascular development of cardiovascular disease. Thus pa-
outcomes. Though none of these trials demonstrated tients must be advised to have sufficient dietary and
adverse or beneficial cardiovascular outcomes, they lifestyle modifications to maintain optimum weight
raised concerns over the use of DPP 4 Inhibitors and when on therapy with insulin.
associated heart failure. The FDA recommends dis-
continuation specifically of saxagliptin and alogliptin Diabetic agents and weight gain: Obesity and abdom-
in patients who develop heart failure (10) (11). Further, inal adiposity are risk factors for diabetes and also
large scale studies on the safety of these drugs is pose an adverse cardiovascular risk as well. Agents
underway. used in the management of diabetes may influence
this and be weight neutral or can promote weight
SGLT 2 Inhibitors: SGLT 2 Inhibitors like Empagifloz- loss or weight gain.
in and Canagliflozin are novel oral hypoglycaemic
agents. Multiple trials examining their association Drug Effect Drug name Weight effects
with cardiovascular disease, have been performed (Kg)
in patients with high risk of coronary artery disease. Weight gain Insulin + 4-5
In a trial examining the effects of empagiflozin, at Weight neutral Sulfonylureas +1.6-2.6
three years of taking the drug, the primary outcome Weight loss Meglitinides +0.7-1.7
(a composite of death from cardiovascular causes, Thiazolidinediones +4.1-4.8
nonfatal myocardial infarction, or nonfatal stroke) DPP inhibitors +0.00 to 0.4
occurred in fewer patients assigned to empagiflozin Alpha glucosidase + 0.0 to 0.2
than to placebo (10.5 versus 12.1 percent; hazard ra- inhibitor
tio [HR] pooled analysis 0.86, 95% CI 0.74-0.99). The Metformin -4.58 to +0.4
findings were driven by a significant reduction in risk GLP 1 analogues -2.7 to -3
of death from cardiovascular causes (3.7 versus 5.9 SGLT 2 Inhibitors 2 to 3
percent with placebo; HR 0.62, 95% CI 0.49-0.77). The Amylin analogues -3.1
rate of heart failure related hospitalisations were also
lower in this group. However despite this benefit, Role of aspirin for risk reduction: Despite the estab-
canagliflozin increased the rates of toe and mid foot lished role of aspirin in diabetic patients for second-
amputations. Further studies regarding the same are ary prevention of cardiovascular disease, the role in
ongoing and data that emerges may consolidate the primary prevention is less clear. In a meta-analysis of
position of SGLT inhibitors as potential cardio-protec- 10 trials evaluating aspirin for the primary prevention
tive agents. of CVD in patients with diabetes, aspirin modestly

Metformin: Based on the UKPDS study, Metformin

Cardio Diabetes Medicine

300 Cardio Diabetes Medicine 2017

but significantly reduced the risk of major cardiovas- 2. Haffner SM, Lehto S, Rönnemaa T, Pyörälä K, Laakso M. Mortality from
cular events compared with placebo or no treatment coronary heart disease in subjects with type 2 diabetes and in nondiabetic
(relative risk [RR] 0.90, 95% CI 0.81-0.99). This was subjects with and without prior myocardial infarction. N Engl J Med. 1998
however against an increased risk of major bleed- Jul 23;339(4):229–34.
ing. Aspirin did not significantly reduce the risk of
any of the individual endpoints (MI, CHD, stroke, 3. Diabetes and cardiovascular disease: Epidemiology, biological mecha-
CVD, or all-cause mortality). (9) The American diabe- nisms, treatment recommendations and future research [Internet]. [cited
tes association recommends that aspirin should be 2017 Sep 1]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/
considered for primary prevention in any patient with PMC4600176/
diabetes at increased cardiovascular risk (10-year
risk >10 percent), which would include most men or 4. Standards of medical care in diabetes--2015: summary of revisions. Dia-
women >50 years who have at least one additional betes Care. 2015 Jan;38 Suppl:S4.
cardiovascular risk factor (eg, cigarette smoking, hy-
pertension, obesity, albuminuria, dyslipidemia, or a 5. Selvin E, Marinopoulos S, Berkenblit G, Rami T, Brancati FL, Powe NR, et
family history of CHD). The ADA recognizes that the al. Meta-analysis: glycosylated hemoglobin and cardiovascular disease in
evidence to support this recommendation is weak. diabetes mellitus. Ann Intern Med. 2004 Sep 21;141(6):421–31.
2012 guidelines from the European Society of Cardi-
ology, advise against the use of aspirin in individu- 6. Bertoluci MC, Rocha VZ. Cardiovascular risk assessment in patients with
als without cardiovascular or cerebrovascular disease diabetes. Diabetol Metab Syndr. 2017 Apr 20;9:25.
due to the risk of major bleeding. The Indian national
programme for prevention and control of diabetes, 7. Martín-Timón I, Sevillano-Collantes C, Segura-Galindo A, del Cañizo-Gó-
Cardiovascular disease and stroke in its 2009 rec- mez FJ. Type 2 diabetes and cardiovascular disease: Have all risk factors
ommendation does not suggest offering aspirin as the same strength? World J Diabetes. 2014 Aug 15;5(4):444–70.
primary prophylaxis in patients with a cardiovascular
risk less than 30% due to lack of strong evidence 8. Huxley R, Barzi F, Woodward M. Excess risk of fatal coronary heart dis-
to suggest the same . Therefore this decision on ease associated with diabetes in men and women: meta-analysis of 37
primary prophylaxis must be taken by the treating prospective cohort studies. BMJ. 2006 Jan 14;332(7533):73–8.
physician keeping in mind the level of benefit that it
offers versus the risk of major bleeding it poses on 9. Kunutsor SK, Seidu S, Khunti K. Aspirin for primary prevention of cardio-
an individual basis. vascular and all-cause mortality events in diabetes: updated meta-analysis
of randomized controlled trials. Diabet Med J Br Diabet Assoc. 2017
4. Conclusion: The association of diabetes and car- Mar;34(3):316–27.
diovascular disease is therefore a major cause for
morbidity and mortality in patients with diabetes. The 10. Bae JC. Diabetes Drugs and Cardiovascular Safety. Endocrinol Metab. 2016
risk factors that are related to this association need Jun;31(2):239–44.
careful understanding and are the principal targets of
approach in reducing the risk of cardiovascular dis- 11. Commissioner O of the. Safety Alerts for Human Medical Products - Di-
ease. The role of aspirin in primary prophylaxis has abetes Medications Containing Saxagliptin and Alogliptin: Drug Safety
been debated and must be used after considering Communication - Risk of Heart Failure [Internet]. [cited 2017 Sep 2].
the risk and benefit in the individual patient. The anti Available from: https://www.fda.gov/Safety/MedWatch/SafetyInformation/
diabetic drug armamentarium is rapidly expanding SafetyAlertsforHumanMedicalProducts/ucm494252.htm?source=govdeliv-
and requires close examination of potential effects ery&utm_medium=email&utm_source=govdelivery%20(Accessed%20
on cardiac status. The physician must therefore have on%20April%2012,%202016).
an astute understanding of this quintessential rela-
tionship between diabetes mellitus, its therapy and
cardio-vascular disease for holistic management of
the diabetic patient.

Bibliography:

1. Diabetes Mellitus: A Major Risk Factor for Cardiovascular Disease: A Joint
Editorial Statement by the American Diabetes Association; the National
Heart, Lung, and Blood Institute; the Juvenile Diabetes Foundation In-
ternational; the National Institute of Diabetes and Digestive and Kidney
Diseases; and the American Heart Association. Circulation. 1999 Sep
7;100(10):1132–3.

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Cardio Diabetes Medicine 2017 301

Diabetic Cardiomyopathy: Mechanisms,
Diagnosis and Treatment

Dr. A.K. Das

(Professor and Head of Dept of Endocrinology, Pondicherry Institute of Medical Sciences)

Dr. Kevin T. John

(Senior Resident, Department of General Medicine, Pondicherry Institute of Medical Sciences)

Introduction The epidemic of obesity and sedentary lifestyle is
projected to result in over 300 million people with
The incidence of diabetes mellitus is increasing diabetes mellitus by 2025. Cardiovascular disease is
worldwide and rapidly assuming epidemic propor- responsible for 80% of deaths among diabetic pa-
tions. India is no exception, and currently 25 million tients much of which has been attributed to CAD
Indians are estimated to be suffering from diabe- (coronary artery disease). However, there is an in-
tes. Further projections indicate that India will have creasing recognition that diabetic patients suffer
maximum number of diabetic patients by the year from an additional cardiac insult termed ‘diabetic
2025.1The life span of patients with diabetes has im- cardiomyopathy’.This entity was originally described
proved with newer insulins and oral hypoglycaemic in 1972 on the basis of observations in four diabetic
agents. Unfortunately chronic complications of the patients who presented with HF (heart failure) with-
disease show a rising trend among diabetics living out evidence of hypertension, CAD,valvular or con-
longer. Diabetes, formerly thought of as a problem genital heart disease. The increasing recognition of
of glucose metabolism, actually produces most of its this additional cardiac insult is supported by data
harm by its effects on the cardiovascular system. 2 from epidemiological, molecular and more refined
gnostic studies.
Patients with diabetes are characterised by an in-
creased likelihood for congestive heart failure reflect- Epidemiology
ing the contribution of diabetes to coronary artery
disease (CAD) and its association with hypertension. Diabetes mellitus has reached an epidemic level
Even in the absence of CAD and hypertension, dia- worldwide, with a prevalence of 4% in 1995 and an an-
betics remain vulnerable to CHF. In the Framingham ticipated prevalence of 5.4% in 2025, corresponding
cohort, after adjustment for age, blood pressure, cho- to 300 million adults with diabetes worldwide. 5Car-
lesterol level, obesity, and history of CAD, the pres- diovascular diseases represent the primary cause of
ence of diabetes quadrupled the risk for CHF in men death in this population, due to coronary artery dis-
35 - 64 years old and doubled it in men 65 years or ease or associated hypertension, but also because
older; in women 35 - 64 years of age, it entailed an of a direct adverse effect of diabetes mellitus on
eightfold increase in CHF and fourfold increase in the heart, the so called diabetic cardiomyopathy. In
risk in older women.3 diabetic patients the prevalence of diabetic cardio-
myopathy is 12% and reaches 22% in people over 64
Over the last three decades, a number of epidemi- years old.
ological, clinical and autopsy studies have proposed
the presence of diabetic heart disease, as a distinct As was demonstrated in the Framingham Heart
clinical entity.4However, the existence of diabetic car- Study, diabetes is a strong and independent risk fac-
diomyopathy referring to myocardial disease in dia- tor for developing heart failure, leading this group of
betic subjects that cannot be ascribed to hyperten- patients to a worse prognosis. The risk of heart failure
sion, CAD, or any other known cardiac disease has was 2.4-fold and 5-fold higher in diabetic men and
remained controversial. In this review, we will discuss women, respectively, than in non-diabetic subjects.
the evidences regarding the existence of this specific The incidence of heart failure in diabetic patients is
entity, alongwith its pathophysiology and manage- still increased even after adjustment for age, hyper-
ment.

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302 Diabetic Cardiomyopathy :
Mechanisms, Diagnosis and Treatment

tension, obesity, coronary artery disease or dyslip- of symptoms and signs. There appears to be a long
idemia.6The close correlation between diabetes and subclinical course in most patients before the devel-
heart failure has been demonstrated in many studies. opment of symptoms.7
In the United Kingdom Prospective Diabetes Study
(UKPDS) an increased prevalence of heart failure was Pathophysiology
recorded in patients with diabetes mellitus type 2,
correlating with levels of glycosylated hemoglobin There are two main types of cardiomyopathy: (1) pri-
(HbA1c). The incidence of heart failure is 2.3 cases mary cardiomyopathy, where the cardiac function
per 1000 person-years in patients with HbA1c<6% in is aggravated by a defect in the heart itself, and (2)
contrast to 11.9 per 1000 person-years in patients with secondary cardiomyopathy, where cardiac perfor-
significantly high HbA1c (>10%). There are identifiable mance is affected because of a systemic syndrome.
risk factors for developing diabetic cardiomyopathy, Cardiomyopathy leads to heart failure, which can be
such as increased HbA1c, high body mass index, either diastolic heart failure, with preserved ejection
advanced age, use of insulin, proteinuria, the coex- fraction, or systolic heart failure, with reduced ejec-
istence of coronary artery disease and/or peripheral tion fraction.8 Diabetes can lead to heart failure, not
target organ diseases such as retinopathy and ne- only by augmenting the impact of classical cardio-
phropathy. In a large case-control study, Bertoni et vascular risk factors (e.g. accelerating the appearance
al tested the hypothesis that diabetes mellitus was and progression of coronary artery disease through
independently associated with idiopathic cardiomy- macroangiopathy), but also via a direct deleterious
opathy. After adjusting for age, sex, race, and hyper- effect on the myocardium per se. This condition is
tension, diabetes mellitus was significantly associat- known as diabetic cardiomyopathy, defined as the
ed with idiopathic cardiomyopathy (relative risk 1.58, presence of myocardial involvement in patients with
95% CI 1.55–1.62). Similarly in a large population-based diabetes, characterized by dilatation and hypertrophy
cohort study, the Reykjavik Study, Thrainsdottir et al of the left ventricle, with the concomitant appearance
explored the associations between heart failure and of diastolic and/or systolic dysfunction, and its pres-
abnormal glucose regulation (impaired glucose tol- ence is independent of the coexistence of ischemic
erance or impaired fasting glucose). The odds ratio or hypertensive or valvular heart disease. Myocardial
was 2.8 (95% CI 2.2–3.6) for the association between fibrosis and myocyte hypertrophy are the most fre-
diabetes mellitus type 2 and heart failure and 1.7 (95% quently proposed mechanisms to explain cardiac
CI 1.4–2.1) for the association between abnormal glu- changes in diabetic cardiomyopathy. Several studies
cose regulation and heart failure. have shown that diabetes causes defects in cellu-
lar calcium transport, defects in myocardial contrac-
DEFINITIONS tile proteins, and an increase in collagen formation,
which result in anatomic and physiological changes
Diabetic cardiomyopathy refers to a disease process in the myocardium.
which affects the myocardium in diabetic patients
causing a wide range of structural abnormalities Myocardial fibrosis
eventually leading to LVH [left ventricular (LV) hy-
pertrophy] and diastolic and systolic dysfunction or Myocardial fibrosis, as initially described by Rubler
a combination of these. The concept of diabetic car- et al and confirmed in histological studies in both
diomyopathy is based upon the idea that diabetes is experimental subjects and humans, is a major con-
the factor which leads to changes at the cellular level, sequence of the adverse effects of diabetes melli-
leading to structural abnormalities as outlined above. tus in the heart. Newer echocardiographic techniques
We know that diabetic patients are at increased risk should be used in order to evaluate the myocardial
of hypertension and CAD; however, the idea of the collagen content and its pivotal role in cardiac func-
existence of a diabetic cardiomyopathy suggests that tion. Backscatter is an ultrasound tissue characteriza-
changes can occur and be detected without the pres- tion technique, based on the measurement of myo-
ence of these other factors. Therefore patients with cardial tissue echoreflectivity, that is related to myo-
hypertension and CAD may well have myocardial cardial collagen content. Di Bello et al demonstrated
changes related to these disease processes, but a an increase in myocardial echodensity, as assessed
specific cardiomyopathy may also affect the myocar- by the integrated backscatter index, in 26 insulin-de-
dium secondary to diabetes causing a synergistic ad- pendent diabetic normotensive patients compared
verse effect as seen with a combination of diabetes with 17 age- and sex-matched control subjects. Fang
and hypertension. Diabetic cardiomyopathy can be et al confirmed these results using backscatter in a
subclinical or apparent depending on the presence larger study. Biomarkers of collagen synthesis (pro-

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Cardio Diabetes Medicine 2017 303

collagen type I carboxy-terminal peptide [PICP], ami- sclerosis in epicardial coronary arteries, but also pro-
no terminalpropeptide of procollagen type I [PINP], motes the appearance of structural and functional
carboxy terminalpropeptide of procollagen type III disorders in smaller vessels, resulting in an increased
[PIIICP], amino terminal propeptide of procollagen ischemic burden for the myocardium. Furthermore,
type III [PIIINP]), collagen degradation (CITP), mark- diabetic cardiomyopathy aggravates hypertension,
ers of extracellular matrix turnover (such as MMP) resulting in increased afterload and pressure over-
and their inhibitors (TIMP, tissue inhibitors of MMP), load, and, by contributing to the occurrence of renal
can be used as markers in detecting myocardial fi- failure (diabetic nephropathy), it leads to fluid reten-
brosis.25 Diabetic patients with diastolic dysfunction tion and eventually volume overload. From the patho-
demonstrated an increase in MMP-9 and a decrease physiological point of view, in diabetes, because of
in TIMP-1/MMP-9. Finally, in a small group of diabetic the lack of insulin or because of insulin resistance
patients, a correlation was found between PICP and in the tissues, the body does not use glucose but
left ventricular (LV) systolic parameters (fractional instead uses fatty acids as fuel. Although the heart
shortening and midwall fractional shortening). More tissue of normo glycemic people prefers free fatty
specifically, in diabetic patients, corrected endocardi- acids as fuel rather than glucose, in diabetic pa-
al (r=-0.56) and midwall shortening (r=0.38) was cor- tients this phenomenon is accentuated even further.
related with PICP, whereas the systolic and early dia- On the other hand, myocardial cells of normo glyce-
stolic velocities of the mitral annulus were correlated mic patients with heart failure or patients who have
with glutathione peroxidase (both r=0.44).9 suffered a myocardial infarction use glucose as an
energy source rather than fatty acids. It seems that
Hypertrophy of myocardial cells in this case glucose exerts a protective role against
ischemia. The almost exclusive use of fatty acids in
Studies of cardiac tissue from diabetic animals un- diabetes patients leads to their accumulation into the
der the electron microscope have shown multiple heart muscle, which is followed by the appearance
abnormalities in the structure of myocardial cells: of lipotoxicity. Of particular note is palmitic acid, the
(i) loss of microfibrils; (ii) loss of cell-to-cell connec- accumulation of which influences myocardial con-
tion in the intermediate discs; and (iii) increased lipid tractility and also induces apoptosis of myocardial
deposition in the cytoplasm and loss of components cells. It has been found that persistent hyperglyce-
of the endoplasmic reticulum.10 Furthermore, it has mia in the myocardium of diabetic rats stimulates the
been reported that LV hypertrophy and concentric re- expression of muscle carnitine palmitoyl transferase
modeling are associated with diabetes mellitus, inde- enzyme 1.12 On the other hand, the main feature of
pendently of other confounding factors such as age, diabetes, hyperglycemia, can cause damage to the
obesity, and hypertension. Additionally the NOMAS myocardium via modified proteins (advanced glyca-
Study described diabetes mellitus as an indepen- tion end products, AGEs) and free oxygen radicals
dent determinant of LV mass, in addition to central (ROS-reactive oxygen species). The AGEs, for exam-
obesity as assessed by waist circumference. Fisch- ple, produced by glycation of collagen lead to its ac-
er et al, working with cardiac tissue samples from cumulation in the extracellular matrix and eventually
patients undergoing coronary artery bypass grafting, in fibrosis of the heart, resulting in diastolic dysfunc-
demonstrated no differences in LV hypertrophy and tion. Furthermore, soluble AGEs connected in related
fibrosis between diabetic and non-diabetic patients. receptors (RAGEs), trigger NADPH oxidase, leading
They pointed out that the only differences observed to the production of peroxide and ultimately of free
in cardiac tissue were related to swelling of endo- oxygen radicals. These in turn cause direct damage
thelial cells and basement membrane thickening of to myocyte DNA.
capillaries.
Systolic dysfunction in diabetic
Mechanisms of heart failure in diabetes cardiomyopathy
mellitus
Novel echocardiographic techniques, such as tissue
Many pathophysiological mechanisms are involved Doppler imaging (TDI) and speckle tracking imag-
in the stepwise progression from diabetes mellitus ing (STI), can be used to detect early subclinical im-
to heart failure. These include direct myocardial in- pairment of LV or right ventricular (RV) function in
jury (e.g. in myocardial ischemia or cardiomyopathy), asymptomatic diabetic patients without overt heart
volume overload (e.g. in aortic valve insufficiency), disease. Longitudinal dysfunction was demonstrat-
and pressure overload (e.g. in arterial hypertension).11 ed in many studies using both TDI and STI. Several
Diabetes not only intensifies the process of athero- authors demonstrated that longitudinal strain de-

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304 Diabetic Cardiomyopathy :
Mechanisms, Diagnosis and Treatment

crease was correlated with diabetes imbalance (gly- lar interaction mechanism, and the diabetes mellitus
cated hemoglobin) or microvascular complications per se. Interestingly, it has been demonstrated that in
(microalbuminuria). However, longitudinal alteration diabetic patients both the systolic and diastolic func-
is independently associated with diabetes mellitus, tion of the RV are affected. In addition, van den Brom
regardless of LV hypertrophy or other conventional et al have shown that in diabetic mice the changes
risk factors. On the other hand radial systolic func- caused by diabetes in the functionality of the RV
tion has been less investigated, and with conflicting are in line with those observed in the LV, but the
results.13The initial studies suggested that radial func- changes in geometry and remodeling are not simi-
tion was increased or preserved to compensate for lar. More specifically, LV changes are characterized
alterations in longitudinal function. However, most of by hypertrophy of myocardial cells without dilation,
these studies were based on TDI and its derived ve- while the opposite was observed in the RV. These
locity and strain rate measurements, which depend interesting findings have also been reported by other
on Doppler angle. STI as an angle-independent meth- investigators.15
od could allow a more robust and extensive evalua-
tion of radial function in diabetic as well as in non-di- Clinical presentation and diagnostic approach
abetic patients.
In the early stages of diabetic cardiomyopathy the pa-
Left ventricular diastolic dysfunction in tients are usually asymptomatic. In advanced stages
diabetic cardiomyopathy of diabetic cardiomyopathy overt heart failure occurs.
Patients develop symptoms due to forward heart
LV diastolic dysfunction, as evaluated from the trans- failure (weakness, fatigue, angina, syncope) and
mitral LV filling pattern (i.e. abnormal relaxation and/ backward heart failure (dyspnea, raised jugular vein
or pseudo normal filling), was observed in 47-75% of pressure, lower extremity edema, hepatomegaly).
asymptomatic normotensive patients with well-con- Interstitial and perivascular fibrosis is a histological
trolled diabetes mellitus type 2.TDI, as a more sen- hallmark of diabetic cardiomyopathy, and the extent
sitive technique for the detection of LV dysfunction, of fibrosis correlates with heart weight.16 In addition
enables the measurement of myocardial tissue veloc- to the increase in collagen deposition, crosslinking
ities in the longitudinal direction, and the peak early of collagen fibers may be increased by diabetes,
diastolic myocardial velocity (é) reflects the global LV contributing to a reduction in ventricular compliance.
diastolic function. Studies by Kosmala and Di Bonito Interstitial fibrosis in diabetic hearts can be assessed
reported that é was significantly lower in diabetic pa- by integrated backscatter (myocardial ultrasound re-
tients without hypertension than in normal subjects. flectivity) in two-dimensional echocardiography and
Additionally, Boyer et al found that TDI revealed LV by late gadolinium (Gd) enhancement in cardiac MRI.
diastolic dysfunction in 63% of patients with asymp- Diabetes (mostly diabetes mellitus type 2) is associ-
tomatic diabetes mellitus type 2, while convention- ated with LV hypertrophy or concentric LV remodeling
al Doppler echocardiography was abnormal in only (i.e. increased ratio of LV mass to LV end-diastolic
46% of the subjects. Diastolic variables are related volume). This finding was previously observed most-
to prognosis in diabetic patients without patent heart ly in females using transthoracic echocardiography.
disease.14 A study by From et al demonstrated that However MRI studies have demonstrated that it is not
the E/é ratio was associated with an increase in glob- age- or sex specific. The most frequent echocardio-
al mortality, after adjustment for age, sex, coronary graphic finding in patients with asymptomatic diabe-
artery disease, hypertension, LV ejection fraction, tes mellitus is LV diastolic dysfunction with preserved
and left atrial volume. LV ejection fraction. Diastolic dysfunction is also de-
tectable in diabetic hearts without hypertrophy. There
The right ventricle is also evidence that diabetic patients are at increased
risk of arrhythmias, including sudden cardiac death.
It is known that dysfunction of the RV is associated The underlying arrhythmogenic mechanisms include
with a worse prognosis in a variety of cardiovascular imbalance in autonomic tone, silent ischemia, slowed
diseases, including acute myocardial infarction and conduction, heterogeneities in atrial and ventricular
heart failure. Although most investigators studied the repolarisation, and the extent of myocardial damage
effect of diabetes on the functionality and geometry and scar formation. Currently, the best approach to
of the LV, there are also scanty data indicating that the diagnosis of diabetic cardiomyopathy is detection
diabetes is equally detrimental for the RV. We can of functional, structural and metabolic changes in the
assume that in patients with diabetic cardiomyopathy LV and the exclusion of other heart diseases being
the RV is influenced by both the LV, via a biventricu- responsible for these changes in a diabetic patient:

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Cardio Diabetes Medicine 2017 305

Structural changes include: (i) LV hypertrophy, as- strated in one-third of patients with Type II diabetes
sessed by 2D echocardiography or cardiac magnetic independent of blood pressure or ACE inhibitor use
resonance imaging (CMR); (ii) increased integrated . Similarly Kimball et al.19found increased LV mass
backscatter in the LV (septal and posterior wall); and performance in Type I diabetic patients with mi-
and (iii) late Gd enhancement of the myocardium in croalbuminuria. Framingham showed an association
CMR. Functional changes are due to: (i) LV diastolic between diabetes mellitus and increased LV mass
dysfunction, assessed by pulsed Doppler echo cardi- independent of conventional risk factors in women,
ography and TDI; (ii) LV systolic dysfunction, demon- but not in men. A large echocardiography study of
strated by TDI/SRI; and (iii) limited systolic and/or di- American Indians with diabetes found a reduction
astolic functional reserve, assessed by exercise TDI. in LV systolic chamber size and LV function, despite
Finally metabolic changes are primarily associated increased LV mass in both sexes. It has been sug-
with: (i) a reduced ratio of cardiac phosphocreatine gested that aortic stiffness may contribute to the de-
to adenosine triphosphate; and (ii) elevated myocar- velopment of LVH and diastolic dysfunction in dia-
dial triglyceride content.17Catheter-based diagnosis betic patients by increasing end-systolic wall stress.
of diabetic cardiomyopathy is rarely employed at Erenet al.20also found an association between aortic
present, because other more sensitive and specific stiffness and diastolic dysfunction inpatients with ei-
noninvasive techniques are used instead. Coronary ther hypertension or diabetes or both. Earlier Dop-
angiography is useful for the diagnosis of coronary pler studies have been criticized for underestimating
artery disease that may coexist with and complicate the degree of diastolic dysfunction since they failed
diabetic cardiomyopathy. to account for pseudonormal filling patterns, which
have been observed in up to 60% of normotensive
DIAGNOSTIC METHODS diabetic patients. This suggests that up to 50% of
patients with diastolic dysfunction could be missed
Thus, it is clear from the discussion above that a on standard echocardiography. Pseudo normalized
range of molecular changes may underlie the devel- filling patterns can be picked up by asking patients
opment of diabetic cardiomyopathy. Of clinical rel- to perform the Valsalva manoeuvre whilst assessing
evance is the means by which clinicians diagnose trans-mitral and pulmonary Doppler signals. There-
and characterize this problem, perhaps prior to it fore echocardiography is a useful non invasive tool
becoming clinically manifest. This is important as it to assess for the presence of LVH and systolic and
may allow intervention at a point where significant diastolic dysfunction and can provide prognostic in-
cardiac dysfunction has not yet ensued. formation in diabetic patients suspected of having
cardiomyopathy.
Echocardiography
Tissue Doppler echocardiography
Clinically apparent diabetic cardiomyopathy may
take several years to develop, but echocardiography In standard Echocardiography, a high-veloci-
can detect significant abnormalities well before the ty low-amplitude filter looks solely at blood flow
onset of symptomatic HF. There are different types through the heart to define valvular function. Newer
of echocardiography which are used in diagnosing technologies such as TDI (tissue Doppler echocar-
LV dysfunction. diographic imaging) look promising as they apply a
high-velocity low-amplitude filter to the myocardium
Conventional echocardiography enabling an assessment of myocardial tissue veloc-
ities. The advantage over standard Doppler echo-
Early abnormalities are defined by a preserved LV cardiography is that the results are independent
ejection fraction with reduced early diastolic filling, of changes in pre-load. This provides a particularly
prolongation of isovolumetric relaxation and in- useful tool for defining subtle systolic and diastolic
creased atrial filling, the presence of which confirms dysfunction. In a recent study, although there was a
diastolic dysfunction. A reduction in LV distensibility significant reduction in resting Sm (peak myocardial
is characterized by an increased PEP (pre-ejection systolic velocity) and Em (early diastolic velocity) in
period) and shorter LVET (LV ejection time), resulting diabetic patients,the response to dobutamine stress
in an increased PEP/LVET ratio.Such abnormalities did not differ from control subjects, suggesting that
have been demonstrated in a group of normotensive ischaemia due to small vessel disease may not be
diabetic patients without overt microvascular or mac- important in early diabetic heart muscle disease. TDI
rovascular complications. also quantifies both longitudinal and circumferential
cardiac contraction. Longitudinal (long-axis) contrac-
Galderisi et al. 18 found a 22% increase in LV mass
in diabetic women and, recently, LVH was demon-

Cardio Diabetes Medicine

306 Diabetic Cardiomyopathy :
Mechanisms, Diagnosis and Treatment

tion of the left ventricle is dependent on the integri- and posterior wall of the left ventricle and estimates
ty of longitudinal subendocardial myocardial fibres, the percentage CVI(cyclic variation index). Subjects
whereas radial (short-axis) contraction depends on with high LV masses and concentric hypertrophy
integrity of the circumferential fibres. The former is demonstrate an increased CVI.This has not yet been
more susceptible to ischaemia and fibrosis which applied to diabetic patients.
may result in a relative increase in short-axis velocity
compared with a decrease in long-axis function due Intravenous contrast echocardiography
to compensatory ventricular remodelling. Thus, in 53
patients with diabetes but no LV hypertrophy,normal During the last decade, the use of contrast echocar-
ejection fraction and no ischaemia on dobutamine diography has gained considerable interest because
echocardiography, radial contractility was increased it provides a non-invasive means of assessing integ-
and appeared to compensate for reduced longitudi- rity of the coronary microcirculation and myocardial
nal contractility. In a recent study of 35 patients with perfusion as well as improving assessment of LV
Type II diabetes, the presence of regional systolic function. Contrast agents are used to enhance vi-
abnormalities in patients with an apparently normal sualization of the blood–endocardial interface to as-
ejection fraction questions the concept of isolated sess myocardial perfusion. Furthermore, the proper
diastolic dysfunction. 21 delineation of the endocardial border observed after
contrast administration increases the clarity of the
TDI does not differentiate between active contrac- images and improves the results provided by the al-
tion and passive movement of a myocardial seg- gorithms orientated to the assessment of ventricular
ment. Thus rotation and translation movements of motion. 23
the whole heart,as well as active contraction of seg-
ments adjacent to the analysed segment,may affect Direct assessment of myocardial blood flow and flow
the determined velocity.Strain and strain rate echo- reserve is possible, as microbubble contrast agents
cardiography is a technique for assessing myocardial remain entirely within the intravascular space andt
systolic and diastolic function. This modality has im- heirpresence in any myocardial segment denotes the
proved the quantitative assessment of regional wall status of microvascular perfusion within that region.
motion and the accuracy and reproducibility of test Inastudy by Senior and Swinburn, the sensitivity and
readings. Myocardial strain and strain rate can detect negative predictive value of dobutamine echocardi-
inducible ischaemia and at earlier stages than visual ography for the prediction of recovery of dysyner-
estimation of wall motion or wall thickening param- gistic segments improved significantly from 59% to
eters. Changes in systolic strain rate and strain have 79% and 88% to 95% when contrast opacification
the potential to discriminate between different myo- was observed in the dobutamine non-response seg-
cardial viability states. Measurement of the diastolic ments. Thus contrast LV opacification studies allow
rate of deformation can differentiate physiological more accurate measurements of LV size and mass,
from pathological hypertrophy and restrictive from and myocardial contrast echocardiography provides
constrictive cardiomyopathy. Strain rate assessment an alternative non-invasive assessment of CAD.
has also been implemented in 3D (three-dimensional) Echocardiography relies on resonance of microbub-
echocardiography with promising results. ble contrast agents when excited by diagnostic ul-
trasound frequencies, thus producing an increased
Doppler acoustics ultrasound backscatter from the blood.

Fibrosis alters the acoustic properties of the heart 3D Echocardiography
in animals and humans, and the magnitude of cyclic
variation of myocardial ultrasound integrated back- Conventional 2D echocardiography only provides
scatter and its phase delay with respect to the onset partial information about cardiac function. Although
of the cardiac cycle can be quantified via defining multiple studies have validated the superiority of 3D
alteration in Doppler acoustics.In 54 diabetic patients over 2Dechocardiography to assess LV function, 3D
with normal ventricular systolic function, the cyclic methods have not been embraced in clinical prac-
variation of backscatter in the septum and posterior tice because of the cumbersome methodology used
wall of the left ventricle was significantly reduced and until recently for data acquisition and analysis. In
was related to the presence of neuropathy, retinopa- contrast with 2D echocardiography, 3D echocardi-
thy and nephropathy.22This technique has evolved in ography does not rely on geometric assumptions
the form of video-densitometry which uses Doppler to calculate LV volumes. This constitutes a real ad-
echocardiography to digitize images of the septum vantage in ventricles with odd shapes, wall motion
abnormalities and in patients with cardiomyopathy.

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Cardio Diabetes Medicine 2017 307

Similarly, the unique shape of the right ventricle has assess diastolic function accurately without the draw-
precluded accurate quantification using traditional backs observed with echocardiographic assessment
echocardiography. Transthoracic 3D echocardiogra- of diastolic function.
phy has the potential to overcome these limitations
resulting in precise measurements of right ventricu- SPECT (single photon emission CT)
lar size and function. Real-time 3D echocardiography
is based on the design of an ultrasound transducer Quantitative myocardial perfusion SPECT has ad-
with a matrix array that instantaneously acquires the vanced significantly over the last few years provid-
image contained in a pyramidal volume.Thec oncur- ing a competitive advantage to nuclear cardiology
rentdi splay of multiple tomographic images allows compared with other higher-resolution non-invasive
the anatomically correct examination of any structure imaging modalities for the detection of CAD. In par-
contained withinthe volumetric image.The develop- ticular, gating has provided both perfusion and func-
ment of new software and the use of high-perfor- tional information and attenuation correction SPECT
mance computers now allows rapid mapping of the has improved perfusion information.26
volumetric image, and it is possible to simultaneously
visualize multiple superimposed planes in an interac- Treatment
tive manner. Real-time 3D echocardiographyis being
used in conjunction with strain rates to evaluate fur- The pillars in the treatment of diabetic cardiomyopa-
ther both regional LV systolic dysfunction and dia- thy are related to lifestyle changes, the regulation of
stolic dysfunction.An area where it looks especially blood glucose levels, modification of risk factors for
promising is in predicting the response to biventric- cardiovascular disease, and the treatment of heart
ular pacing in patients with HF and interventricular failure.
conduction delay.24
Lifestyle
CT (computed tomography)
Smoking cessation, healthy eating habits, reduction
The CAC (coronary artery calcification) score, derived in body weight and aerobic exercise are the corner-
originally from electron-beam CT but more recent- stones in terms of lifestyle change. It has been shown
ly from multi-slice CT,has been shown to correlate in people with diabetes mellitus type 2 that, following
strongly with the presence and severity of histolog- reduction of their body weight and increased aerobic
ical and angiographic evidence of coronary athero- activity, the incidence of diabetic cardiomyopathy de-
sclerosis and conventional CHD risk factors, inpar- creased significantly.27
ticular CRP, reflecting stable and unstable plaques.
In 10377 asymptomatic patients, coronary calcium Glycemia and other risk factors
has been shown to provide independent incremental
information in addition to traditional risk factors in The setting of the level of blood glucose is an import-
the prediction of all-cause mortality. Of 101 patients ant target for the treatment of diabetic cardiomyopa-
aged17–28 years with Type I diabetes and duration thy. Achieving euglycemia reduces the risk of major
of diabetes over 5 years, 10.9% demonstrated CAC. cardiovascular events, such as myocardial infarction
Similarly CAC was significantly increased in asymp- or stroke, and the likelihood of developing diabet-
tomatic patients with Type II diabetes compared with ic cardiomyopathy. The modern therapeutic arsenal
non-diabetic subjects. 25Although the CAC score has several effective medications to treat diabetes,
correlates well withCAD,there are no studies to date such as metformin, sulfonylureas, glitazones, insulin,
which show an association with diabetic cardiomy- and some modern drugs, such as GLP1 agonists and
opathy. antagonists of DPP4. Although these drugs appear
effective in treating diabetes in people without con-
MRI (magnetic resonance imaging) comitant heart failure, in patients with heart failure
there are some limitations. The classic example is
MFR (myocardial flow reserve) is not routinely as- metformin, which has been previously contraindicat-
sessed in MPI(myocardial perfusion imaging) stud- ed in heart failure because of the risk of lactic aci-
ies,but it has been hypothesized to affect test ac- dosis.28 However in clinical practice and use, it turns
curacy when assessing disease severity by coronary out that the risk of lactic acidosis associated with
vessel Lumenography.MRIis an emerging diagnostic metformin in people with diabetes and heart failure is
technique that can both perform MPI and assess not so great. Additionally, metformin can upregulate
MFR. Furthermore, MRI is also a very useful tool to cardiomyocyte autophagy, which plays an important
role in the prevention of diabetic cardiomyopathy in
animal models. Metformin has also been reported

Cardio Diabetes Medicine

308 Diabetic Cardiomyopathy :
Mechanisms, Diagnosis and Treatment

to reduce mortality rates and lower all-cause hospi- blocker (ARB), a beta-blocker, and a mineralocorti-
tal admissions. According to some studies, insulin coid receptor antagonist (MRA)—are the most import-
use was considered to be a risk factor for develop- ant pharmacological agents for the treatment ofall
ing heart failure. However, those studies were ret- patients with heart failure and reduced LV ejection
rospective and non-randomized. Consequently, it is fraction, including those with diabetes mellitus. They
not possible to determine whether insulin treatment are usually combined with a diuretic for relieving con-
truly increases the risk of heart failure, or identifies gestion and may also be supplemented by ivabra-
a higher-risk diabetic patient. Pioglitazone causes an dine.
increase in body weightand fluid retention in 5-10%
of patients who use this drug. As a consequence, Angiotensin-converting enzyme inhibitors
it might worsen heart failure and increase the num- and angiotensin receptor blockers
ber of hospitalizations. There is growing evidence to
support the use of incretin-based therapies (GLP1 An ACE-I is indicated in diabetes mellitus type 2
agonists and antagonists of DPP4) for reducing car- and heart failure, since it improves symptoms and
diovascular complications in diabetes. In an animal reduces mortality.30The beneficial effects of ARBs are
model of atherosclerosis, GLP-1 significantly reduced equivalent to those of ACE-I, according to subgroup
plaque burden. Apart from anti-atherogenic effects, analyses of clinical trials, and therefore an ARB can
the GLP1 pathway may also have cardioprotective be used as an alternative in ACE-I-intolerant patients.
properties. Increased activation of the GLP-1 axis can When ACE-I and ARBs are used in patients with di-
improve weight loss and lipid profile, and can lower abetes mellitus, monitoring of kidney function and
blood pressure. Moreover, in a small, non-random- potassium is mandatory ,since nephropathy is a fre-
ized study, GLP-1 infusion was associated with a sig- quent occurrence.
nificant improvement in ejection fraction in patients
who presented with acute myocardial infarction and Beta-blockers
reduced LV function. Additional data are needed to
provide important information about the use of these Beta-blockers are the standard of care in patients
agents for the prevention and treatment of diabetic with systolic heart failure. A subgroup analysis of
cardiovascular complications. One of the most hot- the MERIT-HF trial showed that beta-blockers re-
ly debated clinical questions in diabetes is whether duce mortality and hospital admissions and improve
intensive glycemic control is associated with better symptoms, without significant differences between
cardiovascular outcomes, and how low we should go diabetes mellitus type 2 and non-diabetic patients.
in pursuing glycemic targets. The Diabetes Control Beta-blockers recommended in heart failure and di-
and Complication Trial (DCCT) and the United King- abetes mellitus type 2 are metoprolol succinate in
dom Prospective Diabetes Study (UKPDS) provided the slow release form (MERIT-HF), bisoprolol (Cardiac
consistent evidence that intensive glycemic control Insufficiency Bisoprolol Study [CIBIS II]), and carve-
prevents the development and progression of mi- dilol (Carvedilol Prospective Randomized Cumulative
crovascular complications in patients with type 1 or Survival [COPERNICUS] and Carvedilol Or Metopro-
type 2 diabetes.29However, the Action to Control Car- lol European Trial [COMET]).31 Adverse effects of be-
diovascular Risk in Diabetes (ACCORD), the Action ta-blockers in patients with diabetes mellitus type 2
in Diabetes and Vascular Disease (ADVANCE), and and heart failure include: a) hypoglycemia, especially
the Veterans’ Administration Diabetes (VADT) trials with non cardioselective regimens, and b) negative
revealed no significant effect of intensive glycemic metabolic effects (hypoglycemia, dyslipidemia and
control on mortality or on amelioration of cardiovas- decreased insulin sensitivity).
cular events. The 2013 ESC Guidelines on diabetes,
pre-diabetes, and cardiovascular diseases consider Mineralocorticoid receptor antagonists
tight glycemic control (HbA1c<7%) as a class I indica-
tion to decrease microvascular complications and An MRA is recommended for all patients with per-
class IIa for the prevention of cardiovascular disease. sisting symptoms (New York Heart Association Class
II-IV) and an LV ejection fraction ≤35%, despite treat-
Heart failure treatment ment with an ACE-I (or, if not tolerated, an ARB) and
a beta-blocker, to reduce the risk of heart failure hos-
According to the 2013 ESC Guidelines on diabetes, pitalization and premature death (Class IA).98 The
pre-diabetes, and cardiovascular diseases, three benefit of spironolactone and eplerenone on mortal-
neurohormonal antagonists—an angiotensin-convert- ity did not differ between patients with and without
ing enzyme inhibitor (ACE-I) or angiotensin receptor diabetes mellitus type 2 and heart failure. Monitoring
of kidney function and potassium is mandatory, be-

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Cardio Diabetes Medicine 2017 309

cause of the increased risk of nephropathy in pa- occur in subjects at risk of developing diabetes as
tients with diabetes mellitus.32 well as in those with Type II diabetes. Furthermore,
it has been associated with impaired reactivity in the
Diuretics skin microcirculation of these subjects.35

These drugs are useful for the relief of dyspnea and Summary and conclusion
edema in heart failure with fluid retention, irrespec-
tive of the ejection fraction, although there is no ev- Though the existence of diabetic cardiomyopathy
idence of a reduction in mortality or morbidity. Loop has been often questioned, the evidences are now
diuretics are recommended, rather than thiazides, strong enough to support its entity. Diabetic cardio-
because of their better glycemic profile. myopathy encompasses the spectrum from sub-clin-
ical disease to full blown syndrome of CHF. The
Ivabradine pathophysiology of thecondition remains to be fully
elucidated. Metabolic disturbances, interstitial fibro-
The SHIFT trial, involving 6558 patients with heart sis, cardiomyocyte loss, small vessel disease, and
failure, in sinus rhythm and with heart rate ≥70 bpm cardiac autonomic neuropathy have been incriminat-
(3241 on ivabradine; 30% with diabetes mellitus type ed. Prominent functional sequelae include diastolic
2), demonstrated that ivabradine significantly re- and systolic dysfunction. Though no specific thera-
duced cardiovascular deaths and hospital admissions peutic strategies can be recommended, good glycae-
for worsening heart failure. The beneficial difference mic control and judicious use of ACE inhibitors and
was similar in a pre-specified subgroup analysis of calcium channels blockers are viable options. Newer
patients with and without diabetes mellitus. Finally, insight into molecular basis of the disease will help
the presence of diabetes mellitus is not a contrain- us formulate appropriate drug therapy.
dication for cardiac resynchronization therapy and/
or cardiac transplantation in patients with advanced References
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merase is activated in subjects at risk of developing type 2 diabetes and is
17. Ng AC, Delgado V, Bertini M, et al. Findings from left ventricular strain associated with impaired vascular reactivity. Circulation 106, 2680–2686
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diographic evidence for the existence of a distinct diabetic cardiomyopathy
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(2004) Relationship between aotric stiffness and left ventricular diastolic
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M. P. (2002) Coronary artery calcification at electron beam computed
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Cardio Diabetes Medicine 2017 311

International Lipid Guidelines :
What is Needed for Indians ?

Dr. S. N. Narasingan,

MD, FRCP [ Edin&Glasg] ,FACP,FICP,FCCP[USA]
Former Adjunct Professor The Tamil Nadu Dr. MGR Medical University
Managing Director, SNN Specialities Clinic, & SNN Diagnostic Centre, Chennai

Abstract : ] and newer updated guidelines from ACC/AHA are
highlighted in this chapter .
There are number of guidelines and recommenda-
tions for managing cholesterol .American College Introduction : Why do we need guidelines ?
of Cardiology [ACC] / American Heart Association [
AHA ] guidelines 2013 focussed on Atherosclerotic Many times we get conflicting data in guidelines.
Cardiovascular risk and not on lipid goals . Interna- What is reasonable to do for overall approach to make
tional Atherosclerosis Society [ IAS ] published global sense of the totality of data ? What we should aspire
recommendations in the same year for the manage- to do at a population level is to standardise care and
ment of dyslipidemia . National Lipid Association avoid inequalities. RCTs systematically test effects of
[NLA] guidelines were published in 2014 .Lipid Asso- an intervention on pre-specified outcomes in defined
ciation of India [ LAI ]has released Expert Consensus populations. Their use minimizes confounding . Their
Statement on Management of Dyslipidemia in Indi- ability to generalize results to real-world patients may
ans in 2016. European Guidelines on cardiovascular be limited due to exclusion criteria . Observational /
disease prevention in clinical practice was published Epidemiologic studies have world-wide in scope and
in 2016. .This chapter on Newer Lipid Guidelines : fo- may assess ASCVD risk across populations .Cohort
cuses on interpretation of these international guide- studies : evaluate mortality and morbidity within pop-
lines including recommendations of LAI which may ulations .Guidelines are published based on robust
be applicable for Indians. Many aspects of lipid man- evidence from RCTs , observational / epidemiological
agement targeting LDL- c and other lipoproteins are & cohort studies . Experimental data are taken into
discussed in detail .Indians have typical elevations account.
of triglyceride with low levels of HDL-c and almost
normal LDL- c levels. Atherogenic dyslipidemia which Atherosclerosis is a preventable disorder. Of all the
is the characteristic feature of Metabolic syndrome lipoproteins, it is the LDL Cholesterol which plays a
[MetS] and diabetes is characterised by an increase central role not only in the initiation of atheroscle-
in triglyceride levels with low HDL –c and increase in rosis but also in the progression of atherosclerosis
small dense LDL-c .In view of increasing prevalence ending in clinical cardiovascular events . Most robust
of obesity , MetS and diabetes, there is a need for evidence for the role played by LDL –C comes from
different approach in managing mixed dyslipidemia RCT’s which had used statins. The evidence clearly
.Randomised Control Trials [ RCTs] focussing on lipid shows that by reducing LDL –c, we get substantial re-
lowering therapy have to be conducted for evidence duction in CV morbidity & mortality . Many secondary
and to develop guidelines for Indian patients . Patient prevention trials , primary prevention trials, and trials
centric approach with evidence obtained from epi- conducted in high risk groups, clearly demonstrated
demiological / observational data on the prevalence the important role of LDL-C reduction and the po-
and type of dyslipidemia were given importance in tency of statins in reducing the atherosclerotic car-
the recommendations of LAI which are highlighted diovascular risk .
in this chapter. Recently published guidelines in 2017
are AACE [ American Association of Clinical Endo- NCEP ATP III Guidelines : Many guidelines were pub-
crinologists] ADA [ American Diabetes Association lished by various academic bodies across the globe
.After the publication of National Cholesterol Educa-

Cardio Diabetes Medicine

312 International Lipid Guidelines :
What Is Needed For Indians ?

tion Program – Adult Treatment Panel - III [ NCEP ATP High-Intensity Statin Moderate-Intensity Statin
III ] Guidelines in the year 2001 , we had also seen Therapy Therapy
an updated recommendation from the same organi-
sation in the year 2004 . ACC/AHA recommenda- Daily dose lowers LDL-c on Daily dose lowers LDL-C on
tions on lipid lowering was released in the year 2006 average, by approximately average, by approximately
, mostly concurring with ATP III recommendations . ≥50% 30% to <50%
Recommendations are : LDL-C Goals for High Risk
Patients : < 100 mg/dl in patients with CHD or CHD Atorvastatin (40)-80 mg Atorvastatin 10 (20) mg
risk equivalents including 10 years risk > 20 % and Rosuvastatin 20 (40) mg Rosuvastatin (5) 10 mg
<70 mg/dl as option for very high risk patients . If it Simvastatin 20-40 mg
is not possible to attain LDL-C < 70 mg/dl because Pravastatin 40 (80) mg
of a high baseline LDL-C , it is generally possible to Lovastatin 40 mg
achieve LDL-C reductions of >50% with more inten- Fluvastatin XL 80 mg
sive LDL-C lowering therapy including drug combina- Fluvastatin 40 mg bid
tions1 . ATP III also recommended lowering of Non Pitavastatin 2-4 mg
HDL -c as a secondary goal when Hypertriglyceri-
demia exceeds 200 mg/dl . High & Moderate Intensity Statin Therapy : Ref Table 1
Statins and doses that are approved by the U.S.FDA
2013 ACC/AHA Guideline on the Treatment of Blood but were not tested in the RCTs reviewed are listed in
Cholesterol to reduce atherosclerotic cardiovascular italics .
risk in adults : Stone NJ, et al. 2013 ACC/AHA Blood
Cholesterol Guideline circulation JACC, Nov 12, 2013 . New perspective on LDL and / or Non HDL-C Treatment
Goals : The expert panel included RCTs with robust
Main focus on ASCVD risk reduction : 4 statin ben- evidence for framing guidelines and was unable to find
efit groups in secondary and primary prevention are RCT evidence to support continued use of specific LDL-
identified for high-intensity and moderate intensity c and / or Non-HDL –c treatment targets . Global risk
statin therapy . assessment for primary prevention is recommended
by using new pooled cohort equations to estimate 10-
1. Individuals with clinical ASCVD : [Seconday Pre- year ASCVD risk by a new risk calculator . 7.5% risk
vention ] Atherosclerotic CVD  includes CHD, threshold for primary prevention was selected based
stroke, and PAD:High-intensity statin therapy on analyses . Some patients do not tolerate statins
should be used to achieve at least a 50% reduc- and may require treatment with lower doses. With few
tion in LDL - C unless otherwise contraindicated. exceptions, use of lipid-modifying drugs other than
For those older than 75 yrs, moderate dose statin statins is discouraged. Only statins have data of CV
may be used . protection .Non-statin lipid lowering drugs have no
evidence of CV protection. Measuring lipids during
2. Individuals with primary elevations of LDL–C follow-up of drug-treated patients is done to assess
≥190 mg/dL [Primary Prevention] High-intensity adherence to treatment and not to see whether a
statin therapy should be used to achieve at least specific LDL-C target has been achieved .
a 50% reduction in LDL -C unless otherwise
contraindicated Implementation of ACC / AHA Guidelines in clinical
practice in India : Is this possible ? These guidelines
3. Individuals between 40 and 75 years of age with are intended for US population . It is very difficult to
diabetes & without clinical ASCVD with LDL-C implement the same for Indians for the following
70-189 mg/dL : A moderate-intensity statin- that reasons : Use of high dose statin may be difficult in
lowers LDL-C by 30% to 49%. High-intensity statin patients with multiple co-morbidities & in Asian patients
is a reasonable choice if the patient also has a 10- .Over estimation of CV risk by presently developed
year risk of ASCVD exceeding 7.5% calculator was highlighted in the subsequent
publications . There was no recommendation for
4. Individuals without clinical ASCVD or diabetes LDL goal . This becomes difficult in Indian scenario
who are 40 to 75 years of age with LDL-C 70-189 . Asian subjects were not considered who have high
mg/dL and an estimated 10-year ASCVD risk of TG and low HDL . MetS was totally neglected for
7.5% or higher : A Moderate - or High-intensity recommendation in spite of an increasing prevalence
statin therapy. in US . We have problems of overweight ,Obesity and
MetS with > 69 million people suffering from diabetes
in India. Atherogenic dyslipidemia is the risk factor in
MetS and in diabetes which was not addressed . Lower
statin dose are frequently used in our population .
Adequacy of statin therapy cannot be determined

GCDC 2017

Cardio Diabetes Medicine 2017 313

without measuring on treatment LDL . ACC/AHA < 200 mg/dl of triglyceride. Clinicians need to focus
Guidelines2013 raised several questions that need to on the residual risk contributed by high triglycerides
be answered . 5 . Meta-analysis of 5 landmark trials (ACCORD, BIP,
FIELD, HHS, VAHIT) with 7389 patients with diabetes
Indian Scenario on Lipids and Lipoproteins : India and or CVD, concluded that lowering TG in people
Heart WATCH Study which evaluated for dyslipidemia who had elevated levels > 200mg/dl with PPAR alpha
prevalence in a population of 6400 subjects revealed agonists-Fibrates reduced.
higher TG levels with low HDL –c with normal or
marginally elevated LDL –c levels . CV events by 25% 6. In different studies in the last
2-3 decades , TG reduction, with or without statin,
High prevalence of Metabolic syndrome among has shown to cause significant risk reduction in
urban subjects in India was highlighted in a multisite patients with high TG and low HDL-C (Atherogenic
study2: 33.3% of men and 40.4% of women are having Dyslipidemia)7 . Triglycerides can be measured in
metabolic syndrome features with constellation of the non-fasting or fasting states. RCTs showing CV
multiple risk factors .Atherogenic dyslipidemia was benefit of triglyceride reduction are scanty . Lowering
typically seen in this study . triglycerides reduces the risk of CVD is still debated8.
Saroglitazar, a novel lipid lowering drug which has
ICMR – INDIAB Study 2014 : Prevalence of Dyslipidemia both PPAR alpha and gamma agonistic activity has
in urban and rural India was evaluated in this study . shown in clinical trials to lower triglycerides markedly
Higher prevalence of TG [29.5%] with higher prevalence in diabetics. This is a promising molecule which
of low HDL [72.3%] and 13.9% subjects were seen with has been approved in India for managing diabetic
Hypercholesterolemia . dyslipidemia.

Non HDL-C is a better indicator of residual Role of HDL-C : Trials to raise HDL-C levels by using
risk than LDL-C CETP Inhibitors like Torcetrapib ,failed to show
beneficial effects in spite of having a favorable HDL
Meta analysis of 62,154 statin-treated patients in rise in number of studies . Therapeutic Lifestyle
8 trials [4S, AFCAPS, LIPID, CARDS, TNT, IDEAL, Changes, such as smoking cessation, weight loss
SPARCL, JUPITER ] published between 1994 and 2008 ,physical activity ,moderate alcohol consumption
revealed the following: 1 SD increase in LDL-C, Apo B ,w-3 fatty acids have been found to show beneficial
and Non HDL increase the risk of CV events by 13% , effects in increasing HDL . However, there is still lack
14% , and 16% respectively indicating the strength of of evidence that raising HDL reduces CV Risk . HDL-C
association with CVD is greater for non HDL-C than for is not recommended as a target of therapy9.
LDL-C and ApoB 3. People who had LDL levels < 100
mg/dl with Non-HDL level of > 130 mg/dl had hazard Role of Lp(a): Lp(a) >50mg/dl independently predicts
ratio of 1.32 indicating CV risk of 32% when compared the presence of symptomatic & angiographic CAD.
to people who had uncontrolled LDL levels of > 100 Primary objective is to treat LDL and Non-HDL
mg/dl with Non HDL level of < 130mg/dl had hazard aggressively with high dose statin . Niacin is the only
ratio of 1.02 indicating CV risk of 2% . Conclusion : Non drug that lowers Lp(a). Novel Lipid lowering drugs like
HDL-C is associated with increased risk for future CV Apo B blockade by AntiSense Oligonucleotide (ASO) [
events , even if LDL is under control with statins. Mipomersen ] MTP Inhibitor [ Lomitapide ] and PCSK9
inhibitors [ Evolocumab ] have shown reduction in
RoleofApo-B: Apo-B is the key atherogenic lipoprotein Lp (a) with marked reduction of LDL – c . European
which is a more sensitive measure of risk than LDL-c Atherosclerosis Society recommends screening for
.It provides information on LDL particle size which is elevated Lp(a) in those at moderately high or high
difficult to measure directly . A recent analysis of the ASCVD risk .
combined data set from the TNT and IDEAL studies
showed that on-treatment level of apo-B was clearly International Atherosclerosis Society: Global
superior to that of LDL-c as a predictor of CV events, recommendations for the management of
but it was not superior to non - HDL-c 4 . dyslipidemia10 : LDL –C and Non-HDL-C as target of
Therapy : LDL is the major atherogenic lipoprotein and
Role of Triglycerides: Prove IT-TIMI 22 trial conducted VLDL is an additional atherogenic lipoprotein . Non-
in ACS patients stressed the role of high triglyceride HDL includes LDL + VLDL .LDL –C is the traditional
as a risk factor after reaching the LDL goal of 70mg/ primary target for clinical intervention and Non-HDL-C
dl with high dose Atorvastatin 80 mg/day. People who is also an appropriate target for clinical intervention
had >200 mg/dl of triglyceride had higher CV risk of based on huge body of evidence . Advantages of
sudden cardiac death, fatal and non-fatal reinfarction Non-HDL –C as Target : It does not require fasting for
in a 30 day follow up compared with people who had accurate measurement. Non HDL subsumes most

Cardio Diabetes Medicine

314 International Lipid Guidelines :
What Is Needed For Indians ?

cases of elevated triglycerides predominantly affecting LAD. There is a need for
development of risk calculator taking into account
Growing evidence favor Non HDL has greater predictive conventional risk factors and other risk factors which
power than LDL-C .Non –HDL is also considered are peculiar to Indians. We are currently witnessing
equivalent to apo lipoprotein- B in predictive power . overweight, obesity, features of metabolic syndrome
with insulin resistance. There is an increasing
Secondary Prevention : Achieving an optimal prevalence of diabetes which had crossed 69 million
atherogenic cholesterol level : The optimal LDL-C in with features of atherogenic dyslipidemia in nearly
patients with established ASCVD is < 70 mg/dl or 90% of diabetics. Hence we need individualised,
non-HDL-C of < 100 mg/dl . Most patients with ASCVD patient centric approach to bring down the CV risk.
deserve maximal statin therapy when it is tolerated . We require separate guidelines to suit our patients.
To achieve an LDL-C < 70 mg/dl, some patients will High dose statin are preferred for high risk and very
require add on drugs to statins [ i.e .ezetimibe and / or high risk individuals, whereas moderate dose statin
bile acid resins ] with uptitration to high dose may be the correct
approach for Indian subjects. Indians respond quickly
Secondary Prevention : Patients with Hypertrigl- to moderate dose statin therapy and statin intolerance
yceridemia : For those with high triglycerides, has been reported which needs to be tackled. We
Nicotinic acid or a Fibrate are alternative add on drugs require LDL goals to have a good adherence for
.However , risk reduction with combined drug therapy lifestyle modification and pharmacotherapy. If we
comparable to that with high-dose statins has not are not able to reach the goal of LDL with high dose
been documented in RCTs .Subgroup analysis of RCTs statin we may have to add Ezetemibe not only to
and atherosclerosis imaging provides some evidence reduce the LDL but also to reduce CV risk as has
of benefit of combined drug therapy . been highlighted in the recent studies. We require non
statin drugs like Fibrates, Nicotinic acid, and omega 3
National Lipid Association [ NLA ] recommendation fatty acids to tackle high triglyceride levels in specific
for management of dyslipidemia 9 : An elevated level situations . At present we may not consider HDL as
of atherogenic cholesterol – cholesterol carried by target of therapy. We need to pay more attention to
apo B-containing lipoprotein particles (non-HDL-C non HDL which covers LDL and VLDL. Statins will
and LDL-C) – is causally related to the development play a major role in bringing down non HDL levels.
of atherosclerosis. Targets of Therapy : Atherogenic Though we don’t have convincing data for marked
cholesterol (non-HDL-C and LDL-C) levels are CV risk reduction with TG lowering therapy, we are
the primary targets of therapy. Elevations in apo forced to continue the combination of drugs in view of
B-containing particles, and cholesterol carried by predominant peculiar dyslipidemia in our population
those particles, are considered a “ root cause” of . Emphasis has to be given for therapeutic lifestyle
atherosclerosis, and of primary importance for changes which is a corner stone in the management
prevention. Non-HDL-C testing is universally available, of dyslipidemia not only in primary prevention but
requires no additional cost, and may be measured in also in secondary prevention. It is appropriate to say
the non-fasting state. An elevated triglyceride level is that we need patient centric approach with our own
not a target of therapy per so, except when very high recommendations/guidelines.
[severe ] . Moderate or high-intensity statin therapy
should be the first line agent .Starting with a moderate Lipid Association of India Expert Consensus
dose and titrating as necessary to achieve treatment Statement on Management of Dyslipidemia in Indians
goals is a reasonable approach . An alternate drug : 2016 : Part 1 Journal of Association of Physicians of
Bile Acid Sequestrant [ BAS] Cholesterol absorption India [JAPI] Supplement copy March 2016 ,Vol : 64
inhibitor like Ezetimibe ,Fibrate and Niacin . These drugs ,Issue No.3 .Visit www.lipid.net.in for full text
may be considered in those with contraindications to
statin . CardiovascularRisk Stratification in Indians : Table : 1

What is needed for Indians ? Low-DensityLipoprotein cholesterol :

Number of guidelines were published with a focus on LDL-C should be the primary target for therapy. LDL-C
LDL lowering. We don’t have cholesterol management lowering to a low level is essential to achieve the
guidelines for Indians. We have a huge burden of desired reduction in the risk of vascular disease. In
CV disease in our country.CV deaths are increasing those with elevated levels of ASCVD risk, lower LDL-C
in alarming preportions. Young people are getting levels are associated with better outcomes. LDL-C
affected with CAD. This occurs one decade earlier levels <50mg/dL is safe.
when compared to western counterparts. Moreover
CAD is diffuse with multi vessel involvement,

GCDC 2017

Cardio Diabetes Medicine 2017 315

Non HDL-c (Non-High-Density lipoprotein Cholesterol: Table : 2 Comparison of International Guidelines In-
cluding recommendations of LAI :
Non-HDL-C, which is equal to total cholesterol –
HDL-C and this includes all atherogenic lipoproteins .It Highlight the role of ACC/AHA ESC/EAS NLA IAS LAI
is more accurate predictor of ASCVD risk, particularly Lifestyle   
in patients who have elevated TG (e.g. diabetes, obese   
persons, those with metabolic syndrome) and those Highlight the need to
already on statin therapy. LAI recommends non- engage the patient   
HDL-C as a co-primary target, as important as LDL-C, as a partner   
for lipid lowering therapy. Non-HDL-C level should be   
kept within 30mg/dL of LDL-C levels. Statins remain Highlight the role   
the first line agent for lipid lowering, regardless of of lipid modification   
whether LDL-C is the target for therapy or non-HDL-C. in the prevention of
CVD
Relevance of HighTG Levels
Highlight the need
Elevated TG is associated with increased risk of for risk assessment
ASCVD, independent of LDL-C levels. A combination
of high TG and LDL-C imparts even greater risk. In general use
High TG is one of the components of atherogenic an absolute risk
dyslipidemia.Keep TG<150 mg/dL, preferably strategy
<100mg/dL. In patients with elevated TG levels, rule
out secondary causes of the same and intensify Risk categories
lifestyle modification, which can reduce TG by as easy to identify and
much as 50%. Unless TG is very high (>500 mg/dL), agreed
statin should be the first drug . Routine addition of a
fibrate or another non-statin drug must be avoided. Good summary of
Only when TG is not sufficiently lowered with above RCT data
measures, a non-statin drug should be added.
Table : 3 THE APPROACH : Comparison of International
High Density Lipoprotein Cholesterol Guidelines

Low HDL-C is an independent risk factor for ASCVD. Use doses seen in ACC/AHA ESC/EAS NLA IAS LAI
It becomes even more relevant when LDL-C is not trial scenarios    
elevated. Life style modification plays an important    
role in raising HDL-C. Among pharmacological Emphasis on higher
agents, statins remain mainstay in the treatment of intensity statins for    
low HDL-C also. Although several other agents have established ASCVD   
been tried specifically for raising HDL-C, none of them  
has been shown to result in clinical benefit. Highlight the role
of lipid modification
Usage of statins for Lipid Management & Statin in the prevention of
Intolerance : The clinical benefit of statins depends CVD
primarily on the extent of LDL-C reduction and not on
the type of statin used. The type of the statin and dose Plus TARGETS
to be used should be based on the degree of LDL-C
reduction that is required to reach the target LDL-C % Reductions √
in a given patient. Atleast moderate- or high intensity
statin therapy is required to bring about a clinically THE BAD : Comparison of International
meaningful reduction in LDL-C in most patients. Guidelines

The ACC/AHA 2013 guidelines on the treatment of ACC/AHA and ESC/EAS guidelines seek to lower
blood cholesterol to reduce ASCVD risk : A comparison LDL-C with statin therapy as their principal aim LAI
with ESC/EAS guidelines for the management of also recommends the same . ACC/ AHA Guidelines
dyslipidaemias 2011 11 . Recommendations from LAI : Treats risk alone with guidance only on treating AS-
has been added apart from NLA & IAS for comparison CVD risk and discard the use of lipid targets It is
12. Ref .Table 2 ,3,4 & 5 simply fire and forget approach .Do not recommend
additional lipid-lowering therapies among those with
high residual risk despite achievement of 50% re-
duction in LDL-C . ESC/EAS Guidelines & LAI rec-
ommendations : Treats risk and more : Treats CVD
risk, create a greater understanding of the role of
LDL-C in CVD assessment (LDL-C monitoring) . In-

Cardio Diabetes Medicine

316 International Lipid Guidelines :
What Is Needed For Indians ?

dividualized patient care approach : assessing other ADA Recommendations : Diabetes Care , Supple-
lipid-mediated factors “residual risk” :TG-rich lipo- ment 1 January 2017 . Ref Table 6
proteins remnants , HDL-C , Non-HDL-C & Apo B
. Recommends LDL-C and other lipid measures for Age Risk factors Recommended
monitoring efficacy, compliance, assessing residual < 40 years None statin Intensity *
risk and allow a greater scope for modifying individ-
ual patient care by considering additional therapies None
if clinically warranted .
ASCVD risk factor(s) *** Moderate or high
Table : 4 THE BAD : Comparison of International Guidelines ASCVD ASCVD High

ACC/AHA ESC/EAS NLA IAS LAI 40–75 years None Moderate
ASCVD risk factors High
Targets    ASCVD High
ACS and LDL cholesterol Moderate plus
Lower is better    >50mg/dl in patients who - Ezetimibe
cannot tolerate high
Scope for other ath-    dose statins
erogenic lipids

Scope for other LLT    > 75 years None Moderate
ASCVD risk factors Moderate or high
CKD as a high risk   ASCVD High
group √ ACS and LDL cholesterol Moderate plus
>50mg/dl Ezetimibe
Table : 5 THE UNCERTAIN : Comparison of International Guidelines: patients who cannot tolerate
high –dose statins
ACC/AHA ESC/EAS NLA IAS LAI
What to do at the ? ? ? ?? * In addition to lifestyle therapy
Extremes of age
Promot- ** ASCVD risk factors include LDL cholesterol > 100 mg/dl ,
A new risk calcu- ? ? ing JBS high BP, smoking, and overweight and obesity and family history
lator ? 3 score of premature ASCVD

Reducing the pri- -√ AACE Guidelines for Dyslipidemia Management 2017:
mary Prevention
threshold [For √ ?√ -? ASCVD Risk Categories and LDL-C Treatment Goals. Ref : Table 7
Young]  ?-
? ?? ?? Category 10 year risk LDL-C Non- Apo
Reducing the pri- Apo HDL-c B [mg/
mary prevention Progressive ASCVD dl]
threshold (For Extreme including unstable <80
Old) Risk angina in patients after <70
achieving an LDL-C
What do our pa- <70 mg/dL
tients want √
Established clinical CV
2016 ACC Expert Consensus Statement : This is a dif- disease in patients with <55
ferent compared to ACC/AHA Guidelines 2013 . The DM, < 55 < 80 < 70
statement stressed the role of Non-statin therapies CKD 3/4, or HeFH
for LDL-C lowering in the management of ASCVD
risk . Non HDL-C thresholds are included in high risk History of premature
patients . Ezetimibe is preferred as the initial non sta- ASCVD (<55 male,
tin therapy . Colesevelam has a modest hypoglyce- <65 female)
mic effect that may be of benefit in some diabetic
patients with fasting triglycerides <300 mg/dl or in 2017 Focused Update of the 2016 ACC Expert Consensus
patients who are ezetimibe intolerant . Decision Pathway on the Role of Non-Statin Therapies for
LDL-Cholesterol Lowering in the Management of Athero-
2016 European Guidelines on CVD prevention in clini-
cal practice : Total CV risk should guide the intensity sclerotic Cardiovascular Disease Risk :
of the intervention . Non HDL –c is included as a tar-
get . Non statin therapy mainly Ezetimibe is recom- In 2016, the American College of Cardiology published
mended . the first expert consensus decision pathway (ECDP)
on the role of non-statin therapies for low-density
lipoprotein (LDL) –cholesterol lowering in the man-
agement of atherosclerotic cardiovascular disease

GCDC 2017

Cardio Diabetes Medicine 2017 317

(ASCVD) risk. Since the publication of that document, 5. Fruchart JC, Sacks F, Hermans MP, et al. The Residual Risk Reduction
additional evidence and perspectives have emerged Initiative: a call to action to reduce residual vascular risk in patients
from randomized clinical trials and other sources, with dyslipidemia. Am J Cardiol. 2008;102(10 Suppl):1K-34K.
particularly considering the longer-term efficacy and
safety of proprotein convertase subtilisin / kexin 9 6. Lee M et al.Atherosclerosis 2011;217; 492– 8
(PCSK9) inhibitors in secondary prevention of ASC-
VD. Most notably, the FOURIER (Further Cardiovas- 7. N Engl J Med. 2010:363(7):692-4 Diabetes Care 32:493–498, 2009
cular Outcomes Research with PCSK9 Inhibition in
Subjects with Elevated Risk) trial and SPIRE-1 and -2 8. Børge G Nordestgaard, Anette Varbo Lancet 2014; 384: 626–635
(Studies of PCSK9 Inhibition and the Reduction of
Vascular Events), assessing evolocumab and boco- 9. Terry A. Jacobson et al , National Lipid Association recommendations
cizumab, respectively, have published final results of for patient-centered management of dyslipidemia: Part 1 – executive
cardiovascular outcomes trials in patients with clinical summary* Journal of Clinical Lipidology 2014 ;8 473 – 488 .
ASCVD and in a smaller number of high-risk primary
prevention patients. In addition, further evidence on 10. An International Atherosclerosis Society Position Paper 2013,Global Rec-
the types of patients most likely to benefit from the ommendations for the Management of Dyslipidemia [ Full report ]
use of ezetimibe in addition to statin therapy after
acute coronary syndrome has been published. Based 11. Kausik K.Ray et al , European Heart Journal doi : 10.1093 /eurheartj
on results from these important analyses, the ECDP / ehu 107 .
writing committee judged that it would be desirable
to provide a focused update to help guide clinicians 12. 12. SS Iyengar,Raman Puri ,S.N.Narasingan ,Lipid Association of India
more clearly on decision making regarding the use Expert Consensus Statement on Management of Dyslipidemia in Indi-
of ezetimibe and PCSK9 inhibitors in patients with ans 2016 : Part 1 Journal of Association of Physicians of India [JAPI]
clinical ASCVD with or without comorbidities. Supplement copy March 2016 ,Vol : 64 Issue No.3

Conclusion

There is a need for absolute risk assessment in ev-
eryone and this is the best approach in managing
Lipids . We need to assess the risk and then go with
which ever is greater i.e. a 50% LDL-C reduction or a
target . In those at highest absolute risk we have to
maximise the dose of the statin. We need to decide
whether this is enough for this person’s level of risk
or should we go lower ? Lower could be a greater
percentage reduction in LDL-C or a target .LAI Con-
sensus statement in the management of Lipids for
Indians has solved many issues pertaining to bring-
ing down LDL –c goal to 50 mg in very high risk group
. Almost all academic bodies are now recommending
55 mgs of LDL goal for very high risk group . Infact ,
LAI gets the credit in recommending such low levels
before any other academic bodies attempted to do .
Refer : www.lipid.net.in

References:

1. Grundy SM et al. Circulation. 2004;110:227–239. Smith SC Jr et al.
Circulation, 2006; 113:2363–2372

2. Prakash Deedwania & Rajiv Gupta et al 2014 Diabetes & Metabolic
Syndrome Clinical Research & Reviews Volume 8 , Issue 3 , July Sep
2014 .Pages 156 – 161 ,ELSEVIER

3. Endocrine Practice 2013;19 (Suppl 2):1-48.

4. JAMA 2005; 294: 326-333 , Circulation 2005; 112: 3375-3383 & Na-
tional Lipid Association recommendation . Kastelein JJ, Van der steeg
WA, Holme L, et al: Circulation 2008;117: 3002-3009 .

Cardio Diabetes Medicine

318 Cardio Diabetes Medicine 2017

Maternal Obesity and
Pregnancy Outcomes

Dr. Archana Ambujan
MS(OG)., DRM (Germany)

Consultant in OBG & Fertility Specialist,
Sundaram Arulrhaj Hospitals, Tuticorin

Introduction the abdomen at the level of the umbilicus. It is an
indicator of health risks associated with excess fat
“HEALTH IS WEALTH “ is an Old English Saying around the waist. A waist circumference more than
.Weight is an indicator of general health of a person. 88cm (or 35 inches) in women is associated with
Being Underweight is not considered healthy & so is health problems like Diabetes ,Hypertension & Heart
being Overweight. Disease.

Obesity is a Silent Epidemic emerging gradually all Obesity may be Central Obesity which is android
over the world. Worldwide obesity has more than type with apple shaped fat distribution or Lower body
doubled between 1980 &2014.There is a higher prev- Obesity which is Gynaecoid type with pearshaped fat
alence of obesity in females than males. According distribution .Central Obesity is at high risk for Co-
to WHO (2014) in the Global scenario more than 1.9 morbidities & Complications.
billion individuals are overweight and more than 600
million are obese .26 % Non pregnant women in the Obesity & Pregnancy
age group of 20-39 are either overweight or obese.
Increasing rate of Maternal obesity is a major chal-
India stands third in the world in the incidence of lenge to obstetric practice.Maternal Obesity has a
obesity only next to China & US & India is racing detrimental effect on both the Mother & Baby .Ma-
ahead to the top. More than 30 million people in India ternal risks during pregnancy include Gestational
are obese. Diabetes & Preeclampsia. Fetal risks during preg-
nancy include congential anomalies & stillbirth Ma-
Hence “Obesity “is the no longer a “Disorder”, but it ternal obesity can pose problems before pregnancy
is a “Disease” of serious concern. with inability to conceive (Infertility),during pregnancy
both antepartum & peripartum,neonatal problems&
Definition longterm complications.

According to WHO ,Overweight & Obesity are defined Infertility
as abnormal or excessive fat accumulation that pres-
ents a risk to health .It is estimated by BMI and waist The beginning of the problems of Maternal obesi-
circumference. ty is Infertility.An Obese women is about thrice as
likely to be in fertile as a normal woman.It is seen
BMI is used as a measure of Obesity. It is the ratio that adolescent obesity is associated with a threefold
of the weight to square of height of a person (kg/m2) increased risk. Obesity is strongly associated with
PCOS ,a disorder which is characterized by central.
WHO recommended cut offs for BMI obesity, hyperandrogenism &insulin resistance with
compensatory hyperinsulinemia. Obesity also leads
Underweight ≤ 18.5 Kg/m2 to poorer prognosis in women undergoing various
Normal BMI 18.5-24.9 Kg/m2 Assisted Reproductive treatments.Pregnancy rates in
Over Weight 25.0-29.9 Kg/m2 ART is halved for women with BMI>35kg/m2.In IVF
Obesity ≥30 Kg/m2 also obese women require higher doses of gonado-

Waist circumference is a measurement taken around

GCDC 2017

Maternal Obesity & Pregnancy Outcomes 319

tropins & have an increased miscarriage rate. Even iology. It is this metabolic function of the adipose tis-
5% weight loss iproves fertility outcomes. It is shown sue that causes the pathology associated with obesity.
than 5% weight loss leads to 56% regular cycles,48%
spontaneous ovulation,32% spontaneous pregnancy Enzymes & Hormones Produced by Adipose
&25 % live birth rates. Tissue

Pregnancy Enzyme / Hor- Function Changes with
mone OBESITY
Pregnancy perse is reported as one of the factor for Aromatase Converts androgens to No change
the development of obesity.Excess Pre pregnancy estrogens with obesity
weight ,weight gain during pregnancy and retention 17- hydrox- Converts estrone to es- No change
of weight after delivery have detrimental effects on ysteroid tradiol & androstendione
both mother & Baby. The Pregnancy complications hydrogenase to testosterone No change
include. 5-reductase Inactivates cortisol
Converts cortisone to Activity is
Early Pregnancy 11- hydrox- cor tisol increased in
ysteroid obese women
Spontaneous Miscarriage, Recurrent Miscarriages, dehydrogenase Affects food intake,
Congenital Anomalies – NTD, CHD, Spinabifida, Om- type 1 timing of puberty, bone Circulating
phalocele Leptin development, and im- leptin levels
mune function are increased
Late Pregnancy in obese
TNFα Represses genes in- women
Gestational HTN, PreEclampsia, Eclampsia ,Gesta- volved in the uptake and Expression
tional Diabetes, Preterm birth / PROM, IUGR, IUFD storage of nonesterfied of TNF is in-
fatty acids and glucose creased in the
Peripartum adipose tissue
of obese
Higher rate of C-Sections ,PPH, Anaesthesia com- women
plications, Wound infection/breakdown ,Postpartum
Endometritis , Postpartum thrombosis,Difficulty in GDM
Breast Feeding
Gestational Diabetes Mellitus (GDM) is the most com-
Fetus/Neonate mon complication of pregnancy in Obese women.
The prevalence of GDM Varies from 1 to 20 % and
Fetal Macrosomia , Shoulder dystocia , Childhood is rising worldwide in line with increasing trends of
Obesity Maternal obesity and Type-2 DM. The incidence of
GDM rises disproportionately with increasing obesity.
Pathophysiology of Obesity in Pregnancy Based on the meta analysis of the literature ,the risk
of developing GDM is about two ,four and eight times
Adipose tissue is a storehouse of energy. It provides higher among overweight, obese and severely obese
structural support & the fat serves as a cushion from women respectively compared with normal-weight
trauma. Adipose tissue also functions as an endocrine pregnant women. Pregnancy is a state of insulin
organ, the non fat cell of the adipose tissue produce resistance triggered by the pregnancy hormones &
enzymes & hormones which influence the body phys- adipokines secreted from the placenta such as TNF
α,Placental lactogen, placental growth hormone,
cortisol and progesterone which reverses at delivery.
The insulin resistance is compensated by increased.
Insulin secretion from pancreatic beta cell in normal
pregnancy.GDM develops when the mother does not
secrete enough insulin to meet the metabolic stress
of insulin resistance .As GDM and Obesity share
many of the same health consequences,obese wom-
ens & their off spring are at a greater risk of adverse
outcomes.

Cardio Diabetes Medicine

320 Cardio Diabetes Medicine 2017

GDM Weight gain in Pregnancy

Pre eclampsia Institute of Medicine recommend total weight Gain Ranges for Preg-
nant Women by Prepregnancy Body Mass Index (BMI)
There is a there fold increase in risk of preeclampsia
associated with obesity. Obesity increases the risk Category Kilograms Recommend-
of “all forms” of pre eclampsia. Furthermore pre ec- ed Total Gain
lampsia is associated with an increased risk of later
life cardiovascular disease. Preeclampsia leads to hy- Underweight - BMI <18.5 kg/m2 12.5 to 18 28 to 40
pertension through various mechanisms,
1. Reduced availability of No secondary to in- Normal - BMI 18.5 to 24.9 kg/m2 11.5 to 16 25 to 35

creased ADMA (Assymmetic Dimethylarginine) Overweight - BMI 25.5 to 29.9 kg/ 7 to 11.5 15 to 25
& oxidative Stress. m2
2. Increased Sympathetic tone.
3. Increased expression of angiotensinogen by ad- Obese - BMI >30kg/m2 5 to 9.1 11 to 20
ipose tissue.
4. Adipose tissue produces several inflammatory Antenatal Care
mediators that alter endothelial function
Adjustments to Routine prenatal care in obese wom-
en (TABLE 1)

Peripartum care

This includes the following

a) Pre OP Cardiac evaluation by electrocardiogram,
Echo cardiogram and cardiology consultation
especially if patient has GDM or Hypertensiuon.

b) Give Pre operative / Pre delivery broad spectrum
antibiotics.

c) Use a larger delivery /Operating table.

d) Because of the increased risk of PPH, blood
products should be made available.

RISK FACTOR RECOMMENDED CARE
Increased risk of neural tube defect
• Preconception folic acid supplementation (4 mg daily) ideally 3 months
prior to pregnancy & through the first trimester

• Maternal serum AFP (15-20 weeks)

Increased risk of hypertensive disorders • Detailed fetal anatomy survey (18-20 weeks)
of pregnancy, including preeclampsia • Baseline 24-hour urinalysis in second trimester
• Baseline liver and renal function tests in second trimester

• Blood pressure and urine dip for protein at each prenatal visit

• If positive, check a definitive 3-hour 100-g glucose tolerance test (GTT)
to confirm the diagnosis of GDM

Increased risk of gestational diabetes • If negative, repeat OGTT(DIPSI) at the usual gestational age of 24-28
(GDM) weeks

Increased risk of unexplained stillbirth • Consider early screening with 2-hour nonfasting 75-g glucose load test &
check blood sugar levels after 2hrs (DIPSI) at initial visit

Consider weekly antepartum fetal testing with NST and/or BPP beginning at
36 weeks

Table 1: Adjustments to Routine prenatal care in obese women

GCDC 2017

Maternal Obesity & Pregnancy Outcomes 321

e) Place preumatic compression stocking prior to Literature Review
during & until patient is fully ambulatory.
Pre-pregnancy maternal weight & Pregnancy out-
f) Additional DVT prophylaxis with LMWH should comes
be considered.
Study Outcome Type Of Study Result
g) Begin early ambulation. h)Delay suture removal Chu SY et al GDM Meta-analysis
to allow the skin to heal completely. (2007) 3.6-fold &
Gestational Observational 8.6-fold risk
Contraception & Future Pregnancy Weiss JL et al HTN study for obese &
(2004) Pre eclampsia Observational severely obese
After present delivery the women should be advised Weiss JL et al study
to continue the weight losing maintenance therapy (2004) Caesarean de- Observational 2.5-fold risk
as before ,as future conception will give better results HAPO STUDY livery, neonatal study for obese
when planned of the women had GDM,75 gm 2hr (2010) adiposity women
OG TT should be performed at 6 wks Postpartum. Meta-analysis
Birth spacing for 1-2 yrs is advisable ,Progestin bear- Scothard KJ et Congenital 1.6-fold risk
ing IUCD is the effective method of Contraception. al (2009) anomalies Observational for obese
OG’s should be avoided due to the thrombotic side study women
effects and failure rates directly proportional to in- Reynolds RM ↑CV event in
creased BMI.After completion of family husband can et al (2013) Adult offspring ↑BMI, inde-
go for vasectomy. pendent of ma-
ternai glycemia
Management of obesity results in PIH,
CS, ↑neona-
a) Life style modification –Diet & Exercise in con- tal birth wt &
sultation with a Dietician & Physiotherapist. body fat

b) Drugs –Orlistat -Selective inhibitor of gastric and Obese women
pancreatic lipase that inhibits absorption of lip- are at ↑ odds
ids in intertine. of congenital
anomalies
c) Sibutramine –Non adrenaline & 5HT reuptake
inhibitor, acts as appetite inhibitor. 0.29 fold risk
of hospital ad-
d) Metformin –Insulin sensitizer. mission for a
CV event
e) Bariatric Surgery –
Conclusion
1. Restrictive –Vertical banded gastroplasty, Lap-
aroscopic adjustable gastric banding. a) Excess Maternal Weight at any phase of preg-
nancy has negative effects on pregnancy out-
2. Male absorptive –Bilo pancreatic diversion. comes.

3. Combination of Both. b) It predisposes women to various complications.
especially Gestational diabetes & Hypertension
4. Laparoscopic sleeve gastrostomy is now pop- which eventually lead to more serious long term
ular particularly in younger women. problems like non communicable diseases.

It is an irreversible reduction in the size of the stom- c) A child born to an obese mother is more sus-
ach to 15 % of its original size..This reduces the hun- ceptible to obesity in adolescence& adulthood &
ger hormone ghrelin giving the person earlu satiety. also Diabetes.
This procedure helps to reduce 30-50% of weight in
6-12 mts.weight losing surgery should be done at- d) Hence it is very important to reduce weight be-
least 1 year before planning pregnancy. fore planning a pregnancy

e ) Weight reduction should be done be Diet ,Exer-
cise ,Drugs or Bariatric surgery according to the
individual need.

Cardio Diabetes Medicine

322 Cardio Diabetes Medicine 2017

Reference

1. American Diabetes Association: Gestational diabetes mellitus, Diabetes
Care 27 (Suppl.l):S88-S90,2004

2. WHO: Obesity and Overweight [Internet].WHO.[cited 2012 Aug 20]
Available from : http://www.who.int /mediacentre/factsheets/fs311/en

3. Aggarwal , P.,&Mishra , VK(2004).covariates of overweight and obesity
among women in North India.Honolulu: East West Centre.25p, (East
West Centre working papers no.116,population and health series).

4. Yu C ,Teoh T ,Robinson S.Obesity in pregnancy BJOG.2006;113:1117-25
5. Institute of medicine /National Research Council(committee to Reex-

amine IOM pregnancy Weight Guidelines,Food and Nutrition Board and
Board on Children,Youth and families)2009 Weight gain during pregnan-
cy:reexamining the guidelines.Washington,DC:National Academies press.
6. Misra A ,Khurana L.Obesity and the metabolic syndrome in developing.
Journal of clinical Endocrinology & Metabolism.2008;93:s9-30[PubMed]
7. Wang Y , Beydoun MA ,Liang L ,Caballero B ,Kumanyika SK.will all
Americans become overweight or obese?estimating the progression and
cost of the US obesity epidemic.Obesity.2008;16;2323-30[PubMed]
8. Roberts JM,Gammill HS ,Preeclampsia;recent insights.Hyperten-
sion.2005;46;1243-9[PubMed]
9. Bodnar LM,Catov JM,Klebanoff MA,Ness RB,Roberts JM.Prepragnancy
body mass index and the occurrence of severe hypertensive disorders of
pregnancy .Epidemiology.2007;18:234

GCDC 2017

Cardio Diabetes Medicine 2017 323

04. Investigations

1. Risk Stratification in Asymptomatic Diabetics :Role of Selective Imaging with Cardiac CT
and Myocardial Perfusion Imaging - Dr.Avijit Lahiri

2. Monitoring in Diabetes - Dr. Kevin Shotliff
3. Post Revascularisation Status – Myocardial Perfusion Imaging - Dr.Shrikant Solav
4. Role of Nuclear Imaging in the Evaluvationof Non – Coronary Artery Disease -

Dr. Deepanjan Mitra
5. Evaluvation of Cardiac Syncope and ECG Markers of Sudden Cardiac Arrest - Dr. Ameya

Udyavar
6. Myocardial Imaging Products : Continuing Evolution for the Better - Dr.N. Ramamoorthy
7. Pitfalls in Computer ECG Interpretations - Dr. V. Balchandran
8. Echocardiographic Evaluvation of a Diabetic Patient - Prof. Dr. V. Amuthan
9. Biochemical Evaluation of Dyslipidaemia - Dr. Devaki Nair
10. ECG Evaluation in Patients with Acute Coronary Syndrome - Dr.Senthilkumar Nallusamy
11. Strain and Strain Rate Imaging in Early Detection of Ventricular Systolic Dysfunction - Is

this the Best Investigation? - Dr. R. Balamurugan
12. Cardiac MRI vs PET Scan - Dr. G. N. Mahapatra
13. Mechanical Circulatory Support for Advanced Heart Failure - Dr. Liviu Klein

Cardio Diabetes Medicine

324 Risk Stratification in Asymptomatic Diabetics :Role Of Selective
Imaging With Cardiac CT And Myocardial Perfusion Imaging

GCDC 2017

Cardio Diabetes Medicine 2017 325

Risk Stratification in Asymptomatic Diabetics : Role of
Selective Imaging with Cardiac CT And Myocardial
Perfusion Imaging

Dr.Avijit Lahiri,
Dr. Shreenidhi Venuraju

Dr. Ram Dhillon

British Cardiac Research Trust, St John’s Wood, London, United Kingdom

Abstract: patients.Women with type 2 diabetes are particularly
prone to developing cardiovascular complications [3] .
Coronary heart disease (CHD) is currently the lead-
ing cause of death worldwide; in the presence of Diabetes has been regarded as a “coronary risk
diabetesthe risk of cardiovascular disease increases equivalent,” implying a 10-year cardiovascular risk
exponentially, and particularly effects Asian popu- of >20% for every diabetes patient. This was based
lations. The arteriosclerotic process in diabetic pa- on the landmark study by Haffner et al. (Ref 1).Thus
tients occurs earlier, is often ‘silent’, more diffuse diabetic patients without previous myocardial infarc-
and often accelerated compared to the non-diabetic tion had a high risk for myocardial infarction, as high
population. Screening and risk stratification for as- as the risk of re-infarction in a non-diabetic individ-
ymptomatic atherosclerosis in diabetic subjects has ual with previous myocardial infarction. The impact
been extensively studied in recent years. New medi- of diabetes on coronary heart disease has been ob-
cal guidelines have acknowledged the heterogeneity served in various studies, such as Whitehall, Paris
in risk and suggested that further risk stratification Prospective Study, and the Helsinki Policeman Study.
in patients with diabetes is warranted. These studies demonstrated that patients with diabe-
tes and impaired glucose tolerance have 2-4 times
Introduction: higher risk of developing cardiovascular disease than
the non-diabetic patient population. This and other
Diabetes is an important chronic disease and its inci- studies led to the development of aggressive risk
dence is globally increasing and thus considered as factor management even in diabetic patients without
an epidemic [1]. The World Health Organization (WHO) known coronary disease. Multiple mechanisms ap-
estimated that there were 30 million people with di- pear to be involved in the genesis of atherosclerosis,
abetes worldwide in 1985. This number increased to including endothelial dysfunction, hypercoagulability,
135 million by 1995 and reached 217 million in 2005. and platelet dysfunction, with hyperglycemia being
By the year 2030 WHO predicts this number will the common trigger.
increase to at least 366 million. This extraordinary
growth in type 2 diabetes is occurring equally in both Screening of CAD in Asymptomatic Diabetic
developing and developed countries [1]. Patient:

There is a close relationship between type 2 diabetes The prevalence of silent myocardial ischemia (SMI)
and the development of coronary artery disease.CVD in diabetic population varies in different studies,
is the major cause of morbidity, mortality, and health- ranging from 12% to almost 57% [20, 21].One estimate
care costs for patients with diabetes. Patients with is that 20% of patients with diabetes have coronary
type 2 diabetes have a two to four-fold higher risk of atherosclerosis. [22]
a cardiovascular event when compared with non-dia-
betic patients. [2]25% of all patients hospitalized with However, in an asymptomatic and uncomplicated
STEMI, NSTEMI and unstable angina suffer from di- cohort of patients with type 2 diabetes, 46.3% had
abetes according to the GRACE registry. Moreover, evidence of coronary artery calcification reflective of
the progression of coronary artery disease appears coronary atherosclerosis. This variability underlines
to be more rapid when compared with non-diabetic the difficulty to have a cost-effective screening and

Cardio Diabetes Medicine

326 Risk Stratification in Asymptomatic Diabetics :Role Of Selective
Imaging With Cardiac CT And Myocardial Perfusion Imaging

the necessity to define the cardiovascular risk in the and to determine its association with myocardial per-
asymptomatic diabetic population who could benefit fusion abnormalities (Anand et al.)(Ref 4)
from this screening. Due to the high rate of cardio-
vascular mortality and morbidity in the type-2 diabet- (figure-1).
ic population, there has been considerable interest
in establishing the incidence of subclinical or occult
CAD and the factors influencing it. The exercise-ECG
has poor accuracy for detecting CAD in asymptomat-
ic diabetic patients. Though the DIAD study investiga-
tors reported a 20% prevalence of silent myocardial
ischemia in a large asymptomatic diabetic cohort
(n=1123) using SPECT imaging, this was not a cost-ef-
fective method for screening large populations.

Improvements in risk stratification by Diagram showing the protocol used to compare CAC
imaging subclinical atherosclerosis imaging and myocardial perfusion imaging in asymp-
tomatic diabetic patients
The presence of calcium in coronary arteries is a
specific marker of atherosclerosis, independent of Risk factors and coronary artery calcium (CAC) scores
its etiology. were prospectively measured in 510 asymptomatic
type 2 diabetic without prior cardiovascular disease.
Using electron beam tomography (old method) orthe Significant CAC (>100 AU) was found in 46.3%. Age,
current ultra-fast multidetector CT scanners enables systolic blood pressure, the duration of diabetes,
the acquisition of thin slices of the heart and coro- United Kingdom Prospective Diabetes Study (UK-
nary arteries gated to cardiac diastole. Thus CT Coro- PDS) risk score, CAC score, and extent of myocardi-
nary Calcium Imaging (CAC) has become established al perfusion abnormality were significant predictors
as new evolving method for non-invasive detection of of time to cardiovascular events. No cardiac events
coronary atherosclerotic ‘burden’.(Ref 2 and 3) or perfusion abnormalities occurred in subjects with
CAC< 10 AU during follow-up. CAC and MPS findings
CAC imaging has been established as marker of were synergistic for the prediction of short-term car-
prognosis in intermediate risk patient population. A diovascular events. Figure shows the relationship be-
meta-analysis of 4 studiesshowed that CAC scores tween increasing atherosclerotic burden (CAC Score)
remained predictive of coronary events, even after and ‘total ischaemic burden’ from SPECT sestamibi
adjustment for established cardiovascular risk fac- imaging
tors. The event rates in individuals with even mild
coronary calcification (CAC scores of 1 – 100) were (figure-2).
twice as high, compared to those with no detectable
coronary calcium (RR = 2.1). CAC scores > 400 were
associated with very high relative risks (RR = 4.3 to
17), after adjustment for age, sex, and other cardio-
vascular risk. (Ref 3)

Though the calcium score represents an estimate of
the total plaque burden present in an individual, it
does not correspond directly to the degree of luminal
narrowing of a given vessel.

Diabetes and Calcium Score:

CAD is often asymptomatic and is associated with
worse prognosis in diabetic patients.We established
the value of CAC imaging in diabetic patients, the
technique promises to be an effective test for early
detection of silent CAD.

We prospectively evaluated the prevalence of CAC in
asymptomatic uncomplicated type 2 diabetic patients

GCDC 2017

Cardio Diabetes Medicine 2017 327

The figure shows the relationship between increasing Further development in novel bio-markers may help
coronary artery score (EBCT) and the ‘total ishcaemic’ earlier detection of diabetic patients at higher risk of
burden from the sestamibi SPECT myocardial perfu- developing coronary atherosclerosis. Osteoprotegrin
sion imaging, showing a close relationship between is an interesting biomarker which has been linked to
increasing CAC score and size and severity of the increasing CAC scores in diabetes. This type of ‘mod-
perfusion abnormality. elling’, where one combines risk factors, bio-mark-
ers, CT and functional imaging, may provide a more
Based on these trials there is now strong evidence cost-effective and accurate method of detecting
that that coronary artery calcium imaging may be those at risk. (Ref 5 and 6)
beneficial in diabetic patients with moderate to high
cardiovascular risk factors. References

current Guidelines and Future Trends: 1. Haffner SM1, Lehto S, Rönnemaa T, Pyörälä K, Laakso M.Mortality from
coronary heart disease in subjects with type 2 diabetes and in nondiabetic
According to the 2010 ACC/AHA Guidelines for as- subjects with and without prior myocardial infarction. N Engl J Med. 1998;
sessment of CV risk, in asymptomatic adults with 23: 339(4):229-34.
diabetes, 40 years of age and older, measurement
of CAC is reasonable for cardiovascular risk assess- 2. Raggi P, Shaw LJ, Berman DS, Callister TQ. Prognostic value of coronary
ment (Class IIa B). The 2012 European Guideline for artery calcium screening in subjects with and without diabetes. J Am Coll
CV risk assessment also acknowledges that Com- Cardiol2004;43:1663–1669.
puted tomography for coronary calcium should be
considered for cardiovascular risk assessment in as- 3. Budoff MJ, Shaw LJ, Liu ST, et al. Long-term prognosis associated with
ymptomatic adults at moderate risk. (IIa) coronary calcification: observations from a registry of 25,253 patients. J
Am Coll Cardiol. 2007. 49(18):1860-70.
The 2013 ACC/AHA Guideline on the Assessment
of Cardiovascular Risk clearly states that “assessing 4. Anand DV, Lim E, Hopkins D, et al. Risk stratification in uncomplicated
CAC is likely to be the most useful of the current type 2 diabetes: prospective evaluation of the combined use of coronary
approaches to improving risk assessment among in- artery calcium imaging and selective myocardial perfusion scintigraphy. Eur
dividuals found to be at intermediate risk after formal Heart J. 2006 ,27(6):713-21.
risk assessment.”
5. Anand DV, Lahiri A, Lim E et al. The Relationship BetweenPlasma
Osteo-
protegerin Levels and CoronaryArteryCalcification in Uncomplicated Type
2 Diabetic Subjects. J Am Coll Cardiol2006;47:1850–7

Conclusion:

The number of patients with diabetes type 2 will in-
crease dramatically over the next few decades. For
adequate risk stratification, assessment of coronary
artery atherosclerosis would be advantageous. In as-
ymptomatic patients, screening for coronary artery
disease is less established. Although a substantial
number of patients may have silent ischemia, not
all patients may benefit from imaging to detect isch-
emia. Newer imaging modalities to detect sub-clinical
atherosclerosis in the form of CAC imaging and new-
er biomarkers help detect increased cardiovascular
risk may provide an important diagnostic modality.
CAC imaging provides excellent risk stratification in
patients with diabetes, with an increase in mortality
for each increase in CAC score category. The mortali-
ty risk is higher for each CAC category in the patients
with diabetes than in those without. However, about
40% of adult diabetic patients have a CAC score <10
and a very low mortality rate. Rapid progression of
CAC signifies patients at higher risk for CHD events.

The overall evidence supports the use of CAC scan-
ning for risk stratification and to guide management
in the asymptomatic DM patient.

Cardio Diabetes Medicine