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Published by , 2018-09-22 10:39:45

22sep

22sep

Cardio Diabetes Medicine 2018 48

cerebrovascular disease and peripheral arterial women with the PCOS phenotype is required.
disease and end stage liver failure and neoplasia Additionally, the role of PCOS among South
have not been proven by longitudinal follow up Asian descent and their risks of obesity related
studies. This lack of corroborating outcome data obstructive sleep apnoea and neoplasia have
may be due to the intrinsic approach to manag- not been well recorded.
ing PCOS in the current day through multidisci-
plinary care to encourage and enable lifestyle Therefore the management of PCOS requires a
modification, the liberal use of metformin, a pos- holistic life cycle approach from puberty well into
sible protective effect of the oestrogen excess the post menopausal phase; with a shift in focus
that is present among with PCOS or the lack of a from reproductive to metabolic problems. There
good national level accurate data sets of an ade- is no doubt that the condition of PCOS will draw
quately long term follow up, particularly in South into its care pathway expertise from paediatri-
Asian countries. cians, endocrinologists, gynaecologists, derma-
tologists, surgeons and most importantly the
The effect of obesity on the metabolic and repro- primary care physician teams. Another aspect to
ductive symptoms of PCOS is mediated through providing appropriate care in the management of
insulin resistance. The prevalence of the meta- PCOS is addressing the psychosocial issues and
bolic syndrome in PCOS is reported to reach a factors affecting the wellbeing of affected wom-
high proportion of 35% from the 3rd decade of en. The occurrence of obesity was recognized
life, with the risks for prediabetes and overt type by western studies as the chief determinant of
2 diabetes to reach as much as 40% during the poorer quality of life of women with PCOS. Nev-
reproductive years. It is noteworthy that one in ertheless, community based large scale data
three overweight women have been reported to carried out in Sri Lanka clearly showed that the
be at risk of having PCOS. Furthermore, one unit hirsutism and cosmetic problems did override on
increase of BMI (kg/m2) is reported to increase the problems of well being; in that young South
the risk for PCOS by 9%. The temporal trends Asian women perceived overweight and obesi-
of the prevalence of obesity among women with ty less as a problem as opposed to increased
PCOS show an increase from 51% in the 1990s body hair in a male distribution and loss capi-
to 74% in the following decades. Furthermore, tal hair, alongside acne and the frequent occur-
the long-term weight gain over 10 years among rence of acanthosis nigricans. This factor has a
women with PCOS is significantly greater than clear message that the social aspects of medical
unaffected women as is central obesity with a practice can also determine the health seeking
progressive increase in waist hip ratio between behaviours and care pathways in a chronic care
20-25 years and 40-45 years. This is consistent model throughout the life cycle of an affected
with reports from a prospective birth cohort of in- woman from South Asia.
creased weight gain in early adulthood in women
with symptoms of or a diagnosis of PCOS com- Therefore, all capacity building educational pro-
pared with controls. Nevertheless, in depth stud- grammes for primary care physicians and grass
ies of the role of puberty and its inherent issues root level health workers in South Asia must in-
of increased adiposity along with an increase in clude and emphasis on the relevant aspects of
insulin resistance among young women of South PCOS – as a marker of metabolic risks among
Asian descent and their link with the propensity young women and enable early recognition of
to PCOS have not been carried out so far. Going the PCOS phenotype, with the provision of a ho-
even beyond, the risk for maternal hyperglycae- listic multi-disciplinary approach that promotes
mia and hypertension during pregnancy, birth healthy lifestyle and addressing psycho-social
weight and the role of fetal programming and aspects to the condition. These aspects have
methylation among the offspring of South Asian been incorporated into the first ever well formu-

Cardio Diabetes Medicine

Cardio Diabetes Medicine 2018 49

lated international clinical practice guidelines on
PCOS of 2018 that have been endorsed by most
professional organizations throughout the world.

References:

1.Wijeyaratne Chandrika N, Udayangani SAD,
Balen AH. Ethnic specific polycystic ovary syn-
drome: epidemiology, significance and implica-
tions. Expert Rev. Endocrinol. Metab. 2013; 8(1):
71-7
2.Fauser BC, Tarlatzis BC, Rebar RW, Legro RS,
Balen AH, Lobo R, Carmina E, Chang J, Yildiz
BO, Laven JS, Boivin J, Petraglia F, Wijeyeratne
CN, Norman RJ, Dunaif A, Franks S, Wild RA,
Dumesic D, Barnhart K. Consensus on women’s
health aspects of polycystic ovary syndrome
(PCOS): the Amsterdam ESHRE/ASRM-Spon-
sored 3rd PCOS Consensus Workshop Group.
Fert, Sterility 2012;97:28-38
3.Helena J Teede, Marie L Misso, Michael F
Costello, Anuja Dokras, Joop Laven, Lisa Mo-
ran, Terhi Piltonen, Robert J Norman, Interna-
tional PCOS Network; Recommendations from
the international evidence-based guideline for
the assessment and management of polycystic
ovary syndrome, Human Reproduction https://
doi.org/10.1093/humrep/dey256
4.Kumarapeli V, Seneviratne Rde A, Wijeyaratne
C. Health-related quality of life and psychologi-
cal distress in polycystic ovary syndrome: a hid-
den facet in South Asian women. BJOG. 2011
Feb;118(3):319-28.
5.Wijeyaratne CN, Seneviratne Rde A, Dahan-
ayake S, Kumarapeli V, Palipane E, Kuruppu N,
Yapa C, Seneviratne Rde A, Balen AH. Pheno-
type and metabolic profile of South Asian women
with polycystic ovary syndrome (PCOS): results
of a large database from a specialist Endocrine
Clinic. Hum Reprod. 2011 Jan;26(1):202-13.
Epub 2010 Nov 23.

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Cardio Diabetes Medicine 2018 50

DIABETIC CARDIOVASCULAR DISEASE

Dr.Nihar Mehta
MD(Medicine),DNB(Medicine),DNB(Cardiology)
Fellowship in interventional cardiology,S.Korea
Fellowship in intervenntional cardiology,Mount Sinai,Newyork

Consultant cardiologist
Jaslok hospital&Reseach centre

bhatia hospital,K.J.Somaiya superspeciality hospital

Abstract -

Diabetes Mellitus diabetes patients who have AF affirm the stroke
risk associated with diabetes in the setting of
Cardiovascular disease (CVD) remains the prin-
cipal comorbid condition and primary contributor AF.
to mortality in the patient with diabetes, usually
in the form of coronary heart disease (CHD), but INTRODUCTION:
also in the incremental risk associated with di-
abetes for cerebrovascular disease, peripheral Cardiovascular disease (CVD) remains the prin-
vascular disease, heart failure (HF), and atrial cipal comorbid condition and primary contributor
fibrillation (AF). to mortality in the patient with diabetes, usually
in the form of coronary heart disease (CHD), but
Atherosclerotic Vascular Disease also in the incremental risk associated with di-
abetes for cerebrovascular disease, peripheral
Patients with diabetes have a twofold to fourfold vascular disease, heart failure (HF), and atrial
increased risk for CHD, CV mortality, and all- fibrillation (AF). For these reasons, continuing
cause mortality compared to those without dia- effort toward mitigating the risk of CVD in diabe-
betes. Diabetes is associated with an increased tes remains a global public health imperative. 1-3
risk for MI. Diabetes, one of the most common chronic dis-
In addition to CHD, diabetes increases the risks eases in the world, affects an estimated 285 mil-
of stroke, cerebro­vascular disease, and periph- lion adults in 2010. It is estimated that diabetes
eral arterial disease. Diabetic patients have a will affect more than 430 million persons, 7.7% of
twofold increased stroke risk compared with the global adult population, by 2030.
nondiabetic persons. Hyperglycemia is associ-
ated with a twofold to sixfold increased risk for
subsequent adverse clinical outcomes.

Heart Failure

In the ambulatory setting, diabetes is associated
independently with a twofold to fivefold increased
risk for HF over that in persons without diabetes,
and patients with diabetes have worse outcomes
once HF has developed.

Atrial Fibrillation Figure 1: Estimated number of Adults with DM
in 2010 and projected for 2030 stratified by age
Diabetes increases risk for AF, and in the pa-
tient with AF, diabetes increases absolute stroke group and developed and developing countries
rate/year by 2% to 3%. The inclusion of diabe-
tes as one of seven categorical classifications
used in the CHA2DS2–VASc score and guide-
line recommendations for anticoagulation for all

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Cardio Diabetes Medicine 2018 51

ASSOCIATION BETWEEN GLUCOSE Figure 3: Adverse clinical outcomes after
LEVEL AND CVD
acute coronary syndrome during more than 1
Only relatively recent overviews of studies have year follow up, according to diabetic status,
confirmed a progressive association between among patients in TRITON-TIMI 38 trial.
glucose levels and cardiovascular risk, which ex-
tends well below the diabetic threshold. This as- The graded association of increased risk ob-
sociation is consistent across different measures served with diabetes in the setting of ACS ex-
of glucose exposure and appears to be log-linear tends to glucose values in the range well below
as already suggested in the early 1990s by Wil- the diabetes threshold.
son et al. Furthermore, the overviews suggested
that the magnitude of the association was simi-
lar for coronary, cerebrovascular, and combined
cardiovascular events.
More recent Framingham reports have charac-
terized the hazard ratios for diabetes as predic-
tor of incident CVD were similar across follow-up
periods, whereas the age- and sex-adjusted
CVD incidence rate decreased by 50% between
the earlier period (1950-1966) and the later peri-
od (1977-1995) of follow-up.

Figure 2: Age adjusted cardiovascular disease Figure 4: Post admission glucose levels and

(CVD) mortality rate among Framingham Heart mortality in cohort of patients admitted for acute
Study participants with and without diabetes MI with hyperglycemia on arrival, after multivari-
mellitus. ate adjustment.

DIABETES AND ACUTE CORONARY RELATIONSHIP OF HYPERGLYCEMIA
SYNDROME: AND ATHEROSCLEROSIS

Diabetes is associated with an increased risk Hyperglycemia may increase atherosclerotic risk
for MI. Across the spectrum of acute coronary but given the associations between severity of
syndrome (ACS) events, in which diabetes may hyperglycemia and risk for atherosclerosis in
affect more than one in three patients, those both type 1 and type 2 DM, it probably direct-
with diabetes have worse CVD outcomes after ly influences atherosclerosis development, pro-
ACS events Despite overall improvements in gression, and instability.The principal vascular
outcomes during the past several decades for perturbations linked to hyperglycemia include -
ACS patients with and without diabetes, the endothelial vasomotor dysfunction, vascular ef-
gradient of risk associated with diabetes per- fects of advanced glycation end products,
sists.

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Cardio Diabetes Medicine 2018 52

adverse effects of circulating free fatty acids, in- DIABETIC MANAGEMENT AND CAR-
creased systemic inflammation, and a prothrom- DIOVASCULAR SAFETY
botic state.
Endothelial vasomotor dysfunction, a hallmark All glucose-lowering agents must now demon-
of diabetic vascular disease, is associated with strate designated margins of CV safety to achieve
increased hypertension and adverse CVD out- regulatory approval. In this context, the available
comes. The myriad mechanisms contributing to data on the net CVD safety and efficacy of such
endothelial dysfunction include abnormal nitric medications has been quite limited, and current
oxide biology, increased circulating endothelin management strategies and most guidelines
and angiotensin II, and reduced prostacyclin remain grounded on the proven microvascular
(i.e., prostaglandin I2) activity. High triglyceride disease benefits demonstrated through glucose
(TG) levels, low levels of high-density lipoprotein control alone.
cholesterol (HDL-C), and increased small, dense
low-density lipoprotein (LDL) particles character- The most recent guidelines from the ADA and
ize diabetic dyslipidemia contributing to the pro- EASD endorse a more individualized approach
gression of atherosclerosis. than previously recommended, with more liberal
HbA1c targets for patients with shorter expected
Increased circulating tissue factor, factor VII, von life span and with significant comorbidity, includ-
Willebrand factor, and plasminogen activating in- ing prevalent CVD, suggesting a HbA1c target
hibitor 1, with decreased levels of antithrombin III of 8% (or higher). Given the landmark findings
and protein C, disturbances of platelet activation, from EMPA-REG OUTCOME, LEADER, IRIS,
aggregation, morphology, and life span further and SUSTAIN-6 trials, the method that lowers
contribute to increased thrombotic potential, as glucose levels matters, particularly those with
well as to the acceleration of atherosclerosis. established CVD. Whether empagliflozin, liraglu-
Diabetes is associated with lipid-rich atheroscle- tide, semaglutide, or pioglitazone would prove ef-
rotic plaque with increased inflammatory cell fective in primary prevention remains unknown.
content, expression of tissue factor, and expres-
sion of the receptor for advanced glycation end THE OMINOUS OCTET: HEART
products. FAILURE IN DIABETES

Increased myocardial vulnerability in the setting
of diabetes and probable synergistic effects be-
tween such factors and diabetes that increase
HF risk, yielding the concept of “the ominous oc-
tet” of common conditions in diabetes that may
underpin HF risk.

TABLE 1: Mechanism implicated in Diabetic

Vascular Disease

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Cardio Diabetes Medicine 2018 53

Figure 5: Approach to the management of hyperglycemia

Figure 6: The Ominous Octet: Heart Failure in Diabetes

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Cardio Diabetes Medicine 2018 54

METABOLIC MODIFICATIONS CON- GLYCEMIC CONTROL IN DIABETES
TRIBUTING TO HF RISK IN DIABETS AND HF

Diabetes causes a variety of morphologic chang- Poor glycemic control is associated with risk of
es in the myocardium, with abnormalities in my- HF in patients with diabetes, with a stronger as-
ocytes, extracellular matrix (ECM), and micro- sociation in women than men. Meta-analyses of
vasculature. The myocardial accumulation of available data demonstrate no significant effect
advanced glycation end products (AGEs), in- of more versus less aggressive glucose control
cluding macromolecules nonenzymatically mod- on the risk for HF. Therefore, patients with dia-
ified by glucose, the formation and accumulation betes and HF should be treated to achieve the
of which depend on the severity of hyperglyce- recently liberalized HbA1c target of less than
mia, may contribute to HF risk. Deposition of 8% with the avoidance of hypoglycemia, as en-
AGEs within the myocardial ECM adversely af- dorsed for patients with recognized moderate to
fects both systolic and diastolic cardiac function, severe CVD.
largely attributable to AGE cross-linking of matrix Thiazolidinedione medications have a propensi-
collagen. ty to increase plasma volume and to precipitate
incident or worsening HF; their use requires cau-
tion in patients with any degree of HF, and they
are contraindicated in patients with NYHA Class
III or IV HF

Figure 7: Cardiac Metabolic Modifications occuring in Diabetes

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Cardio Diabetes Medicine 2018 55

The modulators of the incretin axis, the GLP-1 In patients with HF who fail to achieve accept-
RAs and DPP4 inhibitors, appear to have some able HbA1c targets with oral agents, insulin re-
favorable effects on a variety of intermediate mains an acceptable option.
markers associated with myocardial dysfunction
and HF but saxagliptin and alogliptin potentially SGLT2 inhibitor empagliflozin reduced HF hospi-
increases HF risk. talization by 38% in the EMPA-REG-OUTCOME
trial that involved more than 7000 patients with
Although Metformin historically was thought to type 2 DM and established CVD. A similar effect
be contraindicated in the setting of HF, those was seen with canagliflozin in CANVAS.
product cautions were removed in 2006.The
best available evidence supports consideration In summary, numerous metabolic and patholog-
of metformin in patients with stable and compen- ic abnormalities associated with diabetes may
sated HF, especially in the context of the avail- explain the increased HF risk and inform drug
able CVD outcomes data, low risk of hypogly- development efforts toward new therapeutic
cemia, low cost, and favorable tolerability profile targets. In addition to ongoing research in this
Insulin therapy remains an option in patients who area, clinical efforts should focus on the optimal
fail to achieve benefit with conventional oral glu- application of existing risk-mitigating therapies
cose-lowering therapies, although some concern in patients with diabetes and HF. As for specific
persists based on the plausibility that insulin may glucose-lowering agents, metformin may provide
exacerbate signs and symptoms of HF by in- an advantage, as is also likely with SGLT2 in-
creasing renal sodium reclamation, contributing hibitors. Thiazolidinediones should be avoided.
to increased intravascular volume. In the ORI- The GLP-1 RAs appear safe. Data regarding
GIN trial, patients randomly assigned to receive the DPP4 inhibitors varies from drug to drug.
insulin glargine versus usual care tended to have Saxagliptin and alogliptin should probably be
fewer hospitalizations for HF, although this dif- avoided for patients with HF until more safety
ference was not statistically significant (4.9% ver data have accumulated.

sus 5.5%; P = 0.16).

Figure 7: EMPAREG and CANVAS Trial Outcomes

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Cardio Diabetes Medicine 2018 56

DIABETES AND ATRIAL FIBRILLATION abetes mellitus in the Framingham Heart Study,
Type 2 DM is independently associated with 1950 to 2005. Circulation. 2009;119:1728–1735.
4. Standl E, Schnell O, McGuire DK. Heart failure
AF21 and aggravates risk for stroke and systemic considerations of antihyperglycemic medications
thromboembolism, resulting in guideline recom- for type 2 diabetes. Circ Res. 2016;118:1830–
mendations for systemic anticoagulation for all 1843.
patients with diabetes who have AF. Although 5. Huxley RR, Filion KB, Konety S, Alonso A.
warfarin has historically been the mainstay of Meta-analysis of cohort and case-control studies
systemic anticoagulation for AF, the novel oral of type 2 diabetes mellitus and risk of atrial
anticoagulants dabigatran, rivaroxaban, apix- fibrillation. Am J Cardiol. 2011;108:56–62.
aban, and edoxaban now offer alternatives. For 6. Lip GY, Nieuwlaat R, Pisters R, et al. Re-
each therapy, the subanalyses of efficacy and fining clinical risk stratification for predicting
safety for patients with diabetes participating in stroke and thromboembolism in atrial fibrillation
the pivotal registration trials of these medications using a novel risk factor-based approach: the
suggest similar or even favorably amplified ben- EuroHeart Survey on Atrial Fibrillation. Chest.
efit/ risk balance. In fact, with similar relative risk 2010;137:263–272.
reductions with the novel agents versus warfarin 7. Hess K, Grant PJ. Inflammation and thrombosis
and the greater absolute risk for stroke observed
in each trial, patients with versus without diabe- in diabetes. Thromb Haemost. 2011;105(suppl
tes have more favorable number needed to treat 1):S43–S54.
(NNT) for benefit . 8. American Diabetes Association. Standards
of medical care in diabetes—2016: summary
CONCLUSION of revisions. Diabetes Care. 2016;39(suppl
1):S4–S5.
Overall, diabetes increases risk for virtually all 9. Fox CS, Golden SH, Anderson C, et al. Update
CVD complications and, most notably, athero- on prevention of cardiovascular disease in
sclerotic vascular disease, heart failure, and atri- adults with type 2 diabetes mellitus in light
al fibrillation. The regonition of this association of recent evidence: a scientific statement
comes with the requirement of cardiovascular from the American Heart Association and the
safety demonstration for all antidiabetic med- American Diabetes Association. Circulation.
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which provides great promice for future manage- Management of hyperglycemia in type 2 dia­
ment of diabetic CVD. Selection of appropriate betes, 2015: a patient-centered approach—
agents to manage hyperglycemia in the setting update to a position statement of the American
of cardiovascular disease is of paramount impor- Diabetes Association and the European
tance to target the deadly duo of diabetes and Association for the Study of Diabetes. Diabetes
Care. 2015;38:140–149.
CVD. 11. American Diabetes Association. Standards
of medical care in diabetes—2015. Diabetes
References Care. 2015;38(suppl):S1–S2.

1.American Diabetes Association. Classification
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3. Preis SR, Hwang SJ, Coady S, et al. Trends 12. Pladevall M, Riera-Guardia N, Margulis AV, et
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Cardio Diabetes Medicine

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glitazones, metformin and sulfonylureas: meta- 19. Bangalore S, Kumar S, Fusaro M, et
analysis of published observational studies. al. Short- and long-term outcomes with
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GUIDELINES FOR HYPERTENSION MANAGEMENT

Dr. A.N. RAI

MD, MRCP (UK), FRCP (Glasgow)
FICP, FICC, FICN

Former Prof & Head Department of
Medicine and Principal, ANMCH,
Gaya Chairman of AIMS, Gaya

Newer Guidelines for HTN Classification SBP DBP
<120 <80
· Till 2016 all guidelines on Hypertension in- Normal 120–129 <80
cluding our indian guideline defined Hyper- Elevated
tension with BP140/90 mm Hg or above. Hypertension 130–139 80–89
Stage 1
· AHA/ACC in 1917 came out with new
guideline which defined BP 130/85 mm Hg
or above.

· This put clinicians world over in dilemma Prevalance of Hypertension
that which guideline to follow in diagnosis
and treatment of Hypertension.

· Then recently on 9th June 2018 ESH came 5≥130/80 or re- ≥140/90 or reported
out with new guideline which again defined ported BP Med BP Med
Hypertension with BP 140/90 or above.

New AHA/ACC Guidelines

· Published November 13th, 2017 Overall, 46% 32%
Crude
· Guidelines for the Prevention, Detection, Men Wom- Men Women
Evaluation, and Management of High Overall, en
Blood Pressure in Adults Age/ Sex
adjusted 48% 43% 31% 32%
· Sought to determine the optimal targets for
BP lowering during antihypertensive ther-
apy in adults

· In prior guidelines, there was insufficient Study Selection
evidence to demonstrate benefit of BP

goal<140/90 · Total of 33 publications from 15 studies con-
sidered
· Newly completed trials allowed to deter-
mine whether lower BP goal conferred ad- · 14 publications excluded because out-
ditional benefit either in general population comes reported in another publication,
or specific subpopulation

outcome presented by subgroup, no out-

come of interest, no in-trial results present-

ed, intent to treat analysis not presented or

event counts unavailable

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Analysis of Results Normal BP Elevated BP (120-
129/<80)
Any lower BP target vs. standard or higher (<120/80)
BP target found that greater BP lowering sig- Promote optimal Nonpharmacologic
nificantly reduced the risks of: Therapies
1.Major CV event (RR: 0.81) lifestyle habits Reas-
2.MI (RR: 0.86) sess in1 year Reassess in 3-6
3.Stroke (RR: 0.77) months
4.Heart Failure (RR:0.75)
Major CV event: composite outcome of CV
death, stroke, MI, and heart failure

Recommendations for Treatment

Stage 1 Hypertension Stage 2 Hypertension
(130-139/80-89) (≥140/90)

Nonpharmacologic Clinical ASCVD or 10 Nonpharmacologic
Therapy yrCVD risk ≥10% Therapy and Medication

Reassess in 3-6 months Atherosclerotic Cardiova- Reassess in 1 month
sular Disease Calculator

First line initial antihypertensive drugs include ACE, ARB, CCB, or thiazide diuretic

Summary of Guidelines

SBP DBP
<80
Normal <120 <80

Elevated 120–129 80–89
Hypertension 130–139 ≥90
Stage 1

Stage 2 ≥140

Give Meds if ASCVD risk greater than 10% for stage 1 and all people in stage 2

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Cardio Diabetes Medicine 2018 60

BP Diagnostic Threshold - Maintained at 140/90 mm Hg

· Classification of BP and the definition of hypertension unchanged from previous guidelines

· Defined as

Office SBP SBP (mm Hg) DBP (mm Hg)
24h ABPM average > 140 > 90
> 130 > 80

HBPM average > 135 > 85

B P diagnostic threshold - maintained at 140/90 mm Hg BP classified as
Optimal, Normal, High normal,Grades 1-3 Hypertension, as per office BP

Catogory Systolic and Diastolic
Optimal < 120 and/or < 80
Normal 120-129 and/or 80-84
130-139 and/or 85-89
High Normal 90-99
140-159 and/or
Grade 1 100-109
hypertension 160-179 and/or
≥ 110
Grade 2 ≥ 180
hypertension <90
≥ 140 and
Grade 3
hypertension

Isolated Systolic hypertension

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Definitions according to office, ambulatory and home BP levels

Catogory Systolic BP (mmHg) Diastolic BP
(mmHg)
Office BP ≥140 and/or ≥90
Ambulatory BP
Daytime (or awake) ≥135 and/or ≥85

Nighttime (or sleep) ≥120 and/or ≥70

24-h ≥130 and/or ≥80
Home BP ≥135 and/or ≥85

Wider use of ABPM / HBPM recommended to confirm
Hypertension diagnosis

· Screening is recommended in all adults > 18 years of age and thereafter every 5 years

Advantages and Disadvantages ABPM HBPM
Identify white coat & masked HTN Y Y
Prognostic evidence
Night time readings Stronger N
Measurement in Y Home setting May be more
relaxed
Potential for measurement error Real life setting
BP Variability information Y
Availability N Day to day BPV
Cost Short term BPV Widely available
Comfortable Sometimes limited
Low
Expensive Y

N

Cells highlighted in Pink colour denote disadvantages
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ABPM / HBPM Clinical Indications Re- ABPM / HBPM Clinical Indications Re-
lated to Diagnosis lated to Treatment

· Conditions in which White coat HTN is more · Evaluation of resistant hypertension
common
· Evaluation of BP control, especially in treated
· Grade I HTN on office BP measurement high risk patients

· Marked office BP elevation without TOD · Evaluating symptoms consistent with hypo-
tension during treatment
· Conditions in which Masked HTN is more
common · Postural and post prandial hypotension in
treated patients
· High normal office BP
· Assessment of nocturnal BP values during
· Normal office BP with TOD / high total CV risk treatment

· Postural and post prandial hypotension in un-
treated patients

· Exagerated BP response to exercise

· Assessment of nocturnal BP and dipping sta-
tus

Screening and Diagnosis of Hyperten-
sion

BP BP Values (mm Hg) Repeat BP atleast every
Optimal < 120 / 80 5 years
Normal
High Normal 120-129/80-84 3 years

130-139/85-89 Year

Consider masked HTN. Use out of of-
fice BP measurement – HBPM / ABPM

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CV Risk Stratification

Other risk factors, asymp- Blood Pressure (mmHg)
tomatic organ damage

or disease High normal Grade 1 HT Grade 2 HT Grade 3 HT
SBP 130-139
No other RF
1-2 RF or DBP 85- SBP 140-159 SBP 160-179 SBP > 180

89 or DBP 90- or DBP 100- or DBP >110
99 109

Low risk Moderate High risk
risk

Low risk Moder- Moderate to High risk
ate risk high risk

> 3RF Low Moderate Moderate to High Risk High to very
risk high risk high risk

OD, CKD stage 3 or diabetes High risk High risk High Risk High to very
high risk

Symptomatic CVD, CKD Very Very High Very High
stage >4 or diabetes with High Risk risk
OD/RFs risk

High risk
=dBbilPosdeoi=aadssbtpeolor,leiocDsdsBbpulPorreeos.dspurrees, sCuKreD, = chronic kidney disease, CV =cardiovascular, CVD= cardiovascular
HT= hypertension; OD= organ damage; RF = risk factor; SBP =systolic

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Managing CV risk Beyond BP •
• 120 to < 130mm Hg
· Statin therapy would benefit hypertensive • 130 to < 140mm Hg
patients at moderate or higher CVD risk • 130mm Hg or lower if tolerated
and those with established CVD by further • 130mm Hg or lower
reducing risk of MI and stroke, even when • 130 to < 140mm Hg
BP is controlled • 120 to < 130mm Hg

· Low dose aspirin recommended for sec-
ondary prevention in hypertensive pa-
tients, but not for primary prevention

BP Targets in Hypertensive patients
Considerations

· Lower BP < 140/90mm Hg in all patients

· If treatment is well tolerated target < 130 /
80mm Hg but not lower than 120mm Hg
and DBP < 80mm Hg but not lower than
70mm Hg

· Targets in hypertensive subgroups

• Age < 65 years

• Age >65 years

• Diabetes

• CAD

• CKD

• Post-Stroke/ TIA

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Lifestyle changes 2013 guideline

2018 guideline

Salt restriction < 5g/ day 5-6g/day

Alcohol consumption Men Men
< 14 units / week Wom- 20-30g ethanol/ day, not to exceed 140g/ week
en
< 8 units / week Avoid Women
10-20g ethanol/ day, not to exceed 80g/ week
Binge drinking

BMI and WC Aim for healthy BMI 20- 25
kg/m2

WC - < 94cm –men
< 88cm -women

Regular aerobic exer- 30 mins, 5-7 days per 30 mins, 5-7 days per week
cise week

Smoking Cessation Y Y

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Initiating - Anti-Hypertensive Treatment

Life Drug Treatment
BP Val- style
BP ues (mm Advice
Hg)

High 130-139/ Y Consider in V high risk patients with CVD, especially CAD
Normal 85-89
BP

Immediate treatment in high After 3-6 months of lifestyle

Grade I 140–159 / / intervention in those with low
HTN 90–99
Y v. high risk patients with to moderate risk without CVD/

CVD/ renal disease / TOD renal disease / TOD

Grade 2 160–179 / Immediate in all pa- Aim for BP control in 3 months
tients
HTN 100–109 Y

Grade 3 > 180 / Immediate in all pa- Aim for BP control in 3 months
HTN 110 tients

Y

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Management of White coat and Masked Hypertension Masked HTN

White Coat HTN

Lifestyle changes to reduce CV risk with

regular follow up and periodic out of office

BP monitoriing Y

Routine treatment not indicated Y
Y
May be considered in patients

with TOD / high CV risk

Anti-Hypertensive drug treatment

Uptitration of Drug Treatment - To be considered if
out of office BP not
controlled

Fixed Dose Single Pill Therapy
Recommended As Initial Therapy

· Combination treatment for most patients
as initial therapy – ACEI / ARB + CCB /
Diuretic

· Initiation with Fixed Dose Combination
preferred in most patients except in the
elderly and low risk Grade I hypertension

· blockers in combination with other agents in
specific conditions like angina, MI, HF

· 3 drug combination of ACEI / ARB + CCB
+ Diuretic, if BP not controlled with 2 drug
combination

· If BP not controlled with 3 drug combination,
add Spironolactone

· In patients with CKD / CAD initial dual
combination therapy recommended. In
CKD patients, diuretics to be replaced
with loop diuretics

· In resistant hypertension, add low doses of
spironolactone to existing treatment

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Strategy for Uncomplicated Hypertension

· Start treatment in most patients with not one
but 2 drugs, except in the elderly and low risk
Grade I hypertension

Initial Therapy Suggested Therapy

Initial Therapy 1 pill dual combination ACEI or ARB + CCB / Diuretic. Monotherapy
in low risk or elderly
Step 2 1 pill triple combination
ACEI or ARB + CCB + Diuretic

Triple combination + Spironolac- Resistant Hypertension - Add Spironolactone

tone 25mg -50mg OD

Step 3

Consider bblockers if there is spe-
cific indication -HF, angina, post
Mi, AF’

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Hypertension management Specific considerations

Recommended Goal

(mm Hg) Elderly Treatment

Diabe- <130 but not lower 130 to <140 ACEI or ARB + CCB / Diuretic
tes than 120 mm Hg

CKD 130 to < 140mm Hg ACEI or ARB + CCB / DiureticRAAS blockers more
HFrEF effective in reducing albuminuria If GFR < 30mL/
min/1.73m2, replace thiazide diuretics with loop
diuretics

ACEI or ARB + b-blocker+ Diuretic / MRA. CCB if
control still not achieved

HF HFpEF All major agents can be used

LVH 120-130mm Hg 130-140 ACEI or ARB + CCB / Diuretic
mm Hg
130mm Hg or lower b blockers + RAS blockers, in patients with history
but not < 120mm Hg. of MI. b blockers and / or RAS blockers in patients
CAD Target DBP <80 mm
Hg but not <70 mm with symptomatic angina

Hg

ESH Guideline Summary

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Differences betweenESH and ACC/AHA Guidelines

BP Diagnostic ESH Guidelines ACC / AHA
Threshold < 140 /90 mm Hg Guidelines

< 130/80mm Hg

BP targets for < 140 / 90mm Hg < 130/80mm Hg
treatment If treatment is well tolerated target
<130 / 80mm Hg but not lower than 120/ 70
mm Hg

Age < 65 years120 to < 130mm Hg Age

BP targets in HTN > 65 years130 to < 140mm Hg Diabe- < 130/80mm Hg
patients with co tes130mm Hg or lower if tolerated CAD-
morbid conditions 130mm Hg or lower CKD130 to < 140mm

Hg

Post-Stroke/ TIA120 to < 130mm Hg

Recommended SCORE ACC/AHA Pooled Cohort
calculator for as- Equations
sessing 10-year

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DIABETIC CARDIOMYOPATHY

Dr. Nitin Burkule, MD, DM, FACC,FASE
Consultant Cardiologist at Jupiter hospital, Thane (M.S.).

Abstract: fraction (HFREF).
The insulin resistance and the hyperglycae-
The insulin resistance and hyperglycemia ad- mia produce advanced glycation end-products
versely affect multiple cellular mechanisms in which alter the properties of cellular proteins,
myocardium. It leads to cardiac remodeling and lipids, and nucleic acids. The glucose metab-
left ventricular diastolic and systolic dysfunction. olite b-N-acetylglucosamine attaches to many
The echocardiography can evaluate the dysfunc- different intracellular and extracellular proteins
tion in myocardial relaxation, compliance and and alter their function. At the myocytes level
contractility. The Positron emission tomography there is grossly altered mitochondrial energet-
or magnetic resonance imaging are research ics, substrate handling, calcium handling and
tools to evaluate myocardial fibrosis, metabo- excitation-contraction coupling. The systemic
lism and microvascular dysfunction. It is feasi- and myocardial oxidative stress and inflamma-
ble to use echocardiography and biomarkers as tion leads to interstitial fibrosis, hypertrophy and
screening tools to detect diabetic cardiomyopa- apoptosis. The excess sympathetic activity, re-
thy in asymptomatic diabetic population, howev- nin-angiotensin-aldosterone system activation
er, efficacy of such approach is not yet validated. and systemic hypertension also contribute to
cardiac remodelling. Both the CAD and micro-
Introduction: vascular dysfunction cause perfusion abnormali-
ty and cellular level ischemia.
In the population affected with Diabetes melli-
tus (DM) there is two to three fold increase in Clinical manifestations:
incidence of heart failure among men and five
fold increase in incidence of heart failure among The patients with DM very frequently present
women1. The diabetic patients present with heart with dyspnoea or fatigue with exertion. The
failure more often than myocardial infarction. cause with impaired exercise capacity can be
There are multiple different ways by which DM either central (DMCM) or peripheral (De-condi-
causes myocardial dysfunction: tioning) or both. This can be differentiated to a
1) Cardiomyopathy through myocyte and myo- great extent by cardio-pulmonary exercise test
cardial interstitial ultrastructural changes, coupled with stress imaging.
2) Ischemia mediated through epicardial coro- The pre-clinical DMCM shows three characteris-
nary atherosclerosis (CAD) and microvascular tics features:
dysfunction, 1) Left ventricular (LV) remodelling (LV concen-
3) Autonomic neuropathy, tric remodelling or LV concentric hypertrophy),
4) Co-morbidities like hypertension (HT), obesity 2) LV diastolic dysfunction (relaxation and com-
or chronic kidney disease. pliance),
3) LV systolic dysfunction
Pathogenesis of Diabetic cardiomyop-
athy: Echocardiography:

The cellular level mechanism leading to diabetic Cardiac remodelling:
cardiomyopathy (DMCM) involve complex path- The LV concentric remodelling is defined as nor-
ways which lead to altered myocardial relaxation mal LV mass ( male < 115 gm/m2, female < 95
and myocardial compliance (Diastolic dysfunc- gm/m2) and increased relative wall thickness (>
tion DD) or reduced contractility. Patients with 0.42). The LV concentric hypertrophy is defined
DM present with both phenotypes of heart failure as increased LV mass ( male > 115 gm/m2, fe-
viz. Heart failure with preserved ejection fraction
(HFPEF) and Heart failure with reduced ejection

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male > 95 gm/m2) and increased relative wall Systolic dysfunction:
thickness (> 0.42). Both types are remodelling The 2D echo guided Simpson’s method of sum-
are classified as stage B heart failure with poten- mation of discs and the 3D echo guided semi-au-
tial to progress to clinical heart failure. tomated LV volume calculations are standard
The 3D echocardiography has improved the ac- methods of measurement of LV ejection fraction.
curacy of measurement of LV volume and mass. The reduced LV ejection fraction (EF) is clear in-
The LV concentric remodelling is early sign of dicator of systolic dysfunction and in presence of
structural changes and myocardial energetics heart failure signs and symptoms the patient is
changes4. The hyperinsulinemia and hyperten- classified as HFREF. However, the global longi-
sion cause LV hypertrophy by increasing both tudinal strain (GLS) is more sensitive marker of
myocyte volume and extracellular (interstitial) preclinical LV systolic dysfunction and predates
volume. the fall in LVEF. The abnormal LV GLS ( absolute
values less than -20%) is associated with devel-
Diastolic dysfunction: opment of LV remodelling, clinical HF and mor-
LV diastolic dysfunction (DD) is found in 50% of tality in type 2 DM.
DM patients6. The LV DD is not specific for DM. There are three types of phenotypic clustering of
The co-morbidities like advanced age, hyperten- cardiac function and remodelling in DM:
sion and increased body mass index are also as- Cluster 1 = Men with preserved systolic and dia-
sociated with increasing grades of DD. The DD stolic function
predates systolic dysfunction. However, the sys- Cluster 2 = Obese and hypertensive women with
tolic and diastolic function may not deteriorate in diastolic dysfunction
parallel to the same extent. Cluster 3 = Men with LV hypertrophy and systolic
The DD is assessed by echocardiography on fol- dysfunction
lowing variables: Both cluster 2 and 3 have increased long term
1)Mitral flow Doppler E and A ratio, E decelera- mortality compared to cluster .
tion time
2)Mitral flow E velocity to Mitral annular early Biomarkers:
diastolic relaxation E’ velocity (E/E’), septal and
lateral E’. There are different biomarkers studied in DM for
3)Left atrial volume (LAV) early detection of cardiomyopathy. The clinical
4)Pulmonary arterial systolic pressure by tricus- utility of these markers as screening tests is not
pid regurgitation jet (TR) established. The biomarkers studied in DMCM
The abnormal values for these variables are as are as follows:
follows: Natriuretic peptides
1.Average E/e’ > 14 Circulating microribonucleic acids
2.Septal e’ velocity < 7 cm/s or Lateral e’ velocity O-GlcNAc detected in circulating erythrocytes
<10 cm/s
3.TR velocity > 2.8 m/s Functional and anatomical testing for
4.LA volume index >34ml/m2 CAD:
E/Eʹ at rest is associated with symptomatic heart
failure and mortality8. The increase in E/eʹ during The indications for performing functional stress
diastolic stress test is also associated with ad- testing or computed tomographic coronary angi-
verse cardiac outcome6. The LA dilatation in ography in DM population are similar to general
DMCM reflects increased LV filling pressures guidelines of non-invasive evaluation of isch-
and also LA cardiomyopathy due to LA myocar- emia. The DM patients have higher pre-test prob-
dial fibrosis. The increased LA volume is predic- ability. There is limited accuracy from the stress
tive of future atrial fibrillation and heart failure. electrocardiogram. The stress echocardiography
has high specificity while nuclear scintigraphy
has highest sensitivity. There is limited “warran-
ty” of a negative stress test in DM patients.

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Cardio Diabetes Medicine 2018 73

Imaging targets of research interest: prevention, optimal control of HT and use of pre-
ferred pharmacotherapies (like renin-angioten-
There are several imaging techniques which sin-aldosterone inhibitors, neprilysin inhibitors
give profound insight in to the cellular level alter- and SGLT-2 inhibitors) in diabetics reduce the
ations in diabetic cardiomyopathy. These tech- incidence of CAD and HF
niques are useful for monitoring the favourable
effects of the investigational cardiac drugs in di- References:
abetic patients. The various imaging targets are
as follows: 1.Kannel WB, Hjortland M, Castelli WP. Role of
Microcirculation (Positron emission tomography diabetes in congestive heart failure: the Fram-
or magnetic resonance imaging) ing- ham study. Am J Cardiol 1974;34:29–34.
Myocardial metabolism (Positron emission to-
mography or magnetic resonance spectroscopy) 2.Thomas H. Marwick, MBBS, PHD, MPH, Re-
Quantification of fibrosis (by mapping the T1 re- becca Ritchie, PHD, Jonathan E. Shaw, MB-
laxation profile by magnetic resonance imaging) CHB, MD, David Kaye, MBBS, PHD Implications
of Underlying Mechanisms for the Recognition
The cardiac screening for asymptom- and Management of Diabetic Cardiomyopathy J
atic DM patients: Am Coll Cardiol 2018;71:339–51

The screening of asymptomatic DM patients for 3.Roberto M. Lang, MD, FASE, FESC, Luigi P.
early detection of CAD and DMCM is based on Badano, MD, PhD, FESC, Victor Mor-Avi, PhD,
the hypothetical assumption that cost effective FASE, Jonathan Afilalo, MD, MSc et al Recom-
screening tests for detection of preclinical dis- mendations for Cardiac Chamber Quantification
ease may lead to effective treatment to modify by Echocardiography in Adults: An Update from
the disease process to reduce the morbidity and the American Society of Echocardiography and
mortality. There is no consensus on which group the European Association of Cardiovascular Im-
of diabetics should undergo screening test to in- aging J Am Soc Echocardiogr 2015;28:1-39
crease the yield and how aggressively to treat
them. The cost implications of case finding strat- 4.Levelt E, Mahmod M, Piechnik SK, et al. Re-
egy and the down-stream tests in false positive lationship between left ventricular structural and
cases is unknown. Screening tests can disrup- metabolic remodeling in type 2 diabetes. Diabe-
tively diagnose a healthy individuals as having tes 2016;65:44–52
disease with detrimental social, psychological,
and financial consequences. 5.Jellis C, Wright J, Kennedy D, et al. Associ-
Experts propose that the high risk DM group ation of imaging markers of myocardial fibrosis
for CAD screening may have features like pe- with metabolic and functional disturbances in
ripheral arterial disease, multiple risk factors, early diabetic cardiomyopathy. Circ Cardiovasc
long-standing DM, resting electrocardiography Imaging 2011;4:693–702
abnormalities, and reduced functional capacity.
Similarly, the high risk DM group for LV dysfunc- 6.Holland DJ, Marwick TH, Haluska BA, et al.
tion screening may have features like macro-al- Subclinical LV dysfunction and 10-year outcomes
buminuria16, reduced functional capacity (by the in type 2 diabetes mellitus. Heart 2015;101:
6-min walk), >65 years of age and DM duration 1061–6
>10 years.
Though targeting pharmacotherapy according to 7.Sherif F. Nagueh, Chair, MD, FASE, Otto A.
screening tests appears reasonable, there is no Smiseth, Co-Chair, MD, PhD, Christopher P.
efficacy study to support screening of these as- Appleton, MD, Benjamin F. Byrd, III, MD, FASE
ymptomatic high risk individuals.
Future studies may help us to understand wheth-
er widespread use of statins, aspirin as primary

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Cardio Diabetes Medicine 2018 74

etal Recommendations for the Evaluation of Left
Ventricular Diastolic Function by Echocardiog-
raphy: An Update from the American Society of
Echocardiography and the European Associa-
tion of Cardiovascular Imaging J Am Soc Echo-
cardiogr 2016;29:277-314
8.From AM, Scott CG, Chen HH. The develop-
ment of heart failure in patients with diabetes
mellitus and pre-clinical diastolic dysfunction a
population-based study. J Am Coll Cardiol 2010;
55:300–5.
9.Benjamin EJ, Levy D, Vaziri SM, D’Agostino
RB, Belanger AJ, Wolf PA. Independent risk fac-
tors for atrial fibrillation in a population-based
cohort. The Framingham Heart Study. JAMA
1994;271:840–4
10.Ernande L, Bergerot C, Girerd N, et al. Longi-
tudinal myocardial strain alteration is associated
with left ventricular remodeling in asymptomatic
patients with type 2 diabetes mellitus. J Am Soc
Echocardiogr 2014;27:479–88
11.Ernande L, Audureau E, Jellis CL, et al. Clin-
ical implications of echocardiographic pheno-
types of patients with diabetes mellitus. J Am
Coll Cardiol 2017;70:1704–16

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02 Clinical Presentation

1 Out Patient Hyperglycemia-Dr.D.Selvaraj
2 Hypoglycemia Challenges-Dr.Aarathy Kannan
3 The triad story of T2D variability, hypoglycaemia& clinical outcomes-Dr.ArulPrakash

4 Micro Albumin Marker for CAD- Dr. Mritunjay Kumar
5 GDM is the mother of NCD- Dr.RajivKovil

6 Revisiting Infertility in Diabetes- Dr.Archana

7 The interplay between Obesity, Pregnancy, HTN and Diabetes- Prof. Chandrika
8 Diabetic Renovascular hypertension- Dr.VK. Goyal
9 Ischemic Stroke & Diabetes bad associates-DrAvaisPathan

10 DM and Nervous System- Dr.B.Kannan

11 CV Risk factors in Healthy individuals – Glass Half empty or Half full-DrKaushal Chattra-
pati

12 Genetic Basis for Coexistence of Diabetes Nephropathy and Cardiovascular Complica-
tions – A systemic review - Dr. Vijay Viswanathan

13 Cardio Renal Syndrome- Dr Kannan baba
14 Erectile Dysfunction- A Clue into Heart- Prof Dr Deepak K Jumani

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OUTPATIENT HYPERGLYCEMIC CONTROL

Dr. D. Selvaraj, M.D.,
S.R.R.A. Hospital, Tuticorin

Globally, the prevalent of Type-2 Diabetes has Antihyperglycemic Therapy

been high and is rising across all world regions. Glycemic Target

This rise is likely to fuelled by an ageing pop- • HbA1c <7%

ulation, economic development and increasing • Preprandial PG <130 mg/dl
urbanization, leading to more sedentary life style

and greater consumption of unhealthy food • Postprandial PG <180 mg/dl
linked with obesity. Some 425 million people

world-wide are 8.8% of adults, 20 – 79 years Individualisation is the key

are estimated to have diabetes. The largest in- • Tight targets (6 – 6.5%) younger health-
crease which takes place in regions where eco- ier
nomics are moving from low income to middle

income levels. India is home to the second larg- • Loose targets (7.5 – 8%)- older comor-

est number of adults having with diabetes prev- bidities, hypoglycemia etc.

alence among all ages in this region. The high- • Avoidance of hypoglycemia
est number of people with undiagnosed diabetes

are in the same countries with largest number of Therapeutic Option Life Style:
people with diabetes; China, India and the Unit-

ed States. • Weight optimization

Glycemic control deteriorates over time as ev- • Healthy diet
idenced from UKPDS and ADOPT, where it is • Increase activity level
conventional glibenclamade, metformin or in- Therapeutic Options
sulin. Failure of oral monotherapy is inevitable Oral agents and non-insulin
by three years, more than 45% of patients fail to injectables:
achieve target glycemic control with OAD mono-
therapy. Insulin initiation is delayed in Type 2 DM • Metformin
patients, AND results in less than ideal glyce- • Sulfonylureas
mic control. As a result, many complications are • Thiazolidonediones
partially associated with this delay. In SOLVE, • DPP-4 Inhibitors
this was evidenced in the high base-line HbA1c, • GLP-1 Receptor Agonist
of enrolled patients with a long disease duration • SGLT-2 Inhibitors
(9.8 ± 7 years) and years of OAD therapy (8.5 ±
6.6 years).

• Megletinide

• Alfa glucosidase inhibitor

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• Bileacidasequestant Implementation Strategy
Initial Therapy:
• Dopamine-2 Agonist
• Advancing to dual combination therapy
Therapeutic Option – Insulin • Advancing to triple combination therapy
• Transition to and titration of insulin
• Human Neutral Protamine Hagedorn
(NPH)

• Human Regular

• Basal Analogues (degluded, glargine,
detemer)

• Rapid Analogues (Dispro aspartate,
glulysine)

• Pre-mixed varieties

Healthy eating, weight control, increased physical activity

Initial Drug Monotherapy Metformin

Efficacy ( HbA1c) High

Hypoglycemia Low risk
Weight Neutral/loss
Side effects GI / lactic acidosis
Costs Low

Metformin+ Metformin + Metformin+ Metformin+ Metformin+

Two Drug GLP-1
receptor
Combination Sulfonylurea Thiazoli- DPP-4 agonist Insulin (usually basal)
dinedione Inhibitor

Efficacy ( High High Intermedi- High Highest
HbA1c) ate

Hypoglycemia Moderate risk Low risk Low risk Low risk High risk
Neutral Loss Gain
Weight Gain Gain Rare GI Hypoglycemia
High High Variable
Side effects Hypoglyce- Moderate
mia HF, fx’s

Costs Low High

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Initial Drug Monotherapy Healthy eating, weight control, increased physical
activity

Metformin

Efficacy ( HbA1c) High

Hypoglycemia Low risk

Weight Neutral/loss
Side effects
Costs GI / lactic acidosis

Low

Metformin+ Metformin + Metformin+ Metformin+ Metformin+

Two Drug Com- GLP-1
receptor
bination Sulfonylurea Thiazolidine- DPP-4 agonist Insulin (usually basal)
Highest
dione Inhibitor

Efficacy ( HbA1c) High High Intermedi- High
ate

Hypoglycemia Moderate risk Low risk Low risk Low risk High risk

Weight Gain Gain Neutral Loss Gain
Side effects
Costs Hypoglycemia Moderate HF, Rare GI Hypoglycemia
fx’s High Variable
Three Drug
Cominations Low High High

Metformin+ Metformin + Metformin+ Metformin+ Metformin+

Sulfonylurea Thiazolidine- DPP-4 GLP-1 Insulin (usually basal)
receptor +TZD
dione Inhibitor agonist

+ TZD +SU +SU +SU

Or DPP-4-1 Or DPP 4-1 Or TZD Or TZD Or DPP-4-1

Or GLP-1-RA Or GLP-1-RAOr Insulin Or Insulin Or GLP-1-RA

Or Insulin Or Insulin

More complex Insulin
insulin strategies (Multiply daily doses)

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Other Considerations: • Lipids:
LDL <100 mg/dl -
Age: Older individuals have reduced life expec- < 70 mg/dl with overt CVD
HDL > More than 40 mg/dl
tancy, higher CVD burden, reduced GFR at risk More than 50 mg/dl
of adverse events for poly pharmacy and ;more TGL < 150 mg/dl
likely to be compromised from hyperglycemia,
for these patients focus must be on drug safety When and how to initiate Insulin?
and HbA1C target must be little lower between
7.5 and 8%. The inclusion of a third drug to antidiabetic thera-
py can be substituted by initiation of insulin ther-
Weight: apy, the choice of which insulin therapy should
to use, should be made after taking into account
Majority of Type-2 patients are overweight or the glycemic problem of the individual patient,
obese and intense life style programme should that is, whether the hyperglycemia is predomi-
be implemented on these patients. Metformin nantly fasting or postprandial. Therapy with in-
should be primary drug and GLP-1 receptor ag- sulin should be initiated unless contra-indicated.
onist should be advised. For selected patients,
bariatric surgery should be advised. When to initiate?

Co-morbid Conditions: At diagnosis, consider insulin therapy if
- HbA1C more than 10%
CAD: Metformin may be useful unless con-
- Markedly symptomatic
tra-indicated.
- Blood Glucose level more than 300 mg/dl
Heart failure: Increased risk of hypoglycemia Second Line:
- Basal insulin can be considered after Met-
stop Metformin if eGFR goes below 30 ml.
formin failure
Renal Disease: Hypoglycemia must be taken
care of. Most of the drugs are contra-indicated if How to initiate:
eGFR goes below 30 ml.
Recommends to initiate with basal insulin at 10
Liver Dysfunction: Most drugs are not test- units or 0.2 to 0.3 units per kg.

ed in advanced liver disease. Insulin is the best
option if disease is severe.

Hypoglycemia: Proper drug selection is the When to intensify?

key in the patients prone to hypoglycemia. - If HbA1C is not controlled with basal insulin.

Guidelines for Glucose DP and Lipid - Add rapid acting insulin before largest meal
or
Control

• HbA1C less than 7% - Change to premixed insulin twice daily.

• Preprandial glucose 70 – 130 mg/dl How to intensify:

- Bolus: Start 4 units / .1 unit per kg or 10%

• Postprandial glucose less than 180 ;mg/dl of basal dose. If HbA1C is; less than 8, consider

basal reduction by same amount.
• Blood pressure less than 130/80 mm of

Hg - Pre-mixed: Divide current basal dose into

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Cardio Diabetes Medicine 2018 80

2/3rd AM and 1/3rd PM, or ½ AM or ½ PM. How to initiate and intensify?

If glycemic target is not achieved - A basal insulin, one dose daily, or once daily
premixed insulin
- Change to basal – bolus or

- Premixed analogue 3 times daily. - Shift to basal bolus if not controlled

• Consider insulin if Which insulin to use?

- Entry A1C > 9, especially if symptomatic. - Basal

- Early A1C < 7.5 as part of dual/triple; therapy. - Premix

Initiation of insulin in recently detect- - Basal bolus

ed patient: Summarize…

Symptomatic and having one of the following: - Insulin is a time tested drug with ;long time
- HbA1C more than 9% safety and efficacy

- FBS more than 250 mg/dl - Do not delay initiation of insulin

- PPBS more than 300 mg/dl - Address patients issue with insulin

- Ketone positive. - Individualise the treatment

Initiation of Insulin in Type-2 diabetic patients - Never hesitate to recommend early insulin
initiation in Type-2 diabetic patients with
with already established diagnosis if trial of

adequate dose of three noninsulin agents for - HbA1C more than 9 at diagnosis
6 – 9 months, fail to achieve HbA1C to target - Past increase of HbA1C after diagnosis
level addition of insulin may be justified.

- If a patient is already on two or more - Multiple infections
agents, continue to have HbA1C in excess of;
9% insulin; may be initiated even if the patient is - HbA1C more than 7% despite mono/
asymptomatic. dual/triple therapy and disease related
complications.
When to initiate?

- As third line after combination of two agents
fail,

- Recommend not to unduly delay commence-
ment of insulin

- Recommends to explain to the person with
diabetes from the time of diagnosis that insu-
lin is the one of the options available.

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Cardio Diabetes Medicine 2018 81

HYPOGLYCEMIA CHALLENGES

Dr. Aarathy Kannan, Md,Dip.diab

Consultant Physician & Diabetologist

Sundarm Arulrhaj Hospitals, Tuticorin

Co-Author : Dr Gurunadharao, DNB Resident

Introduction: appropriate treatment regimen selection and
educational programs for diabetic patients are
India is the capital for Diabetes mellitus. Due some of the major ways to maintain adequate
to newer drugs and intensive glycemic control glycemic control with less risk of hypoglycemia
causes frequent hypoglycaemia in Diabetes and thereby prevent long-term complications.
mellitus. There is an increase of about six folds
death rate due to diabetes has been attributed Definition & Classification :
to patients experiencing severe hypoglycemia
in comparison to those not experiencing severe According to American Diabetes Association
hypoglycaemia . According to UKPDS 0.7 % per 2018 Hypoglycemia is defined as a blood glu-
year of patients taking a sulfonylurea and 2.3% cose less than 70 mg/dL(2). Classically hypogly-
per year of those using insulin experienced se- cemia is identified by Whipple’s triad comprising
vere hypoglycemia. There is acute need to ex- (a) clinical features consistent with hypogly-
amine the clinical spectrum and burden of hypo- cemia, (b) a low plasma glucose level and (c)
glycemia in order to implement adequate control correction of these following elevation of plasma
measures against this life-threatening complica- glucose by intervention.
tion. Early recognition of hypoglycemia & its risk Hypoglycemia in Diabetes can be classified ac-
factors, regular self-monitoring of blood glucose, cording to ADA 2018as follows :(Table 1 )

Table 1 Classification of Hypoglycemia

Level Glycemic Cri- Description
teria

Hypoglycemia alert value ≤70 mg/dL Needs treatment with fast-acting carbohydrate
(level 1) and dose adjustment of glucose-lowering therapy

Clinically significant <54 mg/dL Significantly low to cause serious, clinically
hypoglycaemia (level 2) important hypoglycaemia

Severe hypoglycaemia No specific Associated with severe cognitive impairment &
(level 3) glucose needs external assistance for recovery
threshold

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HYPOGLYCAMIA AND ITS • Presumably caused by a plasma glucose

CONSEQUENCES concentration less than 70mg/dL

Defining Hypoglycemia in diabetes Pseudo – hypoglycemia

Severe hypoglycemia

Requiring assistance of another person to • Any of the typical symptoms of hypoglyce-

actively administer carbohydrates, glucagon, or mia is reported

take other corrective actions • Measured plasma glucose concentration
more than 70 mg/dL but approaching that
Documented symptomatic
hypoglycemia level.

• Typical symptoms of hypoglycemia present • Reactive Hypoglycemia: This is occur-
rence of hypoglycaemia after 3-5 hours after
• Measured plasma glucose concentration a rich meal due to inappropriate secretion
less than 70 mg/dL of insulin in persons whose fasting sugars
were in normal range. This type of hypo-
Asymptomatic hypoglycemia glycaemia also seen in cases of post-gas-
trostomy, gastrojejunostomy, pyloroplasty
• Typical symptoms of hypoglycemia absent or vagotomy. This type of hypoglycaemia is
• Measured plasma glucose concentration also called as Elementary Hypoglycemia or

less than 70 mg/dL HyEpleomgelyntcaerymHiyapCerliinnsiuclianel mSiiag.ns &

Symptoms:

Probable symptomatic hypoglycemia Hypoglycemic sym0ptoms produced early by

• Symptoms typical of hypoglycemia are not Adrenergic features later by neurogenic fea-
accompanied by a plasma glucose determi- tures. Both symptoms are depicted in Table-2

nation

Table-2 : Signs and Symptoms of Hypoglycemia(1)

Adrenergic Symptoms Neuroglycopenic Signs

• Diaphoresis • Confusion
• Pallor Diplopia
• Tachycardia
• Shakiness • Irrational or uncontrolled behaviour
• Hunger Blurred vision
• Irritability
• Anxiety • Slurred speech
• Giddiness Lethargy
• Headache
• Weakness • Extreme fatigue
• Tremulousness Headach
• Nervousness Inability to concentrate
• Palpitation Loss of memory
Motor incordination
Sensory dysfunction

• Disorientation
• Seizures
• Pupillary sluggishness
• Loss of consciousness
• Decreased response to noxious stimuli

Coma

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Physiology of Hypoglycemia : (Flow When the plasma glucose level reaches about
54 - 63 mg/dl , it immediately triggers central ner-
chart 1& Figure 2 )(7,8,9,10) vous system (CNS) mediated autonomic warn-
In the non-diabetic individual, decreased ing symptoms such as hunger, palpitations and
sweating, all of which are subjective awareness
blood glucose levels will trigger a characteris- symptoms of hypoglycaemia. These symptoms
tic and systematically organised sequence of will provoke eating behaviour of the individual
responses .When blood glucose reaches below and will be the last resort before development of
80mg/dl insulin secretion will be suppressed neuroglycopenia and declining cognitive function
which causes peripheral reduction of glucose , both of which reflect CNS glucose deprivation .
uptake along with increased hepatic glucose The level of blood glucose at which these coun-
production, which prevents further fall in blood terregulatory responses to hypoglycaemia occur
sugar. In addition, the fall in intra-islet insulin is referred to as glycaemic thresholds, but still
level leads to the glucagon response to hypo- they may be altered to a higher glucose level
glycaemia by stimulating its suppressive effect following chronic hyperglycaemia or to a lower
on pancreatic alpha-cells, thus causing gluca- glucose level following repeated hypoglycaemia.
gon release. The release of both glucagon and With increase in age the magnitude of counter-
adrenaline is triggered when plasma glucose regulatory function tend to decrease and is more
levels fall below ~ 70 mg/dl . They promote pro- prominent in men compared to (premenopausal)
duction of glucose in the liver by stimulation of women.
glycogenolysis and gluconeogenesis. In addition The further decrease in blood sugar causes
to this, adrenaline also inhibits peripheral glu- neuroglycopenic symptoms because decreased
cose uptake and playing a role in mobilisation of blood sugar causes certain brain region to pro-
gluconeogenic precursors. Cortisol and growth duce symptoms.
hormone are released in response to prolonged
hypoglycaemia, but they have a low significance
for acute glucose counterregulation.

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Figure 2 : Metabolic Arrangements during hypoglycemia

Risk factors of Hypoglycemia in DM • Gastroparesis due to autonomic neuropathy
patients • Drug Interactions:

• Insulin excess – (endogenous secretion or • With sulfonylureas, repaglinide, and

to exogenous doses) nateglinide, particularly if the patient is

• Missed / delayed or inadequate meals elderly (occurs more frequently with the

• Changing exercise routines (increased pe- use of long-acting sulfonylureas)

ripheral glucose uptake) • medications that alter metabolism of

• Erors in OHA or Insulin dose /schedule/ the sulfonylureas (eg, phenylbutazone,

administration sulfonamides, or warfarin).

• Poorly designed insulin regimen • Kidney or Liver disease

• Strict glycemic control • Increasing duration of diabetes- prone for
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Hypoglycemia Unawareness Potential Complications of

• Impaired glucose absorption Hypoglycemia- The major Challenges

• First Trimester of Pregnancy 1. Cardiovascular Risk
2. HAAF
• Lipodystrophy at insulin site causing varying 3. Neurocognitive Dysfunction
4. Beta Cell Mass
insulin absorption 5. Hypothermia
6. Weight Gain
Risk factors of Hypoglycemia in non 7. Quality of Life
DM patients 8. Physical Injuries
9. Hypoglycemic Emergencies
• Extremes of age ( children & old age )
• Drinking too much alcohol Hypoglycemia effect on CV events:
• Kidney or Liver disease
• Sepsis In the ACCORD study and VADT, a clear asso-
• Addisions disease ciation between severe hypoglycemia and CV
• Insulinomas events found( although no cause effect- rela-
• Celiac disease tionship was proven). Hence avoidance of hy-
• Drug induced : pentamidine, NSAIDS, clo- poglycemia is of very important consideration.

fibrate and rifampicin etc
• Genetic : Fructose intolerance/Galactose-

mia/ Lucin sensitivity

CV effects of Hypoglycemia
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CV effects of Hypoglycemia portance in healthy people but may have dan-
gerous consequences in patients with DM, many
Hemodynamic Effects of of whom have coronary heart disease and car-
Hypoglycemia : diac dysfunction. In nondiabetic individuals, the

Hypoglycemia causes pronounced physiological arteries become more elastic during acute hypo-
and pathophysiological effects on the CV system glycemia with a decline in arterial wall stiffness,
as consequences of autonomic system (princi- but in diabetic patients with a duration more than
pally of the sympathoadrenal system) activation 15 years, arterial wall stiffness is greater and ar-
and counter regulatory hormones (principally of teries are less elastic in response to hypoglyce-
epinephrine) release. These effects provoke a mia, manifesting in a lesser fall in central arterial
series of hemodynamic changes which include: pressure.
(1) increased heart rate, (2) increased myocar-
dial contractility, and (3) decreased peripheral Electrophysiological Effects of
arterial resistance . Such hemodynamic chang- Hypoglycemia.
es will cause an increase in cardiac output and
peripheral systolic blood pressure, a decrease in QT prolongation and ST segment depression
central blood pressure, and a widening of pulse were also observed in both insulin-induced and
pressure. The most important consequences of spontaneous hypoglycemia. However, insu-
the above effects are to maintain the supply of lin-induced hypoglycemia may provoke a more
glucose to the brain and heart and to promote the intense sympathoadrenal response and larger
hepatic production of glucose. The rise in heart increases in QT interval. Lengthened QT interval
rate and systolic blood pressure, also it could reflects abnormal cardiac repolarization which
prevent the fall in diastolic blood pressure asso- may be associated with atrial or ventricular
ciated with hypoglycemia.36 Further research tachycardia. Electrophysiological changes are
showed that the rise in heart rate was mediated partially related to hypokalemia. It was shown
via b1 adrenoceptors, while the blood pressure that hypoglycemia induces a fall in serum potas-
changes were mediated via a and b2 adreno- sium via epinephrine release and a direct effect
ceptors. Total peripheral vascular resistance as of insulin. Insulin and epinephrine stimulate NAþ/
well as lower extremity vascular resistance de- Kþ ATPase function that results in a fall of potas-
creased, whereas hepatosplanchnic vascular sium concentration in extracellular fluid leading
resistance was unaffected. The ejection fraction to hypopotassemia. A fall in extracellular potas-
subsequently rose to a peak of 72% coinciding sium concentrations alters the cell’s ionic bal-
with the onset of the acute hypoglycemic reac- ance and prolongs repolarization rate, illustrated
tion. This corresponded to the nadir of blood glu- by the flattered T wave. Heller and coworkers
cose and was associated with rises in heart rate, reported that experimental hypoglycemia was
stroke volume, and cardiac output. The heart associated with significant lengthening of the
rate returned to the resting value within 30 min- QT interval in individuals with and without dia-
utes of the acute hypoglycemic reaction, but the betes. Thereafter, they measured cardiac repo-
ejection fraction, stroke volume, and cardiac out- larization (QT interval [QTc] and QT dispersion
put were still elevated 90 minutes later. The peak [QTd]) during insulin-induced hypoglycemia with
ejection fraction value immediately preceded the and without b-blockade and potassium infusion
maximal increment of plasma catecholamines to establish possible mechanisms . They found
released in response to hypoglycemia. Rise in that QTd was unchanged during euglycemia but
left ventricular ejection fraction due to sympath- increased during hypoglycemia, which was pre-
oadrenal activation. The workload of the heart vented by potassium. QTc increased significantly
is therefore temporarily but markedly increased, during hypoglycemia alone and during potassium
which is unlikely to be of serious functional im- replacement. Interestingly, the increase in QTd/

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QTc during hypoglycemia were both prevented of the proinflammatory cytokine interleukin (IL)
by selective b-blockade. 6, and this was confirmed along with additional
inflammatory cytokines, including tumor necrosis
Prothrombotic Effects of factor a, IL-1b, and IL-8. In addition, increases
Hypoglycemia in both serum tissue plasminogen activator and
aldosterone have been reported under hypogly-
Hypoglycemia is accompanied by a significant cemic conditions, indicating that hypoglycemia
enhancement of platelet aggregation, decreased provoked endothelial dysfunction. Repeated ep-
platelet counts and activated partial thrombo- isodes of hypoglycemia may activate more se-
plastin time, and increased fibrinogen and fac- vere/prolonged inflammation, oxidative stress,
tor VIII. More recently, it was confirmed that hy- and endothelial dysfunction. More recently, the
poglycemia promoted platelet activation, which effects of both acute hyperglycemia and hypo-
was measured via increased platelet–monocyte glycemia in type 1 DM, with or without the simul-
aggregation and soluble P-selectin levels as well taneous infusion of glucagon-like peptide 1, on
as increased plasminogen activator inhibitor 1 oxidative stress (plasma nitrotyrosine and plas-
levels. Gajos et al investigated the effect of low ma 8-iso prostaglandin F2a), inflammation (solu-
blood glucose on thrombin generation and fibrin ble ICAM and IL-6), and endothelial dysfunction
clot properties in type 2 DM. They found that pa- have been evaluated.After 2 hours of hypogly-
tients with low glycemia (<4.5mmol/l)had lower cemia, flow-mediated dilation significantly de-
plasma fibrin clot permeation (Ks), prolonged creased, whereas oxidative stress significantly
fibrinolysis including clot lysis time (t50%), and increased compared with basal values. When
higher peak thrombin generation. Only in patients hypoglycemia was accompanied by the simul-
with HbA1c enhanced thrombin formation and taneous infusion of glucagon-like peptide 1, all
formation of denser fibrin clots displaying lower these phenomena were significantly attenuat-
lysability, especially when strict glycemia control ed; flow-mediated dilation decreased less, and
was achieved (HbA1c) Hypoglycemia induced oxidative stress was not as increased. In addi-
alterations in these coagulation cascade-relat- tion, the increases in adhesion markers (ICAM,
ed factors could have severe effects on the CV VCAM, E-selectin, etc) might contribute to leu-
system, contributing to the occurrence of major kocyte binding to injured endothelial cells, con-
vascular events such as myocardial infarction or stituting a primary step in plaque formation and
stroke. subsequent atherosclerosis.

Proinflammatory and Atherogenic Ef- 2. HAAF :
fects of Hypoglycemia
Hypoglycemia unawareness (HU) is defined as
Although the effects are transient and unlike- the onset of neuroglycopenia symptoms before
ly to exert any long-term consequences on the the appearance of autonomic warning symptoms.
CV system, there is growing concern about its In normal individuals Adrenergic symptoms pre-
long-term effects, especially inflammation and ceeds the onset of neuroglycopenic symptoms,
the related atherogenesis . Under acute insu- because of which the patient perceives hypogly-
lin induced hypoglycemia, patients with type 1 caemia and acts accordingly like taking some
DM not only demonstrated an increase in both carbohydrates etc. But in case of hypoglycaemia
CD40 expression on monocytes and plasma Unawareness the patient can’t perceives the ad-
sCD40L concentrations but also upregulation of renergic symptoms and will directly land into
intercellular adhesion molecule (ICAM), vascu- neuroglycopenia symptoms.
lar cell adhesion molecule (VCAM), E-selectin,
and vascular endothelial growth factor (VEGF),
indicating an inflammatory response. Additional-
ly, hypoglycemia led to increased serum levels

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It will be seen more likely in individuals with ply by systemic hypoglycemia produces marked
• - Longer duration of DM cognitive impairment and leads eventually to
coma and death. In repeated severe hypoglyce-
• Advanced age mia causes both significant neuronal death and
cognitive impairment .According to a sub study
• - History of recent/recurrent hypoglycecmia of the ACCORD trail cognitive impairment at
baseline or decline in cognitive function during
• - Intensive glycemic therapy. the trail was significantly associated with subse-
quent episodes of severe hypoglycemia.
It can be reversed by keeping glucose levels 1. Acute hypoglycaemia produces cognitive
high for a period of several weeks.
impairment . Following cognitive domains
3. Neurocognitive Dysfunction are predominantly affected- Memory, Atten-
tion span, information processing , psycho-
Human brain runs on glucose in contrast to cells motor function and spatial ability, which are
elsewhere, which will generally take their fuel controlled by temporal lobe and its connec-
where they can find it, neurons and glia both rely tions. The cognitive impairment is reversible
on a constant supply of glucose from blood for provided hypoglycaemia to be corrected im-
their metabolic support (with some of that glu- mediately and full recovery will take upto an
cose being metabolised by astrocytes into lac- hour.
tate which is then exported for subsequent use 2. Repeated severe hypoglycaemia causes sig-
by neurons).So acute interruption of this sup-

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nificant neuronal loss and permanent cogni- compensatory mechanism in severe hy-

tive impairment. poglycaemia, reflecting a decrease in en-

3. Chronic hypoglycaemia will cause permanent ergy demand during glucose deprivation.

cognitive impairment especially in learning

and memory. 7. Weight Gain

4. Dementia : Severe hypogycemia leads to fo- • Repeated iatrogenic  hypoglycemia  leads

cal neurological deficit/ TIA leads to neuronal to weight gain, and that such weight gain is

cell death which leads to Dementia. associated with a multifaceted deficit in met-

abolic regulation rather than to a chronic in-

4. Brain Oxidative Metabolism crease in caloric intake.

This increase was mainly attributable • Insulin treatment also causes a significant

to: effect of increase in both body weight and

• higher neuronal glucose oxidation, sug- fat mass.

gesting that when glucose is present in 8. Quality of Life

sufficient amounts, neurons are better able • Poorer QoL leading to increases in anxiety,

to use glucose. depression, healthcare utilization, cost, and

• Decrease in brain glucose consumption in poor adherence to treatment

neurons and astroglia (in 3dRH animals) 9. Injuries

vs preserved neuronal glucose metabolism At risk for fall-related fractures

in control animals under standardized rel- Motor vehicle accidents

atively severe hypoglycemic conditions 1. Emergencies

Hypoglycemia emergencies are three times

5. Beta Cell Mass more frequent in diabetic individuals aged ≥75

Reduced VEGF-A years compared to those 45-74 years old

• Secretion of VEGF-A, but not VEGF-A Nocturnal Hypoglycemia:

gene transcription, in either cultured is- It is mainly due to lack of effective, constant bas-

lets or purified pancreatic beta cells, was al supply of insulin combined with long periods

significantly reduced early on during low of fasting in between meals. Also physiological

glucose conditions, leading in a significant defences to hypoglycemia diminish by lying flat

reduction in beta cell mas and sympathoadrenal responses are inhabited

Increased Apoptotic Endothelial Cells: by slow wave sleep.

• increase in apoptotic endothelial cells Suspect that the patient has nocturnal hypogly-

during hypoglycemia preceded an increase cemia if he or she has early morning symptoms,

in apoptotic beta cell mass severe night time reactions or the somogyi syn-

Average islet size was also reduced in drome.

Hypoglycemia Management:

Both endothelial and beta cell apoptosis were The management of nocturnal hypoglycemia is

prevented by exogenous VEGF-A, suggesting a - Measurement of 3 am blood sugar

possible causative relationship between reduced - Bedtime snacks
VEGF-A and the loss of islet vasculature and

beta cells. - Reduction of night dose of insulin

6. Hypothermia

• Hypothermia is a recognized complication of - Giving night dose of insulin before

severe hypoglycaemia bed time

• Hypothermia is a marker of hypoglycaemia - Relaxing control, especially of fasting
severity and/or duration, which is suggested blood sugar levels
by:

• Associations between hypothermia and

the GCS score and the leukocyte count

• Hypothermia may represent anCiamrdpioortDainatbetes Medicine

Cardio Diabetes Medicine 2018 90

Impact of Hypoglycemia on the Elder- tinued
ly- A major challenge • Complex regimens requiring multiple deci-

• Patients with T 2 DM tend to have longer sion points should be simplified
hospital stays & greater medical costs • Caregivers & staff in long-term care facilities

• Age-related declines in renal function & he- • Need to be educated on the causes &
patic enzyme activity risks of hypoglycemia & the proper sur-
veillance & treatment of this condition
• Interfere with the metabolism of sulfony-
lureas & insulin which increases their hypo- Treatment of Hypoglycaemia: Evi-
glycemic effects dence suggests

• Vulnerability of the elderly to severe hypo- Increase in Within
glycemia BG (Time)

• Partially related to a progressive age-related 15 g Glucose 37.83 mg/dl 20 min
decrease in Beta-adrenergic receptor func-
tion 20 g Glucose 64.8 mg / dl 45 min

• Age-related impairment in counterregulatory 1 mg Gluca- 54 to 216 mg/ 60 min
hormone responses gon dl

• Glucagon response to hypoglycemia is virtu- Recommendation: American Diabetes
ally absent
Association
• Intensification of glycemic control in the
elderly patient For conscious patient : Oral glucose 15-20
gm or any glucose containing carbohydrate and
• Associated with an increased reduction in repeat the glucose measurement 10-15 min lat-
the plasma glucose thresholds to epineph- er, repeat it for 3 times. Once glucose returns to
rine release and appearance of hypoglyce- normal the individual should conume a meal or
mia snack to prevent recurrence of hypoglycemia.
For Unconcious patient : IV administration of
• Older adults with diabetes 50-100mlof 25% Dextrose needed. Glucagon
• Higher risk for the geriatric syndrome, which should be prescribed for all individuals at signifi-
cant risk of severe hypoglycemia. An initial IM or
includes falls, incontinence, frailty, cognitive SC dose of 0.5mg, it can be repeated if there is
impairment & depressive symptoms no symptomatic improvement.
• Cognitive & executive dysfunction with the geri-
atric syndrome I(14.4pt)cemia by the clinician , patient, and

• Interferes with the patient’s ability to caregivers if low cognition and / or declining cog-
perform self-care activities appropri-
ately and follow the treatment regi- nition is found.
men Management of Other forms of Hypoglyce-
mia :
• Assess the elderly for functional status as
part of the overall clinical assessment 1. Hormone replacement in patients with defi-
• To properly apply individualized glyce- ciency of counter regulatory hormones.
mic control goals
2. Reactive hypoglycemia and pseudo hypo-
Impact of Hypoglycemia on the Elderly glycemia –
• Arbitrary short-acting insulin sliding
scales should be avoided i. dietary adjustment

• Careful education regarding the symp-
toms and treatment of hypoglycemia, with regu-
lar reinforcement, is extremely important

• To minimize the risk of hypoglycemia in
the elderly Glyburide should be discon-

a. Avoidance of prolonged fasting or

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Cardio Diabetes Medicine 2018 91

simple sugar consumption reaction
• Access to providers for purposes of
b. Restriction of calory intake,
Reduction of meal size, fre- reporting results and for providing
quent and small feeding, guidance
consumption of high protein • Provider reaction to results increases
and low carbohydrate diet high effectiveness of SMBG
in fibre 4. Hold a High Index of Suspicion for
Hypoglycemia
ii. A small dose of beta adrenergic • Understand patients may not report
blockers “typical” symptoms
• When hypoglycemia is suspected,
3. Intolerance to fructose and galactose- adjust therapy
Avoid foods high in these sugars. • Consider use of continuous glucose
monitoring to detect unrecognized
Intolerance to leucine – A diet deprived of hypoglycemia
milk ( a rich source of leucine) to prevent 5. Clinical surveillance
the possibility of precocious brain dam-
age. 6. Adjustment of medication

Hypoglycemia Prevention 7. Always carry sugar, candy etc

1. Set Appropriate Glycemic Targets: 8. Always carry an Identification card

• Appraise individual patient characteris- Summary:
tics
• Hypoglycemia begets hypoglycemia – a
• More stringent goals: young, newly major challenge
diagnosed, no comorbidities, no micro
or macrovascular disease, strong and • Hypoglycemia continues to cause consider-
effective self-care skills able morbidity and mortality in patients with
diabetes.
• Less stringent goals: older, limited life
expectancy, history of hypoglycemia, • For more episodes , ingestion of 15 gms
longer disease duration, established of carbohydrate is sufficient to reverse the
comorbidities, established vascular hypoglycemia.
disease, limited self-care skills
• Hypoglycaemia is associated with a higher
2. Educate Patients: risk of CVD events in diabetes patients
• Recognition of the signs & symptoms
of hypoglycemia • Physicians have the responsibility to edu-
• Dietary education for improved glyce- cate the diabetes patients about hypogly-
mic control and appreciation of triggers caemia.
for hypoglycemia
• Avoiding missed or delayed meals • Physicians and patients must attempt to
• Appropriate self-treatment achieve an optimal balance between attain-
• Hypoglycemia unawareness ment of good glycaemic control and the risk
• Importance of reporting hypoglycemia of hypoglycaemia.

3. Use Self-Monitoring of Blood Glucose • Elderly patients to be handled with care and
• Patient education: technique and treatment should be individualised.
action
Consequences in Clinical Practice:
• Observing patient’s procedure and
Fear of hypoglycemia often leads to poor com-
pliance. Consequently failure to achieve desired
target A1c level.
• Physicians and patients express fear of

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hypoglycemia, which may impede effective 9. Janice Jin Hwang , Rajita Sinha, Robert Sher-
diabetes management. win , Hypoglycemia unawareness in type 1
diabetes suppresses brain responses to hy-
• To avoid hypoglycemia, some patients inten- poglycaemia
tionally maintain a state of hyperglycaemia.
10. Mechanisms of hypoglycemia unawareness
• Fear of hypoclycemia extends to family and implications in diabetic patients DOI:
members. 10.4239/wjd.v6.i7.912, World J Diabetes
2015 July 10; 6(7): 912-926, ISSN 1948-
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Long-term effects of neonatal hypoglycemia
4. Marisa E Desimone, M.D. and Ruth S Wein- on brain growth and psychomotor develop-
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Glucose concentrations of less than 3.0 ert Sherwin J Clin Invest Hypoglycemia un-
mmol/L (54 mg/dL) should be reported in clin- awareness in type 1 diabetes suppresses
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6. Kathryn Evans Kreider . Katherine Pereira . 14. Evita C Wiegers* Kirsten M Becker* Hanne
Blanca I. Padilla, Practical Approaches to Di- M Rooijackers ,Cerebral blood flow response
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Cardio Diabetes Medicine 2018 93

ERECTILE DYSFUNCTION- A CLUE INTO HEART.

Prof Dr Deepak K Jumani,
Senior Sexual health Physician and Counselor
Asst Prof of Medicine (Sexual Health) Sir JJ Group of Hospitals and Grant Govt

Medical College, Mumbai.

Evidence is accumulating to consider Erec- the diagnosis of DM alone places a patient in a
tile Dysfunction. (ED) as a vascular disorder. high-risk category alongside patients with estab-
Common risk factors for atherosclerosis are lished CAD. In fact has been recognized by the
frequently found in association with ED, and American Heart Association, which established
ED is frequently reported in vascular syn- diabetes as a major cardiovascular risk factor in
dromes, such as coronary artery disease addition to other traditional risk factors is effect
(CAD), hypertension, cerebrovascular dis- of DM is not limited to the incidence of CAD but
ease, peripheral arterial disease, and diabe- persists following an acute coronary event as
tes mellitus. Finally, similar early impairment well.
of endothelium-dependent vasodilatation
and late obstructive vascular changes has Health care providers are now focused on de-
been re- ported in both ED and other vascu- creasing cardiovascular risk in patients with dia-
lar syndromes. betes by treating dyslipidemia and hypertension
and by improving glycemic control.Moreover, the
According to IDF (International diabetes Feder- American Diabetes Association/American Col-
ation) Every 6 seconds one person dies of dia- lege of Cardiology “Make the Link” public aware-
betes and in the same 6 seconds two patients ness campaign has improved knowledge related
develop Diabetes. Of the 417 million diabetics to CVD in patients with diabetes.
across the globe, one third of these diabetics are
in India either in diabetic or prediabetic state, in- Today there is enough scientific wisdom in this
fact India is the diabetes capital of the world and field, from defects in the large blood vessels
is closely competing with China, So China and (macrovasculature) and the small blood vessel
India (Chindia) are the Diabetes Capital of the (microvasculature) to the less well understood
world. The most common complication of Type 2 cellular and molecular mechanisms of CVD in
diabetic men is Erectile Dysfunction. So Chindia patients with diabetes. Atherosclerosis is the
are the Erectile Dysfunction Capital of the world. major threat to the macrovasculature for patients
with and without diabetes. Clinically, dyslipidemia
Diabetes also is a prime risk factor for cardio- is highly correlated with atherosclerosis, and up
vascular disease (CVD). Hyperglycaemia which to 97% of patients with diabetes have raised tri-
is the hallmark of Diabetes results in myocardial glycerides, reduced HDL and raised LDL. In dia-
damage after ischemic events. Cardiovascular betes, the predominant form of LDL cholesterol
disease accounted for 52% of the deaths among is the small, dense form. Small LDL particles are
patients with diabetes in the World Health Orga- more atherogenic than large LDL particles be-
nization multinational study, while data from the cause they can more easily penetrate and form
National Health and Nutrition Examination Sur- stronger attachments to the arterial wall and they
vey (NHANES) showed a rate of 69.5%. In fact, are more susceptible to oxidation. The oxidised
the risk of an acute coronary event in a patient LDL is proatherogenic and initiates several ab-
with DM (type 1 or type 2), with no prior cardiac normal bio- logical responses, such as attracting
history, is similar to that of patients without di- leukocytes to the intima of the vessel, improving
abetes but with established CAD.is means that the ability of the leukocytes to ingest lipids and

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differentiate into foam cells, and stimulating the the factor that initially increases cardiovascular
proliferation of leukocytes, endothelial cells, and risk in these disease processes-.
smooth muscle cells, all of which are steps in the
formation of atherosclerotic plaque. Also Glyca- Researchers have found a reduced production
tion of LDL particles lengthens its half life and of the potent vasodilator NO and an increased
increases the ability of LDL to promote more ath- secretion of the vasoconstrictor and growth fac-
erogenesis and Paradoxically glycation of HDL tor endothelin-1 in subjects with the metabol-
shortens its half life making it less protective ic syndrome, and these abnormalities not only
against atherogenesis. Hypertriglyceridemia can enhance vasoconstriction, but are associated
lead to increased production of the small, dense with the release of pro-inflammatory cytokines.
form of LDL and to decreased HDL transport of Pro-inflammatory cytokines cause or exacerbate
cholesterol back to the liver. injury by a variety of mechanisms including en-
hanced vascular permeability, programmed cell
Diabetes decreases NO bioavailability because death (apoptosis), recruitment of invasive leu-
of either insulin deficiency or defective insulin kocytes, and the promotion of reactive oxygen
signaling (insulin resistance) in endothelial cells. species (ROS) production.
Hyperglycemia also acutely inhibits the produc-
tion of NO in arterial endothelial cells. Capillary The first defence against a thrombotic event
basement membrane thickening associated with is the vascular endothelium. Diabetes contrib-
prolonged hyperglycemia is a structural hallmark utes to widespread endothelial dysfunction.
of diabetic microvascular disease. Thickening Patients with diabetes exhibit enhanced ac-
of the basement membrane impairs the amount tivation of platelets and clotting factors in the
and selectivity of transport of metabolic products blood. Increased circulating platelet aggregates,
and nutrients between the circulation and the tis- increased platelet aggregation in response to
sue. In fact, in skeletal muscle of patients with platelet agonists, and the presence of higher
type 2 diabetes, exercise-stimulated oxygen de- plasma levels of platelet coagulation products,
livery from the capillaries is delayed, which may such as beta-thromboglobulin, platelet factor 4,
account in part for the poor exercise tolerance and thromboxane B, demonstrate platelet hyper-
found in people with type 2 diabetes. activity in diabetes.

The basement membrane thickening increas- Myocardial damage in the absence of CAD
es microvascular permeability because of al- (macrovascular) is most likely related to micro-
terations in the physical dimensions of the vascular dysfunction. Microvascular damage in
meshwork and changes in the normal electrical the diabetic heart may lead to the myocardial
charge surrounding the pores between endothe- injury, fibrosis, and hypertrophy found in diabet-
lial cells. These abnormalities allow for the trans- ic cardiomyopathy. In type 1 diabetic patients
port of large molecules normally excluded from without CAD, impaired coronary flow reserve
passage across the microvasculature. In clinical (dependent on the microvasculature) predicts
terms, transcapillary leak of albumin in the kid- diastolic dysfunction and may be related to au-
ney provides an important indicator of microvas- tonomic neuropathy. Microvascular disease, in-
cular disease. cluding endothelial dysfunction caused by DAN(
Diabetic Auto Neuropathy) and decreased NO
Diabetes has long been considered a state of bioavailability is of crucial importance.
chronic, low-level inflammation, and there is
some evidence to suggest that this immune acti- Diabetes has been associated with sexual dys-
vation may pre- cede insulin resistance in diabet- function both in men and in women. Diabetes is
ic and pre-diabetic states and ultimately may be an established risk factor for sexual dysfunction
in men; a threefold increased risk of erectile dys-

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Cardio Diabetes Medicine 2018 95

function (ED) was documented in diabetic com-
pared with nondiabetic men. Among women, the
evidence regarding the association between dia-
betes and sexual dysfunction is less conclusive,
although most studies have reported a higher
prevalence of female sexual dysfunction (FSD)
in diabetic women as compared with nondiabetic
women.

Recently, a pathophysiologic mechanism Figure 1. The artery size hypothesis. (A) Early stage of the
was proposed to explain the link between atherosclerotic process. Significant vascular obstruction
ED and CAD called the artery size hypothesis. (50% lumen artery narrowing) of penile circulation lead-
Given the systemic nature of atherosclero- ing to erectile dysfunction symptoms is shown. (B) Late
sis, all major vascular beds should be affect- stage of the atherosclerotic process. Significant vascular
ed to the same extent. However, symptoms obstruction of coronary circulation leading to angina pecto-
rarely become evident at the same time. This ris is shown. TIA transient ischemic attack. (Adapted with
difference in rate of occurrence of different permission from Eur Urol.10)
symptoms is proposed to be caused by the
different size of the arteries supplying differ-
ent vascular beds that allow a larger vessel
to better tolerate the same amount of plaque
compared with a smaller one. According to
this hypothesis, because penile arteries are
smaller in diameter than coronary arteries,
patients with ED will seldom have concomi-
tant symptoms of CAD, whereas patients with
CAD will frequently complain of ED. Available
clinical evidence appears to support this hy-
pothesis

The artery size hypothesis is a pathophysiologic mechanism recently proposed to address this
association

The issue of the temporal relation between onset and the occurrence of CAD symptoms.
symptoms of ED and CAD has been addressed
by 2 recent retrospective studies. Montorsi This period is a great window of opportunity to
et al6 calculated a mean time interval of 39 the treating physician that we can change the
months (range, 1 to 165 months) between ED

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Cardio Diabetes Medicine 2018 96

life style of our patients control his metablic im- 7. Diabetes Control and Complications Trial Re-
balance and retard the onset of critical ailments search Group. e effect of intensive treatment of
like Myocardial infarction or stroke in them. diabetes on the development and progression
So Definitely diagnosing Erectile Dysfunction of long-term complications in insulin-dependent
which is nothing but penile angina or penile diabetes mellitus. N Engl J Med. 1993;329:977–
attack can be a clue to incidence of heart attack 986.
in near future. 8. UK Prospective Diabetes Study (UKPDS)
Group. Intensive blood-glucose control with sul-
Acknowledgents: I thank Maria Ida Maiorino, phonylureas or insulin compared with con- ven-
Giuseppe, Bellastella Katherine, Esposito of tional treatment and risk of complications in pa-
Naples & Joseph Emmanuel Thomas, MD; Jo- tients with type 2 diabetes (UKPDS 33). Lancet.
Anne Micale Foody, MD of USA for their literary 1998;352:837–853.
inputs and observations. 9. Huxley R, Barzi F, Woodward M. Excess risk of
fatal coronary heart disease associated with dia-
Disclosure: No conflict of Interest. betes in men and women: meta-analy- sis of 37
prospective cohort studies. BMJ. 2006;332:73–
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