Cardio Diabetes_2017 book

vv

478 NAFLD and CVD - Importance and Therapies

hepatitis A and B if they are not already immune, the
pneumococcal vaccine, and standard age-appropriate
vaccinations.
3.All patients avoid heavy alcohol consumption. In
patients with or at risk for NAFLD, heavy alcohol use
is associated with hepatic steatosis, hepatic injury,
and fibrosis.
4.Management of patients with NAFLD includes
optimization of blood glucose control in patients
with diabetes and treatment of hyperlipidemia. Statin
therapy has been shown to be safe in patients with
NAFLD.
5.Vitamin E is given for patients with advanced
fibrosis on biopsy who do not have diabetes or
coronary artery disease.
6.Thiazolidinediones improve histologic parameters
in patients with NASH, but likely need to be used
long-term and their use has been associated with
serious adverse events.
7.Patients with NASH-related cirrhosis should
undergo screening for HCC.

References

1. Torres DM, Williams CD, Harrison SA. Features, diagnosis, and treat-
ment of nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2012;
10:837.

2. Adams LA, Lymp JF, St Sauver J, et al. The natural history of nonalcohol-
ic fatty liver disease: a population-based cohort study. Gastroenterology
2005; 129:113.

3. Barker KB, Palekar NA, Bowers SP, et al. Non-alcoholic steatohepatitis:
effect of Roux-en-Y gastric bypass surgery. Am J Gastroenterol 2006;
101:368.

4. Harrison SA, Torgerson S, Hayashi P, et al. Vitamin E and vitamin C
treatment improves fibrosis in patients with nonalcoholic steatohepatitis.
Am J Gastroenterol 2003; 98:2485.

5. Sanyal AJ, Chalasani N, Kowdley KV, et al. Pioglitazone, vitamin E, or
placebo for nonalcoholic steatohepatitis. N Engl J Med 2010; 362:1675.

6. Rinella ME. Nonalcoholic fatty liver disease: a systematic review. JAMA.
2015;313:2263–2273. doi: 10.1001/jama.2015.5370. [PubMed] [Cross
Ref]

7. Ahmed A, Wong RJ, Harrison SA. Nonalcoholic fatty liver disease review:
diagnosis, treatment and outcomes. Clin Gastroenterol Hepatol 13:2062-
2070 [PubMed]

GCDC 2017

Cardio Diabetes Medicine 2017 479

Foot Care in Type 2 Diabetes

Dr.Vijay Viswanathan MD., Ph.D., FICP, FRCP (London & Glasgow)*

& Anitha Rani.A**

*Head & Chief Diabetologist, M.V.Hospital for Diabetes & Prof. M. Viswanathan Diabetes Research Centre
(WHO Collaborating Centre for Research, Education and Training in Diabetes), Royapuram, Chennai.
** Prof. M. Viswanathan Diabetes Research Centre

Abstract: poor socio-economic conditions (2). Diabetic foot
complication imposes a huge challenge on physical
Diabetic foot infection is a common cause for condition, health care cost and socioeconomic bur-
hospital admission among diabetic patients and most den to both patient and also to the nation.
expensive in India. In the past decades lower limb
amputation is reduced to 50 percent, through proper Risk of Amputation:
diabetic foot care and management of diabetes along
with proper foot care. Foot ulcer can be attributed to In India foot infection is considered as a significant
several social and cultural practices. Non healing ulcers cause of amputation (3).It has been estimated that up
cause severe and might leads to the amputation of to 50% of all non-traumatic lower limb amputations
toe, foot or a part of leg. Apart from glycemic control, are performed on diabetic patients(4). In diabetic
an appropriate dietary pattern and management of patients, foot problems is considered as the major
personal habits plays a major role in preventing foot contributing factor towards increased morbidity and
ulcers. Further in order to manage neuropathic foot, a mortality and further the economic impact of foot dis-
prompt and regular inspection and examination of the ease is substantial. The prevalence of diabetic foot
neuropathic foot and treatment of deformities, ulcers, complications has been observed to be higher in ru-
and infections are required. All diabetic patients have ral population than in the urban settings (5), The dia-
to examine the potential foot problems once in a year betic foot scenario is worsen as the rural areas lacks
irrespective of symptoms. Early recognition of these proper healthcare resources specifically in managing
problems and diabetic foot.

the ability to adapt the appropriate/ therapeutic foot- Foot problem in diabetic patients is due to loss of
wear to reduce the pressure peaks are key element sensation, decreased blood flow to the vessels, injury
in the management of diabetic foot. and infection which leads to deformities, abnormal
pressure dynamics and foot ulcer. The state of isch-
Introduction: emia immune compromised condition can leads to
the rapid spreading of infection.
Globally diabetes and its co morbid condi-
tions pose a major threat on public health resources, Signs and symptoms of Diabetic Foot:
when considering the population growth and increas-
ing prevalence of diabetes, diabetes burden in India Patients with Diabetes may develop various foot re-
would become enormous. Among other complica- lated problems; even the minor problem may worsen
tions, diabetic foot amputation is a frequent com- and resulted in serious complications.
plication in developing countries like India. Patients
spend higher percentage of their income towards the Inflammation is considered as one of the earliest sign
hospital admission when compare to patients without of tissue injury.
foot complication (1). It is due to the fact that among
Indian population, diabetic foot disease is influenced Pain is the major natural warning system which alerts
by socio-cultural factors such as the prevalence of the patient to take action.
barefoot walking, lack of awareness on diabetic foot
complications, and lack of diabetes care facilities and Monitoring the temperature of the skin reduces the
risk of developing foot ulceration among high risk

Cardio Diabetes Medicine

480 Foot Care in Type 2 Diabetes

patients. Skin temperature measurements can be Sensation Sensation is reduced or full
used as a diagnostic tool for diabetic foot ulcer- absent to touch, vibration, pain
ations, decubitus wounds, and Charcot arthropathy. and pressure

High temperature gradients between feet may predict Ankle reflex absent
the onset of neuropathic ulceration and self-monitor-
ing may reduce the risk of ulceration. Diabetes and Foot care:

Fever and chills, bad odor or pus from foot ulcer and Management of diabetes along with regular foot care
shiny, tight skin on the foot which turns dark, cold, prevents foot sores which are difficult to treat and
or pale. requires amputation. The suitable strategy to prevent
the diabetic foot complications includes appropriate
Foot weakness or trouble moving the foot and in- diabetes management through regular monitoring
creased size or deepness of the foot ulcer. Muscle of blood sugar levels, regular physical activity and
pain or cramps that occur when you exercise and healthy diet plan. The assessment and management
go away with rest. of diabetic foot ulcer can best be achieved by the
vascular management of ischemia and existing co
Foot pain with little or without sensation, redness, morbid conditions, controlling the infection, removing
warmth, swellingness in foot, thickening of toe nails. necrotic tissues and off –loading the planter pressure.

Clawed toes, raised arch, foot drop, muscle wasting Preventive measures:
and other deformities are the major signs of motor
neuropathy. Micro vascular and macro vascular complications in
DM are responsible for major morbidity and mortal-
Dry skin, fissuring, distended dorsal veins, warm ity in diabetic patients. Prevention of these compli-
foot, increased blood flow and bounding pulses are cations should be the aim while managing diabetes.
the major signs of autonomic neuropathy. The most essential components of foot management
are regular inspection and examination, identification
Diabetic foot ulcer can be diagnosed through blood of at-risk foot and appropriate treatment of ulcers
test, biopsy, ankle brachial index, arterial Doppler, and infections.
monofilament, bone scan, CT, MRI, ultrasound and
X-ray. Non healing ulcers cause severe damage to tissues
and bones which might leads to the amputation of
Clinical symptoms: toe, foot or a part of leg. Hence regular foot care is
necessary in case of foot ulcer development. Patient
Clinical symptoms Neuropathic ulcer education should focus on the foot hygiene, skin
and nail care routines, appropriate foot wares and
Deformity in foot Clawed toes, possible high appropriate foot care administered by qualified pro-
arch, possibility of charcot de- fessionals can reduce injuries that may lead to foot
formities ulceration.

Temperature and Warm temperature, foot pulse Regular feet inspection: Check the feet for cracks,
cuts, tenderness, swelling, blisters for once a day.
foot pulse id present but often bounding,
Regular washing of feet: Once a day wash the feet
dilated with prominent veins in lukewarm water and gently dry them specifically
between the toes. Appropriate use of moisturizing
Condition of the Sweating is reduced which re- cream or lotion on the tops and bottoms of the feet
skin sulted in dry skin helps to keep the skin soft.

Presence of the Callus is present in weight Trimming of toe nails: Trim the toe nails as a straight
across and file sharp ends.
callus bearing areas and they are
Avoid barefoot: In order to prevent injury in the feet
very thick avoid bare foot, even in house and ware clean, dry
socks.
Location and Ulcer is present in the planter

characteristic of aspects of foot or toes and is

ulcer usually painless with punched

out appearance surrounded by

callus.

GCDC 2017

Cardio Diabetes Medicine 2017 481

Wear proper shoes: Wear a comfortable shoe which healed, the foot deformity, calluses and increased
provides proper support for heal, arch and ball por- pressure will still be present. In addition the scar tis-
tion of foot. sue from previously healed ulcer is not a strong tis-
sue and is thus vulnerable to shear forces of walking.
Regular foot checkups: podiatrist can inspect the ear- Special measures are therefore necessary to protect
ly signs of nerve damage, poor circulation or other the vulnerable sites of previous ulceration, such as
foot problems. education of the patients about walking and change
to therapeutic shoes to prevent recurrence of these
Keeping good control of diabetes, cholesterol and ulcers. Intensive management and foot care educa-
blood pressure will help to control these problems. tion can prevent newer foot problems and surgery in
diabetic foot disease and the patients following strict
Smoking affects blood circulation and leads to am- control develop lesser complication (9).
putation.
Management of diabetes and its complications in a
Identification of high risk foot: rural setting poses a formidable challenge. It is also
been reported that diabetic patients who wore foot-
Most often, the at-risk foot can be identified by the wear both inside and outside their homes developed
presence of neuropathy. Sensory loss due to poly- lesser foot problems than those patients who wore
neuropathy can be assessed by measuring the pres- footwear only when they went outside their homes
sure perception, vibration perception and heat and (10). The reduction of pressure peaks by providing
cold sensation. A simple device Tip-therm and grad- special shoes turns out to be an effective tool for
uated tuning fork can be used to detect high risk managing the neuropathic foot. Findings from ran-
foot (6, domized trial showed the usefulness of therapeu-
tic footwear in preventing foot ulcers varies, with
7). After identification of the at-risk foot, the patient some studies showing benefits and a few others
has to be assigned to a risk category, which could not showing any beneficial effects. Several studies
guide the subsequent management (8). have shown that the regular wearing of therapeutic
footwear’s, foot education and diabetic foot care
Post treatment and prevention of recurrent of practices, prevents ulceration reduces re-ulceration
diabetic foot ulcer: and amputation. The effectiveness of different types
of footwear insole in the diabetic neuropathy foot
Even though the diabetic foot ulcer is healed, the showed that the therapeutic footwear is useful to
foot deformity, calluses and increased pressure are reduce new ulceration and consequently the am-
still present. In addition the scar tissue from previ- putation rate in diabetic population Different kinds
ously healed ulcer is not a strong tissue and is thus of insoles such as molded EVA (Ethylene vinyl ace-
vulnerable to shear pressure during walking. Hence tate), MCR (Microcellular rubber) or PU (polyurethane)
customized care of treatment is therefore important foam were used to develop therapeutic foot wear for
to protect the vulnerable sites of previous ulceration, the patients with foot ulcer. Thus the importance of
such as education of the patients about walking and the footwear and its role in reducing ulceration and
change to therapeutic shoes play a major role in pre- prevention of amputation has to be stressed to the
venting recurrence of these ulcers. patients and their family members. Patients must be
made to wear the prescribe footwear at all times so
Prevention and management: as to maintain compliance in wearing and barefoot
walking must be strictly avoided.
Through proper foot care and management of di-
abetes, the lower limb amputation can be reduced Conclusion:
considerably. The suitable strategy to prevent the
diabetic foot complications and foot ulcer includes Diabetic foot infection and amputation can be pre-
appropriate diabetes management through moni- vented by ensuring good glycemic control, proper
toring of blood sugar, regular exercise and healthy foot care along with regular treatment of insignificant
diet plan along with the regular intake of prescribed foot lesions in people with diabetes. Since the risk
medication. factors for diabetic foot infection is high among the
diabetic patients, primary and secondary prevention
The simple foot care management tips to the pa- programs are required to reduce the morbidity and
tients, such as how to examine feet daily, pedicure the cost spend towards diabetic foot complications.
section, and usage of proper footwear can prevent
and reduce foot complications, thereby preventing
severe morbidity, and health care costs, particular-
ly in India. Even though the diabetic foot ulcer has

Cardio Diabetes Medicine

482 Foot Care in Type 2 Diabetes

Amputation must be the last resort and patients have
to be educated about foot care and all measure tak-
en to save the foot in diabetic patients.

References:

1. Kumpatla S, Kothandan H, Tharkar S, Viswanathan V. The cost of treating
long term diabetic complications in developing country: a study from India.
J Assoc Physicians India. 2013; 61(2):102-9.

2. Vijay V, Snehalatha C, Ramachandran A. Socio-cultural practices that may
affect the development of the diabetic foot. IDF Bulletin 1997;42:10–2.

3. Viswanathan V, Kumpatla S. Pattern and causes of amputation in diabetic
patients--A multicentric study from India. J Assoc Physicians India. 2011;
59:148–151.

4. Most RS, Sinnock P: The epidemiology of lower extremity amputation in
diabetic individuals. Diabetes Care 6:87–91, 1983.

5. Viswanathan V, Madhavan S, Rajasekar S, et al. Urban-rural differences
in the prevalence of foot complications in South Indian diabetic patients.
Diabetes Care. 2006; 29:701–703.

6. Vijay V, Snehalatha, R, Seena R and A Ramachandran The rydelSeiffer
tuning fork: an inexpensive device for screening diabetes patients with
high- risk foot 2001, 18(5):155-156.

7. Viswanathan V, C Snehalatha, R Seena, A. Ramachandran. Early recogni-
tion of diabetic neuropathy: evaluation of a simple outpatient procedure
using thermal perception. Postgrad Med J 2002; 78:541 – 542.

8. Bakker K, Apelqvist J, Schaper NC, et al. Practical guidelines on the man-
agement and prevention of the diabetic foot 2011. Diabetes Metab Res
Rev. 2012;28(Suppl 1):225-31.

9. Vijay Viswanathan, Sivagami M, Seena R, Snehalatha C, Ramachandran
A. Amputation Prevention Initiative in South India: Positive impact of foot
care education. Diabetes Care 2005; 28:1019–21.

10. Vijay V, Seena R, Snehalatha C, Ramachandran A. 2000. Routine foot
examination: the first step towards prevention of diabetic foot amputation.
Pract Diab Int., 17: 112–114,

GCDC 2017

Cardio Diabetes Medicine 2017 483

Newer Guidelines on Cardiac Arrest in Nutshell

Dr.S.Senthilkumaran, M.D, Dip.A&E, FCCM (Aus), Ph.D,

Chief of Medical Service, Be Well Hospitals, Erode.

Emphasis on Chest Compressions or CPR with both compressions and rescue breaths
when provided before EMS arrival. However, for the
Untrained lay rescuers should provide compres- trained lay rescuer who is able, the recommendation
sion-only (Hands-Only) CPR, with or without dis- remains for the rescuer to perform both compres-
patcher guidance, for adult victims of cardiac arrest. sions and breaths.
The rescuer should continue compression-only CPR
until the arrival of an AED or rescuers with additional C-A-B Sequenced
training. All lay rescuers should, at a minimum, pro-
vide chest compressions for victims of cardiac arrest. 2015 (Updated):
In addition, if the trained lay rescuer is able to per-
form rescue breaths, he or she should add rescue Although the amount and quality ofsupporting data
breaths in a ratio of 30 compressions to 2 breaths. are limited, it may be reasonable to maintainthe se-
The rescuer should continue CPR until an AED arrives quence from the 2010 Guidelines by initiating CPR-
and is ready for use, EMS providers take over care with C-A-B over A-B-C. Knowledge gaps exist, and
of the victim, or the victim starts to move. specificresearch is required to examine the best se-
quence for CPRin children.
2010 (Old):
2010 (Old):
If a bystander is not trained in CPR, the bystander
should provide compression-only CPR for the adult Initiate CPR for infants and children with
victim who suddenly collapses, with an emphasis to chest compressions rather than rescue breaths
“push hard and fast” on the center of the chest, or
follow the directions of the EMS dispatcher. (C-A-B rather than A-B-C). CPR should begin with 30
compressions (by a single rescuer) or 15 compres-
The rescuer should continue compression-only CPR sions rather than with 2 ventilations.
until an AED arrives and is ready for use or EMS pro-
viders take over care of the victim. All trained lay res- Why
cuers should, at a minimum, provide chest compres-
sions for victims of cardiac arrest. In addition, if the In the absence of new data, the 2010 sequence has
trained lay rescuer is able to perform rescue breaths, not been changed. Consistency in the order of com-
compressions and breaths should be provided in a pressions, airway, and breathing for CPR in victims of
ratio of 30 compressions to 2 breaths. The rescu- all ages may be easiest for rescuers who treat people
er should continue CPR until an AED arrives and is of all ages to remember and perform. Maintaining the
ready for use or EMS providers take over care of the same sequence for adults and children offers consis-
victim. tency in teaching.

Why: Compression-only CPR is easy for an untrained Chest Compression Rate\
rescuer to perform and can be more effectively guid-
ed by dispatchers over the telephone. Moreover, sur- 2015 (Updated):
vival rates from adult cardiac arrests of cardiac eti-
ology are similar with either compression only CPR In adult victims of cardiac arrest, it is reasonable for

Cardio Diabetes Medicine

484 Newer Guidelines on Cardiac Arrest in Nutshell

rescuers to perform chest compressions at a rate of ported an association between excessive compres-
100 to 120/min. sion depth and injuries that were not life-threatening.
Most monitoring via CPR feedback devices suggests
2010 (Old): that compressions are more often too shallow than
they are too deep.
: It is reasonable for lay rescuers and HCPs toperform
chest compressions at a rate of at least 100/min. A TABLE 1BLE1 BLS Dos and Don’ts of Adult
High-Quality CPR
Why
Rescuers Should Rescuers Should Not
Why: There is substantial epidemiologic data demon-
strating the large burden of disease from lethal opi- Perform chest com- Compress at a rate slow-
oid overdoses, as well as some documented success
in targeted national strategies for bystander-admin- pressions at a rate of er than 100/min or faster
istered naloxone for people at risk. In 2014, the nal-
oxone autoinjector was approved by the US Food 100-120/min than 120/min
and Drug Administration for use by lay rescuers
and HCPs.7 The resuscitation training network has Compress to a depth of Compress to a depth of
requested information about the best way to incor-
porate at least 2 inches (5 cm) less than 2 inches (5cm)

such a device into the adult BLS guidelines and train- RESCUERS SHOULD or greater than 2.4 inches
ing. This recommendation incorporates the newly ap- NOT (6 cm)
proved treatment.
Allow full recoil after Lean on the chest be-
Chest Compression Depth
each compression tween compressions
2015 (Updated):
Minimize pauses in Interrupt compressions
During manual CPR, rescuers should perform chest
compressions to a depth of at least 2 inches(5 cm) compressions for greater than 10 sec-
for an average adult, while avoiding excessive chest-
compression depths (greater than 2.4 inches [6 cm]). onds

2010 (Old): Ventilate adequately (2 Provide excessive venti-

d): The adult sternum should be depressed at least breaths after 30 com- lation
2 inches (5 cm).
pressions, each breath (i.e., too many breaths or
Why delivered over 1 second, breaths with excessive
each causing chest force)
Compressions create blood flow primarily by increas- rise)
ing intrathoracic pressure and directly compressing
the heart, which in turn results in critical blood flow 2015 (Updated):
and oxygen delivery to the heart and brain. Rescu-
ers often do not compress the chest deeply enough It is reasonable for rescuers to avoid leaningon the
despite the recommendation to “push hard.” While chest between compressions, to allow full chest wall-
a compression depth of at least 2 inches (5 cm) is recoil for adults in cardiac arrest.
recommended, the 2015 Guidelines Update incorpo-
rates new evidence about the potential for an up- 2010 (Old):
per threshold of compression depth (greater than
2.4 inches [6 cm]), beyond which complications may Rescuers should allow complete recoil of the chest
occur. Compression depth may be difficult to judge after each compression, to allow the heart to fillcom-
without use of feedback devices, and identification pletely before the next compression.
of upper limits of compression depth may be chal-
lenging. It is important for rescuers to know that the Why
recommendation about the upper limit of compres-
sion depth is based on 1 very small study that re- Full chest wall recoil occurs when the sternum re-
turns to its natural or neutral position during the
decompression phase of CPR. Chest wall recoil cre-
ates a relative negative intrathoracic pressure that
promotes venous return and cardiopulmonary blood
flow. Leaning on the chest wall between compres-
sions precludes full chest wall recoil. Incomplete re-
coil raises intrathoracic pressure and reduces venous
return, coronary perfusion pressure, and myocardial
blood flow and can influence resuscitation outcomes.

GCDC 2017

Cardio Diabetes Medicine 2017 485

Summary of Key Issues and Major Changes: References:

Key issues and major changes in the 2015 Guidelines 1. Neumar RW, Shuster M, Callaway CW, et al. Part 1: executivesumma-
Update recommendations for advanced cardiac life ry: 2015 American Heart Association Guidelines Updatefor Cardiopul-
support include the following: monary Resuscitation and Emergency CardiovascularCare. Circulation.
2015;132(18)(suppl 2).
The combined use of vasopressin and epinephrine
offers no advantage to using standard-dose epineph- 2. Hazinski MF, Nolan JP, Aicken R, et al. Part 1: executive summary:2015
rine in cardiac arrest. Also, vasopressin does not of- International Consensus on Cardiopulmonary Resuscitationand Emergency
fer an advantage over the use of epinephrine alone. Cardiovascular Care Science With Treatment Recommendations. Circula-
Therefore, to simplify the algorithm, vasopressin has tion. 2015;132(16)(suppl 1).
been removed from the Adult Cardiac Arrest Algo-
rithm– 2015 Update. 3. Nolan JP, Hazinski MF, Aicken R, et al. Part 1: executive summary:2015
International Consensus on Cardiopulmonary Resuscitationand Emergency
Low end-tidal carbon dioxide (ETCO2) in intubated Cardiovascular Care Science With TreatmentRecommendations. Resusci-
patients after 20 minutes of CPR is associated with tation. In press.
a very low likelihood of resuscitation. While this pa-
rameter should not be used in isolation for decision
making, providers may consider low ETCO2 after 20
minutes of CPR in combination with other factors to
help determine when to terminate resuscitation.

Steroids may provide some benefit when bundled
with vasopressinand epinephrine in treating IHCA.
While routine use is notrecommended pending fol-
low-up studies, it would be reasonablefor a provider
to administer the bundle for IHCA.

When rapidly implemented, ECPR can prolong viabil-
ity, as it mayprovide times to treat potentially revers-
ible conditions or arrange for cardiac transplantation
for patients who are not resuscitated byconventional
CPR.

In cardiac arrest patients with nonshockable rhythm
and who areotherwise receiving epinephrine, the ear-
ly provision of epinephrineis suggested.

Studies about the use of lidocaine after ROSC are
conflicting, androutine lidocaine use is not recom-
mended. However, the initiation orcontinuation of li-
docaine may be considered immediately after ROSC-
from VF/pulseless ventricular tachycardia (pVT) car-
diac arrest.

One observational study suggests that ß-blocker
use after cardiacarrest may be associated with bet-
ter outcomes than whenß-blockers are not used. Al-
though this observational study is notstrong-enough
evidence to recommend routine use, the initiationor
continuation of an oral or intravenous (IV) ß-block-
er may beconsidered early after hospitalization from
cardiac arrest due to VF/pVT.

Cardio Diabetes Medicine

486 Cardio Diabetes Medicine 2017

Stable Ischaemic Heart Disease in Diabetics :
Medical Therapy vs Revascularization

Dr Gurpreet S Wander Dr Mridul Mahanta
Dr Ravina Sharma
MD (Medicine), DM (Cardiology) Dr Rohin Vinayak
Professor and Head of Cardiology,
Dayanand Medical College & Hospital,
Hero DMC Heart Institute, Ludhiana

Introduction 6. sympathovagal imbalance due to diabetic auto-
nomic neuropathy,
Stable ischemic heart disease (SIHD) is most com-
monly caused by atheromatous plaque that obstructs 7. vascular effects of constitutive exposure to excess
or gradually narrows one or more of the epicardial insulin.
coronary arteries. However, other contributors, such
as endothelial dysfunction, microvascular disease, The clinical findings in patients with IHD are highly
and vasospasm, may also exist alone or in combi- variable ranging from asymptomatic to chest discom-
nation with coronary atherosclerosis and non athero- fort of variable magnitude and other features like
sclerotic causes, including congenital abnormalities heart failure, cardiac arrhythmias, and sudden death.
of the coronary vessels, myocardial bridging, coro- So management of SIHD depends on appropriate di-
nary arteritis in association with the systemic vascu- agnosis of coronary lesion, severity of disease and
litides, and radiation-induced CAD may be the domi- stratification of patient for need of revascularization.
nant cause of myocardial ischemia in some patients1,2 Appropriate work-up include detailed history and
clinical findings,noninvasive testing including resting
Compared with non diabetic persons, patients with ecg,stress ecg.stress imaging,CT coronary angiogra-
diabetes have a two- to fourfold increased risk for phy and invasive coronary angiography in patients
development with suspected SIHD who have survived sudden
death or serious ventricular arrhythmias or with high
of and death from CHD.Diabetes is associated with risk symptoms.
an increased risk for MI.
Management Strategy
Coronary Heart Disease In The Patient With
Diabetes (Medical Therapy vs Revascularization)

Diabetic patients has associated traditional CHD risk Guideline directed medical therapy in patients with SIHD
factors such as hypertension, dyslipidemia, and nu- are oriented toward preventing death while maximizing
merous other implicated mechanisms are involved in health and function. Coronary revascularization is
atherosclerotic disease progression. recommended when it has been shown to extend life.

The principal vascular perturbations linked to hyper- The guidelines identify five complementary
glycemia include strategies:

1. endothelial vasomotor dysfunction, (1) Educate patients about the cause, manifestations,
and treatment options for IHD;
2. vascular effects of advanced glycation end prod-
ucts, (2) Identify and treat conditions that contribute to,
worsen, or complicate IHD;
3. adverse effects of circulating free fatty acids,
(3) Modify risk factors for IHD;
4. increased systemic inflammation,
(4) Use evidence-based pharmacologic treatments to
5. the pernicious effects of hypoglycemia complicat-
ing diabetes therapy,

GCDC 2017

Stable Ischaemic Heart Disease in Diabetics : 487
Medical Therapy vs Revascularization

improve health status and survival; and death or MI with improved event-free survival in pa-
tients with significant reduction of ischaemia. Along
(5) Use coronary revascularization when there is clear the same line, patients with angina or exercise-in-
evidence of the potential to improve health status duced ischaemia early after MI had a better progno-
and survival. sis after revascularization than with medical therapy
alone in the DANAMI study.6
Trials have shown the survival benefit of CABG
(compared to medical therapy alone) for the follow- Various observational studies have addressed the
ing group of patients: impact of revascularization on prognosis. A myo-
cardial perfusion study of 10 627 patients without
LM disease ( VA Coop Study) prior CAD showed an increasing survival benefit of
revascularization over medical treatment in patients
3 vessel disease involves proximal LAD (European with moderate to severe ischaemia, whereas no such
Coronary Surgery Study) benefit was apparent in patients with only mild or
absence of ischaemia.7
3 vessel CAD with low EF (CASS)
A meta-analysis of 24 studies encompassing 3088
For more severe coronary artery disease patients with left-ventricular dysfunction (mean LVEF
(SYNTAX scores > 22 for 3-vessel disease and SYN- = 32 ± 8%) who underwent assessment of viability by
TAX scores > 32 for left main disease), coronary ar- means of thallium perfusion imaging, F-18 fluoro-
tery bypass grafting (CABG) offers a survival advan- deoxy glucose metabolic imaging, or Dobutamine
tage as well as a reduced need for repeat intervention stress echocardiography and were followed for a
at two years(Syntax trial).3 mean of 25 months. In patients with myocardial via-
bility, revascularization was associated with an 80%
Revascularization, by eliminating the target reduction of risk-adjusted mortality compared with
lesion (PCI) or bypassing the narrowed epicardial ves- medical treatment (16%/year vs. 3%/year). This benefit
sel (CABG), more effectively relieves myocardial isch- was most apparent in patients with impaired left-ven-
aemia than medical treatment alone. For example, tricular function.8
in the randomized Asymptomatic Cardiac Ischemia
Pilot (ACIP) study,4 57% of patients treated with re- Recently, FFR was compared with angiography for
vascularization were free of ischaemia at 1 year com- guiding PCI in a large-scale randomized trial with
pared with 31 and 36% in the ischaemia-guided and 1005 patients (FAME).9 At 1 year, routine measure-
angina-guided strategies, respectively (P < 0.0001). ment of FFR to select lesions requiring PCI (FFR <
Furthermore, at 2 years follow-up, the risk of death 80%) was associated with lower rates of death or MI
and MI was significantly lower among patients under- than PCI guided by angiography alone. Similarly, de-
going revascularization (4.7%) compared with those ferring revascularization in patients with non-signifi-
receiving ischaemia-guided (8.8%) or angina-guided cant lesions as determined by FFR appeared safe as
medical treatment (12.1%, P < 0.04).Similarly, patients shown during the 5 year follow-up of the randomized
with silent ischaemia after recent MI enrolled into DEFER study10 with similar rates of death or MI (<1%/
the randomized SWISSI II trial5 showed lower rates of year) among patients treated medically and those un-
ischaemia when allocated to PCI (12%) than medical dergoing PCI.
treatment (29%, P = 0.03), a beneficial effect accom-
panied by improved left-ventricular ejection fraction Coronary Revascularization Considerations
(57 vs. 49%, P < 0.001) and an absolute reduction Percutaneous Coronary Intervention In
in clinical events (cardiac death, MI, and revascular- Diabetes
ization) of 6.3% per year in favour of PCI. Along the
same line, patients with angina or exercise-induced The optimal strategy of coronary revascularization
ischaemia early after MI had a better prognosis af- for patients with diabetes remains controversial. Al-
ter revascularization than with medical therapy alone though initial success rates in diabetic and nondi-
in the DANAMI study.6 In the myocardial perfusion abetic patients are similar, diabetic patients exhibit
substudy of COURAGE, PCI compared with medical higher restenosis rates after PCI and worse long-term
treatment showed a greater absolute reduction in outcomes.A variety of metabolic and anatomic ab-
myocardial ischaemia (−2.7 vs. −0.5%, P < 0.0001), and normalities associated with diabetes and a greater
more patients exhibited a relevant reduction in isch- degree of plaque burden may contribute to resteno-
aemia (33 vs. 19%, P = 0.0004), particularly among sis in diabetic patients. Although drug-eluting stents
those with moderate to severe ischaemia (78 vs. 52%, have reduced the need for target lesion revascular-
P = 0.007).Again, there was a graded relationship be-
tween reduction of ischaemia and subsequent risk of

Cardio Diabetes Medicine

488 Cardio Diabetes Medicine 2017

ization in these patients, supporting their preferential intake of saturated fats (to <7% of total calories), trans
use, these patients still experience more restenosis. fatty acids (to <1% of total calories), and cholesterol
(to <200 mg/day). In addition to therapeutic lifestyle
Coronary Artery Bypass Grafting versus changes, a moderate or high dose of a statin should
Percutaneous Coronary Intervention be prescribed in the absence of contraindications or
documented adverse effects.For patients who do not
In general, randomized trials comparing PCI and tolerate statins, LDL cholesterol–lowering therapy with
CABG have reported similar outcomes. In patients bile acid sequestrants, niacin or both is reasonable.
with diabetes, however, CABG yields superior mor-
tality outcomes compared with PCI, with incremen- Type 2 diabetes is associated with a characteristic
tal benefit associated with increasing severity of pattern of dyslipidemia but statin treatment remains
underlying coronary artery disease.(BARI) trial. The the cornerstone of therapeutic lipid intervention in
mortality benefit of CABG over PCI remains despite patients with diabetes endorsing a target of LDL
the widespread availability of drug-eluting stents and less than 100 mg/dL or 35% to 40% reduction from
other advances in devices, techniques, and adjunc- baseline. An optional, more intensive target has been
tive pharmacotherapy(FREEDOM randomized trial). endorsed for patients with diabetes of LDL choles-
Therefore CABG continues to be recommended as terol below 70 mg/dL and non-HDL cholesterol less
the preferred mode of revascularization for patients than 100 mg/dL.
with diabetes and multivessel coronary disease.11
Blood Pressure Management
Revascularization Versus Optimal Medical
Therapy Patients with diabetes should be treated to
achieve a systolic blood pressure (SBP) at least < 140
The BARI 2D trial randomly assigned 2368 patients mm Hg and a diastolic blood pressure (DBP) < 90
with type 2 diabetes and obstructive coronary artery mm Hg, and for patients who can tolerate without
disease to receive prompt reduction, or to intensive adverse symptoms, can target as low as SBP < 130
medical therapy alone. During 5 years of study fol- and DBP < 80. Patients with a systolic blood pressure
low-up, the overall mortality rates between the two of 130 to 139 mm Hg or a diastolic blood pressure
groups did not differ significantly—11.7% in those un- of 80 to 89 mm Hg should initiate lifestyle modi-
dergoing revascularization, and 12.2% in those treat- fication alone (weight control, increased physical
ed with intensive medical therapy alone (P = 0.97). In activity, alcohol moderation, sodium reduction, and
secondary analyses stratified according to the mode emphasis on increased consumption of fresh fruits,
of revascularization, all cardiovascular outcomes vegetables, and low-fat dairy products) for a maxi-
were statistically similar between the PCI and medi- mum of 3 months. If, after these efforts, targets are
cal therapy groups, but CABG compared with medical not achieved, treatment with pharmacologic agents
therapy was associated with a significant reduction should be initiated.
in major adverse cardiovascular events (22.4% ver-
sus 30.5%; P = 0.01). These data provide support for ACE inhibitors and angiotensin II receptor blockers
an initial strategy of intensive medical therapy and (ARBs) have become cornerstones of therapy for
additionally suggest the benefit of bypass surgery. hypertension in diabetes because of their broadly
demonstrated favorable effects on diabetic nephrop-
While recommendations for coronary intervention by athy and CVD outcomes, as well as their modest fa-
percutaneous coronary intervention (PCI) or CABG vorable effects on measures of glucose metabolism.
should be mainly evidence-based, the overall clinical
picture (e.g. advanced age, significant co-morbidities, Dihydropyridine calcium channel blockers generally
need for dual antiplatelet medication) as well as pa- are well tolerated and effectively lower blood pres-
tient preferencesand cost should also be considered. sure.

Guideline Directed Optimal Medical Antagonists of beta-adrenergic receptors (beta block-
Treatment ers) are another key component of effective CVD risk
reduction in diabetes.
Risk Factor Modification
Early in the course of clinical use, beta blockers
Lipid Management were judged to be relatively contraindicated in the
setting of diabetes because of concerns about mask-
Dietary therapy for all patients should include reduced ing hypoglycemia symptoms and adverse effects on
glucose and lipid metabolism. The results of CVD
outcomes trials have allayed these concerns and

GCDC 2017

Stable Ischaemic Heart Disease in Diabetics : 489
Medical Therapy vs Revascularization

support the benefit of beta blockers for patients with day and for men to have 1 or 2 drinks a day unless
diabetes in the chronic ambulatory setting and in the alcohol is contraindicated (such as in patients with a
post-ACS population. history of alcohol abuse or dependence or those with
liver disease).
Randomized trials of thiazide diuretics that included
substantial numbers of patients with diabetes have Pharmacologic Therapy
consistently demonstrated CVD benefits.
Antiplatelet Therapy
Diabetes Management
1. Treatment with aspirin, 75 to 162 mg daily, should
For selected individual patients, such as those with be started immediately and continued indefinitely
a short duration of diabetes mellitus and a long life in the absence of contraindications in patients with
expectancy, a goal hemoglobin A1c (HbA1c) of 7% or SIHD.
less is reasonable. A goal HbA1c between 7% and 9%
is reasonable for certain patients according to age, 2. Treatment with clopidogrel is reasonable when as-
history of hypoglycemia, presence of microvascular or pirin is contraindicated in patients with SIHD.
macrovascular complications, or presence of coexisting
medical conditions. Therapy with rosiglitazone should 3. Treatment with aspirin, 75 to 162 mg daily, and
not be initiated in patients with SIHD. clopidogrel, 75 mg daily, might be reasonable in cer-
tain high-risk patients with SIHD.
Physical Activity
4. Dipyridamole is not recommended as antiplatelet
For all patients 30 to 60 minutes of moderate-intensity therapy for patients with SIHD.
aerobic activity at least 5 days and preferably 7 days
per week, supplemented by an increase in daily lifestyle Medical Therapy for Relief of Symptoms
activities (e.g.walking breaks at work, gardening,
household work) is necessary to improve cardio 1. Beta-blocking agents should be prescribed as initial
respiratory fitness and move patients out of the least-fit, therapy for relief of symptoms in patients with SIHD.
least-active, high-risk cohort (bottom 20%).
2. Calcium channel blocking agents or long-acting
Weight Management nitrates should be prescribed for relief of symptoms
when beta-blocking agents are contraindicated or
BMI and/or waist circumference should be assessed at cause unacceptable side effects in patients with
every visit, and clinicians should consistently encourage SIHD.
weight maintenance or reduction through an appropriate
balance of lifestyle physical activity,structured exercise, 3. Calcium channel blocking agents or long-acting
caloric intake, and formal behavioral programs when nitrates, in combination with beta-blocking agents,
indicated to maintain or achieve a BMI of between 18.5 should be prescribed for relief of symptoms when
and 24.9 kg/m2 and a waist circumference of less than initial treatment with beta-blocking agents is unsuc-
102 cm (40 inches) in men and less than 88 cm (35 cessful in patients with SIHD.
inches) in women (less for certain racial groups).
4. Sublingual nitroglycerin or nitroglycerin spray is
Smoking Cessation recommended for immediate relief of angina in pa-
tients with SIHD.
Smoking cessation and avoidance of exposure to
environmental tobacco smoke at work and home 5. Ranolazine , nicorandil, ivabradine and trimetazi-
should be encouraged for all patients with SIHD. dine should be considered for patients intolerant of
, or insufficiently responsive to beta blockers and
Management of Psychological Factors nitrates.

It is reasonable to consider screening patients with Patient Follow-Up
SIHD for depression and to refer or treat when indicated.
Patients with SIHD should be in follow-up evalua-
Alcohol Consumption tions at least annually for assessment of symptoms
and clinical function, surveillance of complications of
In patients with SIHD who drink alcohol, it SIHD, monitoring of cardiac risk factors, and assess-
might be reasonable for nonpregnant women to have ment of the adequacy of and adherence to lifestyle
1 drink(4 oz of wine, 12 oz of beer, or 1 oz of spirits) a interventions and GDMT. Assessment of the LV ejec-
tion fraction is recommended for patients with SIHD
and new or worsening heart failure or evidence of

Cardio Diabetes Medicine

490 Cardio Diabetes Medicine 2017

intervening MI. The guidelines urge restraint in the computed tomography. Circulation. 2003 Jun 17;107(23):2900-7. Epub
use of routine testing in the follow-up of patients with 2003 May 27.
SIHD if they have not had a change in clinical status .
8. Kevin C Allman, Leslee J Shaw, Rory Hachamovitch, James E Udelson.
Summary Myocardial viability testing and impact of revascularization on prognosis
in patients with coronary artery disease and left ventricular dysfunction:
The decision for revascularization should fo- a meta-analysis. J Am Coll Cardiol. 2002;39(7):1151-1158.
cus on improvement of survival in patients with SIHD
and high clinical risk for mortality with GDMT and 9. Pim AL. Tonino, Bernard De Bruyne, Nico H.J. Pijls, Uwe Siebert, Fumiaki
in those who have inadequate control of symptoms Ikeno, Marcel van `t Veer, et al. Fractional Flow Reserve versus Angi-
and quality of life despite GDMT. Recommendations ography for Guiding Percutaneous Coronary Intervention. N Engl J Med
include CABG for patients with significant left main 2009; 360:213-224
CAD, triple-vessel CAD, or proximal left anterior de-
scending (LAD) disease plus one other major cor- 10. Nico HJ Pijls, Pepijn van Schaardenburgh, Ganesh Manoharan, Eric Boers-
onary artery. CABG is reasonable for patients with ma, Jan-Willem Bech, Marcel van’t Veer, et al. Percutaneous Coronary
double-vessel CAD who have evidence of severe or Intervention of Functionally Nonsignificant Stenosis 5-Year Follow-Up of
extensive myocardial ischemia or mild to moderate the DEFER Study. J Am Coll Cardiol. 2007;49(21):2105-21
LV systolic dysfunction with viable myocardium in
the region of intended revascularization. CABG is
given preference over PCI in patients with complex
three-vessel disease and those with diabetes melli-
tus. It is discouraged to use PCI or CABG for single- or
double-vessel CAD without significant involvement
of the proximal LAD artery in the absence of unac-
ceptable angina after an adequate trial of GDMT, par-
ticularly if noninvasive testing data indicate that they
have only a small area of viable myocardium or do
not have extensive ischemia or reduced LV ejection
fraction.

References:

1. Marzilli M, Merz CN, Boden WE, et al: Obstructive coronary athero-
sclerosis and ischemic heart disease: An elusive link! J Am Coll Cardiol
60:951, 2012.

2. Pepine CJ, Douglas PS: Rethinking stable ischemic heart disease: Is this
the beginning of a new era? J Am Coll Cardiol 60:957, 2012.

3. Patrick W. Serruys, Marie-Claude Morice, A. Pieter Kappetein, Antonio
Colombo, David R. Holmes, Michael J. Mack, et al. Percutaneous Coronary
Intervention versus Coronary-Artery Bypass Grafting for Severe Coronary
Artery Disease. N Engl J Med 2009; 360:961-972

4. Davies RF, Goldberg AD, Forman S, Pepine CJ, Knatterud GL, Geller N et
al. Asymptomatic Cardiac Ischemia Pilot (ACIP) study two-year follow-up:
outcomes of patients randomized to initial strategies of medical therapy
versus revascularization. Circulation. 1997 Apr 15;95(8):2037-43.

5. Erne P, Schoenenberger AW, Burckhardt D, Zuber M, Kiowski W, Buser PT
et al. Effects of percutaneous coronary interventions in silent ischemia af-
ter myocardial infarction: the SWISSI II randomized controlled trial. JAMA.
2007 May 9;297(18):1985-91.

6. Madsen JK, Grande P, Saunamäki K, Thayssen P, Kassis E, Eriksen U, et
al. Danish multicenter randomized study of invasive versus conservative
treatment in patients with inducible ischemia after thrombolysis in acute
myocardial infarction (DANAMI). DANish trial in Acute Myocardial Infarc-
tion. Circulation. 1997 Aug 5;96(3):748-55.

7. Hachamovitch R, Hayes SW, Friedman JD, Cohen I, Berman DS. Compar-
ison of the short-term survival benefit associated with revascularization
compared with medical therapy in patients with no prior coronary artery
disease undergoing stress myocardial perfusion single photon emission

GCDC 2017

Cardio Diabetes Medicine 2017 491

New Lipid Lowering Therapies

Dr. Devaki Nair

Consultant Chemical Pathologist and Clinical lead for Clinical biochemistry,
Royal Free Hospital and North Middlesex University Hospital, United Kingtom.

Introduction tion of apolipoprotein B 100 containing lipoprotein-
Very low density lipoprotein(VLDL)(4).This drug is
Cardiovascular disease remains a major cause for administered as a subcutaneous injection once fort-
mortality worldwide. Epidemiological studies as well nightly. The second agent Lomitapide administered
as clinical trials with various lipid lowering therapies orally inhibits the Microsomal triglyceride transfer
have shown the causal relationship of raised low protein and these results in reduction of synthesis
density lipoprotein cholesterol (LDL-C)(1). It is well of Apolipoprotein B containing VLDL and chylomi-
established that statin therapy is the corner stone crons. Both the drugs have been approved for use
for prevention of cardiovascular disease, but there in homozygous FH. The side effects for both these
remains some residual risk and low High Density drugs include raised transaminases and fatty liver as
Lipoprotein cholesterol (HDL-C) has been implicated they interfere with secretion of VLDL. Skin reaction at
and there is much interest in drug targets to raise the injection site with mipomersen and GI side effects
HDL-C (2). But there the progress has been very slow with lomitapide are not uncommon(4).
from getting these experimental drugs from bench to
bedside, however intervention strategies for raising Another class of drugs – a Pro-protein convertase
HDL –C and are still being investigated. There has subtilisin-like kexin type 9 inhibitor (PCSK9 inhib-
been some rapid progress in assessment and man- itor) has revolutionalised management of patients
agement of patients with high to very high Triglycer- with very high concentration of LDL-C such as those
ide (TG) concentration. Other pharmacological targets with inherited hyperlipidaemia. PCSK9 enzyme a pro-
such as inflammation in prevention of progression of tease is involved in the endocytosis and degradation
atherosclerosis are also being tested. of LDL receptor. Inhibition of this enzyme through
use of monoclonal antibodies has shown promise to
The challenges we face in relation to lipid lowering many of the challenges that we face with statin in
therapy include inadequate response to available lip- reducing LDL –C levels(5) Two of the PCSK9 inhibi-
id lowering therapy (LLT), intolerance to LLT, adverse tors have been approved and further outcome data
interactions with concomitant medication and inad- is expected in the very near future from their exten-
equate response both to raising HDL and lowering sive clinical trial programme. However there have also
LDL-C and TG concentration in those with inherited been some setbacks as one of the drugs in this class
problems. In addition the short and long term side ef- have also been withdrawn in early phase 3 trials, due
fects as perceived by the patients and the problems to lack of effectiveness(6). They exhibit excellent side
associated with adherence may also be a challenge effect profile and are likely to become an alternate
that leads to development of newer therapies for ex- option to statin once cardiovascular outcome trials
ample with less frequent dosing schedule(3). are published.

New LDL lowering therapies While the monoclonal antibodies to PCSK9 only
blocks the extracellular component, another drug tar-
The two new therapies recently approved by FDA to geting inhibition of PCSK9 works by inhibiting both
lower LDL levels include Mipomersen an antisense extracellular and intracellular PCSK9 by inhibiting the
oligonucleotide that binds to apolipoprotein B100 synthesis through a novel interfering RNA (RNAi) to
mRNA inducing degradation and reducing the secre-

Cardio Diabetes Medicine

492 New Lipid Lowering Therapies

PCSK9(9). While Monoclonal antibodies to PCSK9 ers of clinical glycaemia control(10).
requires the drug to be administered fortnightly, the
RNAi to PCSK9 only requires to be administer every The familial chylomicronaemia syndrome (FCS) is
6m after a loading dose of 1 and 3 months(7). An an inherited disorder of lipoprotein lipase deficiency
extensive clinical trial programme is under way for characterised by elevated chylomicrons concentra-
this drug also. tion and a high risk for pancreatitis. Current therapy
for FCS is ineffective and use of Apo C3 inhibition
New HDL raising therapies reduced triglyceride from 1406 to 2083mg /dl and
Apo C3 level fell by 71 to 90%. The concept that re-
There is a large interest in HDL-C as a cardioprotec- duction of Apo C3 liberates the lipoprotein lipase in-
tive and athero protective fraction with an extensive dependent pathway is more likely for the reduction
development programme targeting raising the con- of TG levels(11).
centration of this lipoprotein fraction. Some progress
has been made in investigation of use of cholesteryl Another target for reduction of elevated TG level is
ester transfer protein (CETP) inhibitors. These agents angiopoetin like 3 proteins, the absence of which
inhibit transfer of cholesteryl ester and triglycerides causes familial hypobetalipoproteinaemia charac-
between lipoproteins. Development of three of the terised by low levels of all lipoproteins except lipo-
CETP inhibitors torcetrapib,dalcetrapib and evace- protein(a).A second generation antisense molecule
trapib have all been halted for various reasons such to ANGPTL3 results in favourable cardio metabolic
as off target side effect and lack of effectiveness(8). effects. The trial in humans has shown inhibition
of ANGPTL3 lowered TG levels, LDL and VLDL as
Other drugs include artificially reconstituted r/HDL well as Apo C3. An antibody based as well as an
that is administered as infusion and Apo A1 mimetics. antisense molecule are in development, and there
Direct up regulation of Apolipoprotein A1 synthesis may be differences between the two molecules in
using small proteins is another concept that may lead effectiveness and dosing regimen. There is evidence
to success in this area. RVX208 a novel epigenetic that by inhibiting ANGPTL3 in plasma by blocking its
approach directed to raise HDL –C concentration by synthesis in liver reduces plasma concentration of
regulation of gene transcription. Apo A1 mimetics are atherogenic Apo B containing lipoproteins (10). The
small amphipathic helical peptides that have the bio- drug may also benefit people with fatty liver. Because
logical functions of Apo A1 and these activate all the Antisense oligonucleotide acts on the liver, the doses
steps involved in reverse cholesterol transport that used can be smaller
includes ABCA1 mediated cholesterol efflux(9).
Lipoprotein(a) Lp(a) is a modified LDL molecule, and
New TG lowering therapies on a molar basis Lp(a) is more atherogenic than LDL
-C as it in addition to LDL pathway, additionally apo
There is an explosion of interest in new drugs to tar- (a) component also exerts an adverse outcome. Ionis
get raised TG for both CVD reduction s well as reduc- -Apo(a) –Lrx has the potential to lower Lp(a) by 92.4%
tion in pancreatitis a very important complication of and is a new therapeutic paradigm(12)
very high TG concentration.
Statins have had an enormous impact on CVD pre-
Apolipoprotein CIII (ApoC3) is an important regula- vention worldwide. Clinical trials with LLT have shown
tor of triglyceride concentration with elevated levels the important principle that ‘even lower is even better’
contributing to higher CVD risk. Conversely loss of The need for more effective and better tolerated LLT
function mutation of Apo C3 attenuates the level continues along with the quest for alternate targets
of this lipoprotein and therefore reducing CV event for arresting atherosclerosis. Some of these newer
rates in this population. The expression of Apo C3 therapies are likely to complement existing therapies
is regulated by insulin through the insulin response like statin, fibric acid derivatives in achieving cardio-
element encoded in the Apo C3 gene Plasma con- vascular outcomes far superior to the existing well
centration of Apo C3 is associated with a degree of established benefits.
insulin resistance. Apo C3 inhibition is likely to en-
hance insulin sensitivity and therefore giving a hope References
that these drugs may be particularly of use in dia-
betics. Selective antisense inhibition of Apo C3 syn- 1. Kruth HS. Subendothelial accumulation of unesterified cholesterol: an
thesis is another new concept that has established early event in the atherosclerotic lesion development. Atherosclero-
safety and a dose dependent lowering of TG levels. sis. 1985;57:337-341. 
Volanesorsen is an antisense molecule to Apo C3
and has been shown to substantially improve mark- 2. Ridker PM, Genest J, Boekholdt SM, Libby P, Gotto AM, Nordestgaard
BG, Mora S, MacFadyen JG, Glynn RJ, Kastelein JJ; JUPITER Trial Study
Group..  HDL cholesterol and residual risk of first cardiovascular events

GCDC 2017

Cardio Diabetes Medicine 2017 493

after treatment with potent statin therapy: an analysis from the JUPITER
trial. Lancet. 2010 Jul 31;376(9738):333-9.

3. Banach M, Stulc T, Dent R, Toth PP. Statin non-adherence and residu-
al cardiovascular risk: There is need for substantial improvement. Int J
Cardiol. 2016 Dec 15;225:184-196. doi: 10.1016/j.ijcard.2016.09.075.

4. Cupido AJ, Reeskamp LF, Kastelein JJP. Novel lipid modifying drugs to lower
LDL cholesterol. Curr Opin Lipidol. 2017 Aug;28(4):367-373

5. Abifadel M, Elbitar S, El Khoury P, Ghaleb Y, Chémaly M, Moussalli ML,
Rabès JP, Varret M, Boileau C. Living the PCSK9 adventure: from the
identification of a new gene in familial hypercholesterolemia towards a
potential new class of anticholesterol drugs. Curr Atheroscler Rep. 2014
Sep;16(9):439. 

6. Ridker PM, Tardif JC, Amarenco P, Duggan W, Glynn RJ, Jukema JW,
Kastelein JJP, Kim AM, Koenig W, Nissen S, Revkin J, Rose LM, Santos
RD, Schwartz PF, Shear CL, Yunis C; SPIRE Investigators.. Lipid-Reduction
Variability and Antidrug-Antibody Formation with Bococizumab. N Engl J
Med. 2017 Apr 20;376(16):1517-1526

7. Ray KK, Landmesser U, Leiter LA, Kallend D, Dufour R, Karakas M, Hall
T, Troquay RP, Turner T, Visseren FL, Wijngaard P, Wright RS, Kastelein
JJ. Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL
Cholesterol. N Engl J Med. 2017 Apr 13;376(15):1430-1440.

8. Di Bartolo BA, Duong M, Nicholls SJ. Clinical trials with cholesteryl ester
transfer protein inhibitors. Curr Opin Lipidol. 2016 Dec;27(6):545-549.

9. Zakiev E, Feng M, Sukhorukov V, Kontush A. HDL-Targeting Therapeutics:
Past, Present and Future. Curr Pharm Des. 2017;23(8):1207-1215.

10. Gryn SE, Hegele RA. Novel therapeutics in hypertriglyceridemia. Curr Opin
Lipidol. 2015 Dec;26(6):484-91.

11. Gaudet D, Brisson D, Tremblay K, Alexander VJ, Singleton W, Hughes
SG, Geary RS, Baker BF, Graham MJ, Crooke RM, Witztum JL. Targeting
APOC3 in the familial chylomicronemia syndrome. N Engl J Med. 2014
Dec 4;371(23):2200-6.

12. Schreml J, Gouni-Berthold I. Apolipoprotein(a) Antisense Oligonucleotides:
A New Treatment Option for Lowering Elevated Lipoprotein(a)? Curr Pharm
Des. 2017;23(10):1562-1570.

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494 Cardio Diabetes Medicine 2017

Drugs on Pipeline For Management of Diabetes -
An Overview

Dr. P. Rajavel Murugan, M.D(Gen),DCH

Associate Professor in General Medicine
Govt.Thoothukudi Medical College, Thoothukudi, Tamilnadu

Introduction is being investigated in various clinical trials in order
to further expand its role in diabetes management.
Among all the non communicable diseases occurring
worldwide, diabetes is being placed in the first place. In VERTIS Factorial study, a phase 3 randomized,
India, harboring second most population in the world, double-blind clinical trial with 1233 patients assigned
faces a great threat of increasing trend of non com- to five different treatment arms in order to see the
municable disease especially diabetes. The estimat- effects of this SGLT-2 inhibitor on glucose control , on
ed number of adults with diabetes in 2007 was 246 A1c and fasting glucose levels,conducted last year by
million, of these, 80% live in developing countries, N.B. Amin and colleagues at Pfizer, it was seen that
the largest numbers on the Indian subcontinent and ertugliflozin provided significant reduction HbA1c,
in China. India has 41 million diabetics and this num- fasting plasma glucose, and body weight when com-
ber is expected to increase to 70 million by 2025. pared to sitagliptin. Sitagliptin provided similar A1c re-
As medical fraternity is finding difficult to curtail di- ductions and fasting blood glucose reductions,how-
abetes and its complications, more research is being ever, it did not provide any effect on blood pressure
done to introduce newer drugs with high efficacyinto as opposed to ertugliflozin alone.. This study during
the market. As, the economic burden of treating dia- a 26-week period compared effects of ertugliflozin
betes and its complications is considerable and high, and sitagliptin given alone and in combination. Re-
we need drugs with good therapeutic efficacy, low sults from the study showed greater reductions in
side effect profile and less cost. Though many fasting blood glucose with ertugliflozin 15 mg plus
sitagliptin 100 mg, when compared to each individu-
oral anti diabetic drugs are being used, drugs which al treatment.2 Patients taking ertugliflozin 15 mg ex-
have many therapeutic effects other than lowering perienced the most weight reduction (8.1 lbs) when
glycemic status such as weight reduction, blood compared to the other treatment groups in addition
pressure reduction and effect over dyslipidemia are to blood pressure reduction. The incidence of adverse
gaining more popularity among practitioners. So phy- events was similar across all groups with the most
sicians need to have good update on newer therapies common adverse event being genital fungal infec-
in diabetes to impart cost effective therapy with high tions predominantly in women .
therapeutic profile to the patients. Oral hypoglyce-
mic agents and insulin which areyet to meet market Sotagliflozin
sooner will be highlighted in this article.
This is a Dual SGLT1 and SGLT2 Inhibitor, being in-
Ertugliflozin vestigated for use as adjunct therapy to Insulin in
Type 1 Diabetes. Many studies show that use of new
SGLT-2 inhibitors have shown to decrease blood fast-acting and basal insulin analogs in type 1 diabe-
pressure and provide weight reduction benefits when tes are associated with weight gain, hypoglycemia
used in conjunction with other medications. Because and severehypoglycemic episodes. Several longitu-
SGLT-2 inhibitors do not work in an insulin-dependent dinal studies, indicating that between 4 and 10% of
manner, these agents can be incorporated with other deaths can be attributed to hypoglycemia indicating
agents like metformin for management of hypergly- clear need for the development of new adjunct ther-
cemia. Ertugliflozin, a highly selective SGLT2 inhibitor

GCDC 2017

Drugs on Pipeline For Management of Diabetes - 495
An Overview

apies to insulin that can improve glycemic control TTP273
without these complications.
Glucagon-like peptide-1 (GLP-1) is a member of
Highly selective inhibitors of sodium–glucose cotrans- the incretin family of neuroendocrine peptide hor-
porter (SGLT) 2, the transporter primarily responsible mones secreted from L-cells of the intestine in
for renal glucose reabsorption, are approved for the response to food ingestion. Though GLP-1 has at-
treatment of type 2 diabetes and under exploration tractive multiple metabolic effects such as sup-
in patients with type 1 diabetes . SGLT1 is the primary pression of excessive glucagon production, de-
transporter for absorption of glucose and galactose in creased food intake, delayed gastric emptying and
the intestine. Sotagliflozin is a novel, orally delivered, improvement of β-cell mass and function, their
small-molecule dual inhibitor of SGLT1 and SGLT2 widespread use is hindered by the route of admin-
that was designed to reduce glucose absorption in istration (injection), and by the high incidenceof
the gastrointestinal (GI) tract via SGLT1 inhibition and gastrointestinal Sideeffects (nauseaandvomiting).
renal glucose reabsorption via SGLT2 inhibition.
TTP273 has been identified as an orally bioavailable,
The study published in journal of diabetes care Jul potent, non-peptide agonist of GLP-1R for the treat-
2015showed that there were no cases of severe hy- ment of type 2 diabetes and is anticipated to provide
poglycemia reported, and numerically less hypogly- excellent glycemic control and an attractive safety
cemic events in the sotagliflozin-treated group com- profile for the treatment of type 2 diabetes.   
pared with placebo. Additionally, it has been reported
that treatment with 400 mg sotagliflozin given once A recently-completed 12-week study in 187 patients
daily for 33 patients before breakfast resulted in sig- with T2DM, where notable HbA1c lowering, in addi-
nificant reductions in bolus insulin dose, weight re- tion to a trend for weight loss, was observed with this
duction, significant pre- and postmeal improvements compound compared to Metformin .  The incidence
in glucose levels and 0.55% reduction of HbA1c after of gastrointestinal adverse events noted with treat-
29 days of treatment.No patient on sotagliflozin re- ment is very low. The ongoing LOGRA Phase 2 study
ported any genitourinary infections.3 will evaluate TTP273, for enhanced glycemic control,
weight loss and an attractive safety profile for the
Semaglutide treatment of Type 2 diabetes. 

Currently, GLP-1 receptor agonists are available only Combination of Insulin
as injectables, either once daily or once weekly.
Semaglutide is a long-acting GLP-1 receptor agonist Though Insulin, in many forms, is the prime drug
that is also being developed as once weekly dose being used in type 1 and many situations of type 2
and oral version coformulated with the absorption diabetes, it has to be combined with other drugs to
enhancer sodium N-[8-(2-hydroxybenzoy amino] counter its side effects and therapeutic efficacy. One
caprylate. The phase 2 dose-finding study showed such combination in pipeline, is iGlarLixi (100/33)a
HbA1c and weight reduction were of similar magni- fixed-ratio combination of insulin glargine 100 u/ml
tude to that seen with the injectable GLP-1 receptor and lixisenatide33 mcg/mL, a glucagon-like peptide-1
agonist formulations, and there were no red flags in receptor agonist, for the treatment of type 2 diabe-
terms of safety.Phase 3 trials of injectable semaglu- tes. The mechanisms of action of lixisenatide and
tide have shown that it has a best in class profile insulin glargine are complementary insulin glargine
not just in lowering blood glucose, but also in cutting lowers basal glucose levels throughout the day while
the risk of heart attacks and strokes – the biggest lixisenatide primarily targets glycemic control espe-
long-term danger for diabetes patients. A phase 2 cially PPG excursions. In clinical trials, iGlarLixi was
study(Novel Oral GLP-1 Receptor Agonist Lowers associated with significantly greater reductions from
A1C and Weight in Type 2 Diabetes) randomized 632 baseline in glycated hemoglobin A1C (A1C) than iGlar
adults with type 2 diabetes (mean duration, 6 years) or lixisenatide alone. Reductions in postprandial glu-
to oral semaglutide (2.5, 5, 10, 20, or 40 mg once cose were also greater with iGlarLixi than with iGlar
daily. Results of this studydone byChristophKapitza or lixisenatide. Gastrointestinal events, frequently
et al concluded that treatment with semaglutide may associated with lixisenatide, were less common with
offer a protective effect on beta cell function. Oral iGlarLixi.5
semaglutide significantly reduced not only A1C but
also fasting plasma glucose and body weight. This The IDegLira ,acombination product of insulin de-
novel drug with side effect profile reported only in gludec injection and liraglutide injection intended for
GIT is awaiting approval from FDA.4 the market will be provided in a pre-filled pen con-
taining an IDeg/liraglutide ratio of 100 units/3.6 mg

Cardio Diabetes Medicine

496 Cardio Diabetes Medicine 2017

per mL, to improve glycemic control in adults with merck_and_pfizer_announce_two_pivotal_phase_3_studies_for_ertug-li-
type 2 diabetes inadequately controlled with basal flozin_an_investigational_sglt_2_inhibitor_met_primary_endpoints_show-
insulin. The rate of hypoglycemia with IDegLira was ing_significant_a1c_reductions_in_patients_with_type_2_diabetes. Ac-
lower than that with insulin degludec alone and the cessed July 12, 2016.
rate of gastrointestinal side effects was lower than
with liraglutidealone.Common adverse events report- 3. Arthur T. Sands1⇑, Brian P. Zambrowicz1, Julio Rosenstock2, Pablo Lapuer-
ed during the trials included nasopharyngitis, head- ta1, Bruce W. Bode3, Satish K. Garg4, John B. Buse5, Phillip Banks1,
ache, nausea, diarrhea, increased lipase, and upper Rubina Heptulla6, Marc Rendell7, William T. Cefalu8 and Paul Strumph1;
respiratory tract infection.6 Sotagliflozin, a Dual SGLT1 and SGLT2 Inhibitor, as Adjunct Therapy to
Insulin in Type 1 Diabetes. Diabetes Care 2015 Jul; 38(7): 1181-1188.
Smart’ insulinsor glucose-responsive insulins are be-
ing designed to only turn on when they’re needed 4. ChristophKapitza , KirstenDahlJacob B. JacobsenMads B. AxelsenAnne-
and off when they’re not.  These insulins could en- Flint . Effects of semaglutide on beta cell function and glycaemic control
sure perfect glucose control throughout any given in participants with type 2 diabetes: a randomised, double-blind, place-
day automatically without any untoward events of bo-controlled trial. Diabetologia; August 2017, Volume 60, Issue 8, pp
hypoglycemia. Smart insulin (also known as adap- 1390–1399
tive insulin, smart insulin patch, or MK-2640-001
(Merck)) is a promising and experimental type of in- 5. Ahrén B, Leguizamo Dimas A, Miossec P, Saubadu S, Aronson R (2013)
sulin that automatically manages blood sugars and Efficacy and safety of lixisenatide once-daily morning or evening injections
keeps them in the normal range primarily in type 1ns in type 2 diabetes inadequately controlled on metformin (GetGoal-M).
sometimes in type 2 diabetes without fear of hypo- Diabetes Care 36:2543–2550
glycemia. Though Glucose responsive insulin (GRI),
is a promising treatment option, the research is in 6. Stephen CL Gough,Rajeev Jain,and Vincent C WooInsulin degludec/liraglu-
its infancy - in many cases, human testing of smart tide (IDegLira) for the treatment of type 2 diabetes. Expert Rev Endocri-
nolMetab. 2016 Jan 2; 11(1): 7–19. Published online 2015 Nov 18. doi: 
insulin is not scheduled for several years. 10.1586/17446651.2016.1113129

Conclusion

Ertugliflozin is a novel highly selective SGLT-2 inhib-
itor that has shown to provide reductions in fasting
blood glucose, A1c, weight, and blood pressure.

Ertugliflozin 15 mg in combination sitagliptin 100 mg
provides greater reductions in weight and fasting
blood glucose levels.

Oral GLP 1 agonist semaglutide shows promising re-
sult in reduction of FPG, A1C and body weight.

Sotagliflozin , dual inhibitor of SGLT1 and 2 shows
better glycemic control with less GIT side effects.

Combination insulins like iGlarLixi and IDegLira,
where insulin is combined with Lixisenatide and Li-
raglutidein atitratable fixed-ratio combination show
improved efficacy and comparable or improved safe-
ty outcomes relative to its separate constituents, of-
fering an alternative approach to intensification of
therapy in T2D.

Reference

1. Sicree R, Shaw J, Zimmet P. Prevalence and projections. In: Gan D (ed.).
Diabetes Atlas International Diabetes Federation, 3rd edn. International
Diabetes Federation, Brussels, Belgium, 2006; 16–104.

2. Pfizer Merck and Pfizer announce two pivotal phase 3 studies for ertug-
liflozin, an investigational SGLT-2 inhibitor, met primary endpoints, show-
ing significant A1C reductions in patients with type 2 diabetes. Jul 11,
2016. Available at: www.pfizer.com/news/press-release/press-release-tail/

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Cardio Diabetes Medicine 2017 497

Hyperglycemia & Glycemic Control in ICU

Prof. Dr. S. Arulrhaj MD.,FRCP (G)

Head, Acute Medicine

Dr.Aarathy Kannan, M.D.,

Physician & Diabetologist

Dr. Kiran Palsania & Dr.Bhuvaneshwar

Postgraduate in Internal Medicine, Sundaram Arulrhaj Hospitals, Tuticorin, India

INTRODUCTION Intensive glycemic control reduces morbidity and
mortality in critically ill patients, Hence hyperglycemia
Hyperglycemia is a common complication of critical no longer benign in ICU.
illness, regardless of a history of diabetes mellitus. In
many occasions Critically ill patients without Diabe- OVERVIEW
tes can be hyperglycemic. It has an estimated prev-
alence of approximately 40% in hospitalized patients. Hyperglycemia is exceedingly common in critical ill-
Initially, hyperglycemia was presumed to be an adap- ness and may be seen in virtually all adult medical
tive stress response that was beneficial to survival. ICU patients when the threshold blood glucose (BG)
The fight-or-flight response. value is set at >110 mg/dL. In an observational study,
ICU patients with newly diagnosed hyperglycemia
Hyperglycemia during acute illness is called stress had significantly higher mortality (31%) compared with
hyperglycemia patients with known diabetes (10%) or normoglyce-
mia (11.3%). Van den Berghe and coworkers in 2001
Stress hyperglycemia usually is defined as an in- directly addressed this question and demonstrated
crease in blood glucose above 200 mg / dL in the that targeting strict euglycemia (80 to 110 mg/dL)
presence of acute illness. can lead to meaningful morbidity and mortality re-

RECOGNITION AND DIAGNOSIS OF HYPERGLYCEMIA AND DIABETES IN ICU SETTING

Upon admission: Assess all patients for a history of diabetes, Obtain laboratory blood glucose testing

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498 Hyperglycemia & Glycemic Control In ICU

ductions among surgical ICU patients supported by • Increased hepatic gluconeogenesis and glycog-
mechanical ventilation.(1) enolysis

Three Types of Hyperglycemic Patient • Impaired peripheral glucose uptake
• Known history of diabetes
• Existing, but unrecognized, diabetes • And higher circulating levels of insulin
• Stress hyperglycemia
Counter regulatory hormones, such as glucagon,
HBA1C IS THE KEY FOR ASSESSING THE cortisol, growth hormone, and catecholamine, as
CONTROL OF DIABETES well as elevated levels of cytokines play an import-
ant role in up-regulating hepatic glucose production.
Guidelines From Professional Organizations on the Some of these hormones and cytokines have also
Management of Glucose Levels in the ICU (Table 1) been shown to directly oppose insulin, resulting in
increased lipolysis and proteolysis, which serve to
AACE - Consensus Conference - Blood provide substrates for further gluconeogenesis
Glucose Targets
As patients become bed-bound in the ICU, exer-
Upper Limit Inpatient Glycemic Targets: cise-stimulated uptake in skeletal muscle disap-
• Critical Care: 110 mg/dl (6.1 mmol/L) (Fasting ) pears.The increased counter regulatory environment
• Non-critical care (limited data) of critical illness and the impairments in glycogen
synthase activity compromise glucose uptake in
• Pre-prandial: 110 mg/dl (6.1 mmol/L) the heart, skeletal muscle, and adipose tissue. In-
• Post-Prandial : 180 mg/dL (10 mmol/L) sulin-stimulated uptake by carriers such as GLUT-4
The current ADA guideline for pre-prandial plasma (Glucose transporter type 4 a solute carrier family 2,
glucose is now < 126 mg/dL (2) facilitated glucose transporter member 4) is also de-
creased,leading to Hyperglycemic state.
Pathophysiology
Hyperglycemia and Its Biologic Effects: The higher
Hyperglycemia during critical illness can be best risk of organ failure seen in patients with hyperglyce-
characterized as a state of insulin resistance that mia, likely in part arises from alterations in microcir-
develops in the context of: culation that lead to inadequate oxygen delivery as a
result of endothelial dysfunction. Even when oxygen
delivery is adequate, certain types of tissue appear
to be at risk for bioenergetic failure and cellular death
resulting from mitochondrial dysfunction when faced
with persistent hyperglycemia.

Year Organization Patient Treatment Target Glucose Definition of Updated Since
2009 Population Threshold Level Hypoglycemia NICE_SUGAR
180 140-180 Trial, 2009
2009 American Association ICU patients <70
2009 of Clinical Endocrinol- 180 150 Yes
2008 ogists and American ICU patients 180 <180
2007 Diabetes Association 180 90-140 Not stated Yes
ICU patients <40 Yes
Surviving Sepsis Cam- Not stated “Strict” Not stated No
paign ICU patients with
acute coronary Not stated No
Institute for Health- syndromes
care Improvement ICU patients with
cardiac disorders
American Heart Asso-
ciation

European Society of
Cardiology and Euro-
pean Association for
the Study of Diabetes

Table 1: Guidelines From Professional Organizations on the Management of Glucose Levels in the ICU

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Cardio Diabetes Medicine 2017 499

Hyperglycemia has a number of Immunomodulatory • Direct destruction of beta cells (e.g. parotitic pan-
effects: creatitis).

Can compromise innate immunity by: Impairing poly- • Molecular mimicry: microbial antigens share ho-
morphonuclear neutrophil function,Intracellular bac- mologies with host antigens (e.g. Cytomegalovirus
tericidal activity&Opsonic activity.High glucose levels and Epstein-Barr virus).
can promote excessive inflammation as evidenced
by increasing proinflammatory cytokines (such as tu- • Increased processing and presentation of autoan-
mor necrosis factor-α and interleukins 1β, 6, 8, and tigens during infection or epitope spreading which
18), inducing nuclear factor-κB, and up- regulating make the beta cells a target of the immune system
leukocyte adhesion molecules and enhances autoimmunity.

Number of important biologic effects that may ex- • Increasing inflammation and the secretions of in-
plain the apparent association between glucose flammatory cells such as cytokines.
excursions and poor outcomes in the ICU.Hypergly-
cemia additionally induces formation of advanced • Increased insulin requirement during infection.
glycation end products, which is now recognized to
promote inflammation and endothelial dysfunction. Hyperglycemia Adversely Affects Outcomes
High BG levels lead to oxidative stress and promote a
procoagulant state. Hyperglycemia has been shown Hyperglycemia impacts
to correlate with development of congestive heart fail-
ure, cardiogenic shock, and hospital mortality among • Mortality ↑
patients admitted for acute myocardial infarction
• Morbidity ↑
Infections can elicit diabetes
• Rate of infections ↑
Infections cause metabolic derangements and con-
versely metabolic derangements can facilitate infec- • Length of stay in ICU ↑
tion. The infection can induce diabetes by different
mechanisms including: VENTILATION DURATION IS INCREASED

Hyperglycemia linked to higher mortality regardless
of status of diabetes

Pic1: Stress Hyperglycemia exacerdates illness

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500 Hyperglycemia & Glycemic Control In ICU

Pic 2: Pathophysiology and complications of stress hyperglycemia

Elisabeth Donahey, et al Management of Hyperglycemia in Caritically Ill patients Pharmacy Practice news November 2013

In Early 2000, a blood glucose target of 80 to 110
mg/dL was used in many ICUs based on the results
of Leuven 1 Surgical Trial.

Hyperglycemia Linked to Mortality Acute myocardial infarction:

In 1997 Swedish authors published the results of In diabetes mellitus, insulin glucose infusion in acute
the DIGAMI (Diabetes and Insulin-Glucose Infusion myocardial infarction (DIGAM I), intensive treatment
in Acute Myocardial Infarction) trial, randomized to by use of insulin infusion in MI resulted in 29% low-
a blood glucose target of 126 to 196mg/dL, demon- er mortality compared to the conventionally treated
strated a 28% reduction in mortality. group.

A glucose target of 80 to 110mg/dL was found to
have a statistically significant benefit on intracranial
pressure and seizure incidence in 63 patients with
isolated brain injury. However, a recent meta-analysis
demonstrated that glucose control after a neurologic
event such as ischemic stroke, aneurysmal subarach-
noid hemorrhage, intraparenchymal hemorrhage, or
traumatic brain injury does not yield a mortality ben-

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Cardio Diabetes Medicine 2017 501

efit.Bruno et al reported worse neurological outcome diabetes insipidus, and long-term rehabilitation.
at three months in ischemic stroke patients admitted
with higher blood glucose level. Intensive Insulin therapy in critically ill patient –The
Leuven MICU Study:
In general surgery patients, the relative risk for se-
rious post-operative infections (sepsis, pneumo- The results of SICU trial prompted this obvious ques-
nia, and wound infection) increased 5.7 fold when tion: would implementation of the same protocol also
any post-operative day 1 blood glucose (BG) was > improve outcome for medical ICU patients?
220mg/dL .
The authors randomized 1200 medical ICU patients
Tumul Chowdhury General intensive care to strict normalization of blood glucose levels (80 to
for patients with traumatic brain injury: An 110 mg/dL) with the use of insulin infusion or to con-
update ventional therapy with a more liberal blood glucose
target (180-200 mg/dL).Surprisingly there was no
Hyperglycemia Linked to Morbidity: mortality benefit for IIT and there was a significantly
greater occurrence of hypoglycemia in the IIT group
After an ischemic stroke, the degree of hyperglyce- (18.7% vs. 3.1%, p<0.001).In the subgroup of patients
mia appears to independently predict infarct expan- who were in the ICU for fewer than three days, on IIT
sion and neurologic outcome.Stress hyperglycemia appeared to result in a higher mortality rate (26.8%
also is associated with increased risk for critical vs. 18.8%).
illness polyneuropathy due to cytokine release. Pa-
tients with Critical Illness Polyneuropathy also were
found to have prolonged mechanical ventilation time
and longer ICU stays.

Sub analysis of the Leuven 1 study population, pa-
tients with isolated brain injury were investigated for
degree of intracranial pressure, incidence of seizures,

Pic 3: Hypoglycemia and mortality in ICU Mortality
Saudi J Anaesth. 2014 Apr-Jun; 8(2): 256–263. doi: 10.4103/1658-354X.130742.

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502 Hyperglycemia & Glycemic Control In ICU

Hyperglycemia

What is NICE-SUGAR ? “TIGHT GLUCOSE EXPRESS” WAS
UNSTOPPABLE

DESCRIPTION

3054 patients were assigned to the intensive con-
trol group and 3050 to the conventional control
group.829 patients(27.5%) died in the intensive con-
trol group and 751(24.9%) in the conventional-control
group which is a difference between surgical vs. med-
ical ICU patients.

Severe hypoglycemia (<40 mg/dL) was recorded in
6.8% of patients in the intensive control group, vs.
0.5% in the conventional group.

• It was an Open Label RCT, Multinational POSITIVE POINTS :-

• 6104 critically ill patients were studied for Intensive • Large multi-center study.
Insulin infusion (81-108 mg/dL) vs “Conventional” • Robust statistical analysis.
control (144 – 180 mg/dL) • Use of a uniform insulin protocol between sites.
• The primary outcome in this is unbiased.
• 90 day survival – primary end point • Good representation of critically ill patients
• Enrolled more patients than trials that preceded it.

LIMITATIONS:-

More patients in the IIT group received corticosteroids
which could effect the variable were studying

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Cardio Diabetes Medicine 2017 503

10% if the IIT discontinued prematurely. GLYCEMIC VARIABILITY

No significant difference in the primary outcome, Wide fluctuations in glucose levels induce apopto-
death. sis, endothelial activation, and oxidative stress more
than sustained hyperglycemia Glycemic variability
Inclusion criteria,i.e., length of stay is a subjective has been shown to be a more powerful predictor of
parameter. mortality than mean BG values among a heteroge-
nous group of ICU patients
The study was not blinded to the treating personnel
In one study, for the same degree of glucose control
CONCLUSION OF TRAILS (mean BG ranging between 80 and 110 mg/dL), mor-
tality ranged from 4.2% to 27.5% depending on the de-
Intensive Insulin Therapy (IIT) trail concluded that gree of glucose variability. Krinsley JS. Glycemic vari-
Blood glucose control at or below 110mg/dl reduced ability: a strong independent predictor of mortality in
morbidity and mortality in Critical care patients in critically ill patients. Crit Care Med. 2008;36(11):3008-
SICU 3013

NICE SUGAR study said moderate glycemic control Glycemic variability is usually expressed as the stan-
at 127-179mg/dl was superior to tight glycemic con- dard deviation around the mean glucose value as
trol with decreased mortality and morbidity and major mean amplitude of excursionsGlycemic variability is
complications for patients also associated with outcome in critically ill patients
;specifically ,greater glycemic variability is associated
MANAGEMENT OF HYPERGLYCEMIA IN with significant higher mortality rate.The mortality rate
THE CRITICAL CARE SETTING among non-diabetic patients with a mean glucose
level of 70-99 mg/dL during the ICU stay was 10.2%
SAMPLING for patients with a glucose GV of < 15% vs 58.3% for
patients with a glucose GV above 50%
Blood (vascular catheter) – danger of contamination
with IV fluids Increased glycemic variability not only
increased the mortality rate, but also
Finger stick – inaccurate in patients with edema or morbidities, such as nosocomial infections
anemia and hospital length of stay

MEASUREMENTS ADA 2016 Recommendations : critically ill patient

• Glucometer – fastest, least accurate

• Blood gas machine – fast, accurate

• Laboratory analysis – slowest, most accurate

• Inpatient glycemic Mx – Definition of Terms

Hospital hyperglycemia Any BG>140 mg/dl

Stress hyperglycemia Elevations in blood glucose
levels that occur in patients
with no prior History of diabe-
tes and A1c Levels that are not
significantly elevated(6.5%)

A1c Value>6.5% Suggestive of prior history of
diabetes

Hypoglycemia Any BG<70mg/dl IV insulin protocol with demonstrated efficacy, safety
in achieving desired glucose range without increas-
Severe hypoglycaemia Any BG<40mg/dl ing risk for severe hypoglycemia

INTERPRETATION : Glycemic management in ICU

< 140 mg/dL - monitoring less frequent In critically ill patients, initial treatment of hyperglyce-
mia typically is accomplished with IV insulin therapy.
140 – 180 mg/dL -  HA1C – frequent monitoring The ideal protocol should quickly reach and maintain
target blood glucose, account for the current blood
> 180 mg/dL -  HA1C , consider insulin – monitor glucose and rate of change in blood glucose values,
per algorithm

Cardio Diabetes Medicine

504 Hyperglycemia & Glycemic Control In ICU

balance stability and responsiveness, result in mini- 1) any change in insulin infusion rate (i.e. BG out of
mal rates of hypoglycemia, and clearly communicate target range)
titration instructions and frequency of blood glucose 2) significant changes in clinical condition
monitoring. 3) initiation/cessation of pressor/steroid, renal re-
placement therapy, nutritional support (TPN, PPN,
The Yale insulin Drip protocol encompasses all of tube feedings, etc.)
these elements.This protocol is associated with a Calculate TDD :
low incidence of both severe and moderate hypo- 1. Units of insulin given in last 6 hours -8hours
glycemia. 2. Use 80% of of the calculated Total dose of insulin
3. Use 50% Basal & 50% Bolus insulin according to
Initially, blood glucose monitoring should occur hour-
ly until blood glucose reaches the target range and blood sugar - model
remains within range for 2 to 3 hours; then blood glu-
cose monitoring can occur every 2 hours.When blood The Basal /Bolus insulin concept
glucose is consistently within target, transition from
IV to subcutaneous therapy may be considered Basal Insulin
• Suppresses glucose production between meals
Specific factors to be ensured include that patients
are receiving consistent nutrition, are hemodynam- and overnight
ically stable, are off vasopressors, are receiving a • Nearly constant levels
stable dose of corticosteroids, have minimal periph- • 50% of daily needs
eral edema, and that any infection they might have Bolus Insulin (Mealtime or Prandial)
is resolving. • Limits hyperglycemia after meals
• Immediate rise and sharp peak at 1 hour
A basal – bolus strategy is preferred for conversion • 10% to 20% of total daily insulin requirement at
from IV to subcutaneous insulin.
each meal
The basal – bolus strategy should be considered for Ideally, for insulin replacement therapy, each com-
patients with resolving acute illness who are receiving ponent should come from a different insulin with a
oral nutrition. This strategy consists of administration specific profile
of basal insulin in the form of long-acting (glargine)
or intermediate – acting (isophane) with bolus insulin Continuous Subcutaneous Insulin Infusion
in the form of rapid-acting (regular) with meals.Eighty Devices
percent of the total insulin infusion dose from the
previous 24 hours is divided equally between basal Continuous Subcutaneous Insulin Infusion Devices
and bolus insulin.For patients receiving enteral nutri- : External open-loop pumps for insulin delivery. The
tion, basal insulin with corrective doses of short-act- devices have a user programmable pump that de-
ing insulin is recommend

YALE INSULINE INFUSION PROTOCOL:

Initiating the Insulin Infusion

Insulin infusion: 1 u human regular insulin per 1 cc
0.9% NaCl per infusion pump (increments of 1 u/h)

Priming: Flush 50 cc of Insulin/NS drip through all IV
tubing, before infusion begins (to saturate the insulin
binding sites in the tubing)

Threshold: Start IV insulin if BG >180 mg/dL

Bolus & initial insulin infusion rate:

Initial BG 181-299: divide by 100, round to nearest 1
unit for initial drip rate (NO bolus)

Initial BG >300: divide by 100, round to nearest 1 unit
for initial drip rate AND bolus to be given

Consider hourly BG monitoring again (until stable) IF:

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Cardio Diabetes Medicine 2017 505

livers individualized basal and bolus insulin replace- How to initiate?
ment doses based on blood glucose self-monitoring
results. Advanced insulin pumps also have an “in- Must start basal insulin inj. at least 2 h before dis-
sulin on board” feature that adjusts a high blood continuation of IV insulin infusion to prevent re-
glucose correction dose to correct dose. Device is bound hyperglycemia
about the size of a pager. Usually placed on belt or
in a pocket, and insulin is infused through thin plas- Which insulin to start with?
tic tubing that is connected to the subcutaneously
inserted infusion set. Long-acting peakless basal insulin analogue is pre-
ferred
CSII delivery is regarded as the most
physiologic method of insulin replacement What dose to start with?

Insulin dose given to the patient during the previ-
ous 6 hours should be extrapolated to a 24-hour
dose, and then reduced by 20 percent as a safety
factor to calculate the new TDD

MONITORING OF BLOOD GLUCOSE IN Converting From IV TO SC insulin
CRITICALLY ILL IN PATIENT
Establish 24 hour requirement-Extrapolate from aver-
IV TO SC INSULIN :SOME PRACTICAL TIPS age insulin requirement over the last 4-6 hours (BG
should be in target and insulin dose should be sta-
Till when should IV insulin be continued? ble).Give one half of insulin amount as basal.
• Conversion should be postponed until volume
Give another half of insulin as total bolus - Give bo-
resuscitation or pressor support can be discon- lus dose (1/3 of the total bolus) post meal based on
tinued. proportion of food(carb)consumed,Monitor blood
• Continue IV insulin until patient is able to tolerate glucose 3rd hourly,Give correction bolus for all BG
solid food intake > 140mg/dL .

OUR ICU INSULIN PROTOCOL :

Target Range for Glycemic Control: 80-110 mg/dL
(fasting)

Standard drip 50 units/50 mL 0.9% NaCl .

IV insulin include Regular, aspart

Bolus dose and Initial Infusion rate: Divide initial glu-
cose level by 100, then round to nearest 0.5 units for
bolus AND initial infusion rate

Examples : Initial glucose=326 mg/dL: 326÷100=3.26,
round to 3.5: IV bolus 3.5 units + start infusion @ 3.5
units/hour

Adjusting IV insulin IV insulin drip
No Insulin
Blood glucose level 3units/hour
<100mg/dl 5units/hour
100-150mg/dl 7units/hour
150-200mg/dl 10units/hour
200-250mg/dl
>250mg/dl

Monitoring blood glucose every hourly

IV insulin to S/c Insulin: 80% of total iv infusion in 6
hours given divided 50% into basal and 50% in bolus
insulin according to the blood sugar.

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506 Hyperglycemia & Glycemic Control In ICU

Glycemic management in ICU • Insulin of choice – Regular/Aspart

HYPOGLYCEMIA • Root of choice – IV continuous Insulin Adminis-
tration (Blood Sugar Above 200 with or without
All insulin infusion protocols, no matter how well Ketosis)
executed, almost always lead to some increase in
hypoglycemic events.Hypoglycemia is a potential • Below 200mg/dl intermittent sc insulin
complication of insulin therapy.It is defined as ei-
ther moderate (blood glucose < 70mg/dL) or severe • Once Blood Sugar is below 180 can be switched
(blood glucose < 40mg/dL) and is associated with to sc or Basal insulin
adverse outcomes.
• Avoid large Excursions in Blood Sugar – Glycemic
HIGH RISKCASES variablity

• Patients receiving bicarbonate-based fluid during • Avoid hypoglycemia below 80mg/dl
CVVHD- Prolonged Insulin clearance
• Correct infections strictly
• Hemodynamically unstable patients in need of
inotropic support- as hypoglycemia is associated • Treat the underlying medical & surgical condition
with shock effectively

• Women- Lower counterregulatory threshold CONCLUSION:-

• patients with known diabetes • Hyperglycemia in ICU is never Benign

• Septic patients • Surgical ICU including CABG stringent glucose
control, Fasting glucose <110mg/dl
• Patients with interruptions in or intolerance to nu-
tritional support. • Medical ICU good control . Glucose 140-180mg/dl

• Glycemic management in ICU • IV Rapid acting Insulin is the choice

Recommendations: • Avoid Glycemic variability

• Based on the best available evidence, an approach • Avoid Hypoglycemia
targeting a moderate BG value between 140 and
180 mg/dL, as endorsed by the American Asso- • Development of Institution specific Insulin protocol
ciation of Clinical is essential

• Endocrinologists and the American Diabetes As- References:
sociation, seems most prudent
1. Umpierrez GE, Isaacs SD, Bazargan N, et al. Hyperglycemia: an inde-
• Wide fluctuations in glucose values should also pendent marker of in-hospital mortality in patients with undiagnosed
be avoided, given increasing data pointing to the diabetes. J Clin Endocrinol Metab. 2002;87(3):978-982.
detrimental effects of glycemic variability
2. ACE- Endocrine Practice 10 (1): 77-82, 2004 ;ADA- Diabetes Care 27:
• Hyperglycemia in critically ill patients whether dia- 553-591, 2004
betic or not should be addressed properly. Insulin
therapy should be proactive, with frequent adjust- 3. Elisabeth Donahey, et al Management of Hyperglycemia in Critically Ill
ments to optimize control; Patients Pharmacy Practice News November 2013

• One should avoid the twin dangers of hypogly- 4. Rady et al. Mayo Clin Proc 2005;80:1558–67 Ainla et al. Diabet Med
caemia and uncontrolled hyperglycaemia both of 2005;22:1321–5
which can have harmful and possibly fatal conse-
quences. 5. Tumul Chowdhury General intensive care for patients with traumatic
brain injury: An update S audi J Anaesth. 2014 Apr-Jun; 8(2): 256–
• Target Blood Glucose : below 180mg/Dl 263. doi: 10.4103/1658-354X.130742.

• Fasting below: Blood glucose level in ICU patients 6. Van den Berghe et al. N Engl J Med. 2001;345:1359-1367.
should be maintained below 110 mg/dl (fasting)

• Target Blood Sugar PP-180mg/dl

• Target Blood Sugar Fasting – 110mg.dl

GCDC 2017

Cardio Diabetes Medicine 2017 507

Stroke Thrombectomy

Dr. A.L. Periyakaruppan, MDRD.,

Neuro interventional Radiologist, Chennai

AIM : Sylvian fissure) and virtually no anterior or posterior
cerebral artery occlusions were treated.
Endovascular thrombectomy for large vessel isch-
aemic stroke substantially reduces disability, with Do clinical variables influence benefit from thrombec-
recent positive randomised trials leading to guideline tomy? - Greater clinical severity has been suggested
changes worldwide as a marker of improved response to endovascular
thrombectomy
Robust benefit of endovascular thrombectomy for
internal carotid and proximal middle cerebral artery Stroke severity: Patients with National Institutes of
occlusions Health Stroke Scale (NIHSS) ≥6 definitely benefit. Mild-
er patients still have approximately 10% incidence of
Uncertainty remains for more distal occlusions where large vessel occlusion and so CT angiography (CTA)
the efficacy of alteplase is greater, less tissue is at should be routine. This group has a high risk of later
risk and the safety of endovascular procedures is deterioration. Tandem occlusion of the internal carot-
less established id artery: Very strong benefit in this subpopulation.
Distal MCA (M2) occlusion: Uncertain benefit in trials
The brain imaging options to assess prognosis have
various advantages and disadvantages, but whatever Patients with ASPECTS 6–10 definitely benefit. If AS-
strategy is employed must be fast. PECTS 0–5 benefit is uncertain

INTRODUCTION Patients with CTP core < 70 mL definitely benefit and
CTP > 70 ml benefit is uncertain
Endovascular thrombectomy for large vessel isch-
aemic stroke has been demonstrated in recent ran- Collateral grade—patients with moderate to good col-
domised trials to be one of the most powerful treat- laterals definitely benefit
ments in any field of medicine, with a number needed
to treat of 5.1 patients to achieve an extra individual There is widespread consensus that the current stan-
with independent functional outcome. dard of mTICI 2b/3 (>50% reperfusion of the affected
arterial territory) is too lenient.
IDENTIFYING LARGE VESSEL OCCLUSION
CONCLUSIONS
All the positive trials required proof of large vessel
occlusion using non-invasive angiography, mostly The key principles that can be distilled from the
CT angiography (CTA). An unequivocally hyperdense positive endovascular trials are to achieve rapid and
artery, particularly when visualised using thin slice complete reperfusion, and to consider the extent of
non-contrast CT, has high sensitivity and specificity pre-existing irreversible injury when weighing the po-
for acute occlusive thrombus tential risks and benefits of treatment

Which arterial occlusions are suitable for thrombec- Recommendations
tomy? The trials all included intracranial internal ca-
rotid artery (ICA) and middle cerebral artery (MCA) All stroke patients should be managed as a time crit-
occlusions in the ‘M1’ (horizontal segment proximal ical emergency.
to the Sylvian fissure and usually prior to bifurcation).
Relatively few ‘M2’ occlusions (postbifurcation in the Highest level of priority should also be provided when
transporting suspected stroke patients to hospitals

Cardio Diabetes Medicine

508 Stroke Thrombectomy

capable of offering reperfusion therapies within ap- American Stroke Association focused update of the 2013 guidelines for
propriate timeframes. (Berglund et al 2012 [5]) the early management of patients with acute ischemic stroke regarding
endovascular treatment: a guideline for healthcare professionals from the
Ambulance services should preferentially transfer American Heart Association/American Stroke Association. Stroke 2015;46:
suspected stroke patients to a hospital capable of 3020–35.
delivering reperfusion therapies as well as stroke unit
care. (O’Brien et al 2012 [13] 8. European-Stroke-Organization. Consensus statement on mechanical
thrombectomy in acute ischemic stroke—ESO-Karolinska stroke update
TIA 2014 in collaboration with ESMINT and ESNR. 2015.

Patients with symptoms that are present or fluctuat- 9. Casaubon LK, Boulanger JM, Blacquiere D, et al. Canadian stroke best
ing at time of initial assessment should be treated as practice recommendations: hyperacute stroke care guidelines, update
having stroke and be immediately referred for emer- 2015. Int J Stroke 2015;10:924–40.
gency department and stroke specialist assessment,
investigation and reperfusion therapy where appro-
priate. (Lavallee et al 2007

All patients with suspected transient ischaemic at-
tack (TIA i.e. focal neurological symptoms due to
focal ischaemia that have fully resolved) should be
assessed urgently. (Lavallee et al 2007 [19]

All TIA patients with anterior circulation symptoms
should undergo urgent carotid imaging with CT angi-
ography (aortic arch to cerebral vertex), carotid Dop-
pler ultrasound or MR angiography. Carotid imaging
should preferably be done during the initial assess-
ment but should not be delayed more than 2 working
days

Vascular imaging

All patients who would potentially be candidates for
endovascular thrombectomy should have vascular
imaging from aortic arch to cerebral vertex (CTA or
MRA) to establish the presence of vascular occlusion
as a target for thrombectomy and to assess proximal
vascular access. (Goyal et al 2016 [53

REFERENCES

1. Goyal M, Menon BK, van Zwam WH, et al. Endovascular thrombectomy
for large vessel ischaemic stroke: a meta-analysis of individual patient data
from five randomised trials. Lancet Published Online First: 18 Feb 2016.
doi: 10.1016/S0140-6736(16)00163-X.

2. Berkhemer OA, Fransen PS, Beumer D, et al. A randomized trial of intraar-
terial treatment for acute ischemic stroke. N Engl J Med 2015;372:11–20.

3. Campbell BC, Mitchell PJ, Kleinig TJ, et al. Endovascular therapy
for ischemic stroke with perfusion-imaging selection. N Engl J Med
2015;372:1009–18.

4. Goyal M, Demchuk AM, Menon BK, et al. Randomized assessment of rapid
endovascular treatment of ischemic stroke. N Engl J Med 2015;372:1019–
30.

5. Saver JL, Goyal M, Bonafe A, et al. Stent-retriever thrombectomy after in-
travenous t-PA vs. t-PA alone in stroke. N Engl J Med 2015;372:2285–95.

6. Jovin TG, Chamorro A, Cobo E, et al. Thrombectomy within 8 hours after
symptom onset in ischemic stroke. N Engl J Med 2015;372:2296–306.

7. Powers WJ, Derdeyn CP, Biller J, et al. 2015 American Heart Association/

GCDC 2017

Cardio Diabetes Medicine 2017 509

Obesity And Weight Management-
Current Concepts

Dr. Isaac Christian Moses, MD.,

Medical Director, Sri Ramakrishna Hospital

OBESITY GHRELIN

Obesity is a growing health problem in our society Ghrelin is a peptide hormone produced by ghrelin-
and its treatment has been challenging as it increas- ergic cells in gastrointestinal tract. Ghrelin regulates
es the lifetime risk of hypertension, dyslipidemia, di- appetite .
abetes mellitus, sleep apnea, cardiovascular disease,
and certain cancers. BROWN ADIPOSE TISSUE

PREVALENCE OF OBESITY WORLDWIDE The main function is to convert food into body heat.
Brown adipocytes contain many lipid droplets, and a
Overall, about 13% of the world’s adult population (11% high number of iron containing mitochondria. It has
of men and 15% of women) were obese in 2014. The more capillaries because of its higher oxygen con-
worldwide prevalence of obesity more than doubled sumption. It accumulates around the neck. It plays a
between 1980 and 2014. In India there were 20 mil- key role in keeping people lean.
lion obese women in 2014 compared with 9.8 million
obese men. WHITE ADIPOSE TISSUE

BODY MASS INDEX AND WAIST It contains a single large fat droplet.  They have recep-
CIRCUMFERENCE tors for insulin, sexual hormones, nor epinephrine,
and glucocorticoids and used as a store of energy.
Body Mass Index (BMI) is a measure of weight status It acts as a thermal insulator. White fat accumulates
of an individual. The World Health Organisation rec- around the hips, thighs, buttocks.
ommended that an individual’s relative risk of type 2
diabetes and cardiovascular disease could be more TYPES OF OBESITY
accurately classified using both BMI and waist cir-
cumference. Apple shaped obesity

CAUSES FOR OBESITY Pear shaped obesity

Genetics, Overeating, Consumption of CHO, Fre- COMPLICATIONS OF OBESITY
quency of eating, Physical inactivity, Medications,
Psychological factors, certain disease conditions, High Blood pressure , weight gain, High Cholester-
Metabolism, Environment, Behavior and Culture. ol, Insulin Resistance, Diabetes – Type 2 Diabetes –
Central Obesity, Heart Disease , Stroke, Gall bladder
HORMONAL INFLUENCE ON OBESITY disease, Osteoarthritis, Sleep apnea and respiratory
problems, Some cancers (Endometrial, breast and
LEPTIN colon).

Leptin is a polypeptide hormone, that is produced INSULIN RESISTANCE
by adipocytes as well as the stomach,heart,placenta
and skeletal muscle. Leptin decreases hunger and Effectiveness of insulin in transporting glucose to the
increases energy expenditure. Leptin resistance is cells is diminished. Fat cells are more insulin resis-
similar to insulin resistance. tant. Initially pancreas responds to insulin resistance
by producing more insulin for years.

METABOLIC SYNDROME

Obesity is a major component of metabolic syn-

Cardio Diabetes Medicine

510 Obesity And Weight Management - Current Concepts

drome that results in diabetes, hypertension and ath- A paleo diet is more satiating per calorie
erosclerosis through resistance to insulin and leptin.
Resistance to leptin causes fat deposition within vis- Drawbacks of Paleo diet
ceral organs. The toxic effects of elevated FFAs are
major contributors to the development of metabolic Paleo diet is expensive. Grains or dairy is not con-
syndrome, lipotoxicity, and cardiovascular disease. sumed which is good for health and energy and is
Health benefits of weight loss in adults. MORTALITY difficult for vegetarians. Most athletes need between
3 to 6 grams of carbs per pound of their body weight,
Weight loss of around 5 kg with a history of diabetes per day. This would be very hard to do with just fruits
lowered all-cause mortality. Weight loss of between 5 and vegetables.
kg to 10 kg in obese women with some obesity-relat-
ed illness lowered cancer-related mortality and low- MEDITERRANEAN DIET SECRET
ered diabetes-related mortality.
Mediterranean diet is characterized by a high con-
HEALTH BENEFITS OF WEIGHT LOSS IN sumption of olive oil, legumes, unrefined cere-
ADULTS als, fruits, and vegetables, moderate to high con-
sumption of fish, moderate consumption of dairy
A. Improved lipid profiles - products, moderate wine consumption, and low
consumption of non-fish meat products.
- reduced osteoarthritis-related disability.
MEDITERRANEAN DIET PLAN
B. Lowered all-cause, cancer and diabetes mortality
in some patient groups - Olive oil is the main health-promoting component of
the diet. Regular consumption of olive oil may low-
Reduced blood pressure er all-cause mortality and the risk of cancer, CVD and
several chronic diseases.
Improved glycaemic control
Benefits of Mediterranean Diet
Reduction in risk of type 2 diabetes
Low in Processed Foods and Sugar, Helps You Lose
Potential for improved lung function in patients Weight in Healthy Way, Improves Heart Health, Helps
with asthma Fight Cancer, Prevents or Treats Diabetes, Protects
Cognitive Health and Can Improve Your Mood
MANAGEMENT OF OBESITY
Drawbacks of Mediterranean diet
OBESITY MANAGEMENT
May be more expensive to follow, cooking fresh food
Diet takes time, not designed as diet for weight loss

Low Fat, Low CHO, Moderate Protein, High Fiber, Atkins diet
Low Carbohydrates
A low-carbohydrate diet, usually recommended
TYPES OF DIET for weight loss. It is a high protein high fat and a
very low-carb diet .
PALEO DIET
PRITIN DIET
Benefits of Paleo diet
In more than 100 studies published in peer-reviewed
More energy, Reduced hunger, Increased weight medical journals, the Pritikin diet has been found to
loss, Less harmful chemicals, Improved blood lipids, promote weight loss and also to prevent and control
Higher immune function, Elimination of processed diabetes, hypertension, and heart disease. The Pri-
foods, Increased intake of fruits and vegetables. tikin diet focuses on a wide variety of unprocessed
foods. 
Clinical evidence supporting Paleo diet
“CAUTION” and “STOP” foods on the Pritikin diet
One study showed that cardiovascular risk factors are proven to increase the risk of obesity and/or mul-
were improved in as little as two weeks time by tiple health concerns.
participants adhering to a paleo diet. Further stud-
ies have also demonstrated a link between paleo and “GO” Foods on the Pritikin Diet
improved cholesterol levels. Other reports indicate
that a paleo diet can improve glycemic control and Fruits , Vegetables , Whole Grains , Starchy Vegeta-
heart disease risk factors commonly found among bles , Legumes , Lean Calcium-Rich Foods such as
individuals with type 2 diabetes. nonfat dairy products, and fortified soymilk, Fish (a

GCDC 2017

Cardio Diabetes Medicine 2017 511

rich source of omega-3-fatty acids), Lean Sources of fat dairy foods — and moderate amounts of whole
Protein (non- vegetarian) and plant sources of pro- grains, fish, poultry and nuts. For a standard DASH
tein, such as legumes and soy-based foods. diet consumption of sodium up to 2,300 milligrams
per day is suggested. For Lower sodium DASH diet,
Pros of Pritikin Diet you can consume up to 1,500 mg of sodium a day.
Both versions of the DASH diet include lots of whole
Focuses on Healthy Eating, Allows a Variety of grains, fruits, vegetables and low-fat dairy products.
Foods, starch is allowed in moderation. The DASH diet is low in saturated fat, cholesterol
and total fat.
Cons of Pritikin Diet
DASH Diet Effects
Large Amounts of high fibre Foods and insufficient
healthy fats. No known negative side effects. The combination of
lowering a person’s blood pressure and lowering his
DUKAN DIET LDL cholesterol is a great way to reduce the risk of
heart disease.
A fast, efficient and natural diet, to lose weight with-
out gaining it back. The Dukan Diet is a hyper pro- PHYSICAL ACTIVITY IN ADULTS
tein, healthy and natural easy diet to follow to lose
weight fast. The 2006 NICE guideline conducted a systematic re-
view of RCTs on the effectiveness of physical activity
ORGANIC DIET for weight loss in obese individuals. When physical
activity was compared with diet (600 kcal/day deficit
A diet consisting of only organic food. In fact, there or low-fat) weight loss at 12 months was significantly
is growing evidence that a diet rich in organic prod- greater in the diet group. The volume of physical ac-
ucts isn’t actually better for you. There’s a definite tivity reported in these studies was very low.
lack of evidence.
Physical activity (minimum of 45 minutes, three times
Benefits of Organic foods per week) combined with diet (600 kcal/ day deficit
or low-fat)
Organic produce contains fewer pesticides and is of-
ten fresher because it doesn’t contain preservatives Whilst the addition of physical activity to a dietary
that make it last longer. Organic food is GMO-free intervention enhances weight loss at 12 months or
- Genetically Modified Organisms (GMOs) more, and

Cons of Organic food Diet Physical activity appears to be less effective than diet
as a sole weight loss interventions
Organic foods are more expensive. All foods, includ-
ing organic, are prone to food-borne illnesses like Walking is an excellent form of physical activity for
E. coli and salmonella. Organic fruits and vegetables overweight and obese people. Walking one kilome-
have a shorter shelf life. tre (0.62 miles) on flat ground burns approximately
60 kcal for a 70 kg person and 90 kcal for a 100
THE VEGAN DIET kg person. Such weight-bearing physical activity
may be difficult for some individuals with BMI over
The vegan diet was created by a group of vegetarians.. approximately 35 kg/m2, particularly for those with
In addition to eliminating meat, it eliminates dairy, joint problems.
eggs and animal-derived products, such as gelatin,
honey, albumin, whey, casein and some forms of In these individuals, gradually increasing non-weight-
vitamin D3. bearing moderate intensity physical activities (e.g.,
cycling, swimming, water aerobics, etc.,) should be
 A vegan diet is a very low fat and high fiber diet, encouraged
which gives satiety. Plant-based diets have been
linked with a reduced risk of heart disease, type 2 BENEFITS OF EXERCISE
diabetes and premature death. Vegan diets eliminate
animal foods completely, so they may be low in sev- Helps in weight reduction, boost happiness levels,
eral nutrients. This includes vitamin B12, vitamin D, learn to set - and achieve goals, reduces the risk of
iodine, iron, calcium, zinc and omega-3 fatty acids. heart disease naturally, improves sleep better, an en-
They may cause weight loss and also reduce the risk ergy boost, increases the strength and flexibility, im-
of several diseases. proves memory, increases self-confidence, improv-
ing work performance, less susceptible to disease.
DASH Diet

DASH diet emphasizes vegetables, fruits and low-

Cardio Diabetes Medicine

512 Obesity And Weight Management - Current Concepts

PHARMACOLOGICAL THERAPY ture, Decreased energetic efficiency, and Decreased
caloric intake as an appetite suppressant
Current FDA-Approved Anti-Obesity Drugs
The most common adverse effects were dry mouth,
• ORLISTAT. paresthesia, constipation, insomnia, dizziness, and

• LOCARSERIN. Dysguesia

• PHENTERMINE/ TOPIRAMATE. This combination reduces the blood level of ethinyl
estradiol levels by almost 16% could result in -De-
• SIBUTRAMINE. creased contraceptive efficacy and increased break-
through bleeding.
• NALTREXONE/BUPROPION
The rate of depression and anxiety was 4-7 times
• LIRAGLUTIDE/EXENATIDE higher among patients randomized to high-dose
phentermine/topiramate when compared with those
• METFORMIN. in the placebo group. This drug combination is asso-
ciated with greater weight loss than other available
ORLISTAT strategies and a more favorable side-effect profile. Its
effect on total cholesterol, LDL cholesterol, and HDL
Orlistat inhibits lipase and it is an enzyme that helps cholesterol levels is positive.
in breaking triglycerides down into fatty acids and is
produced in the pancreas and stomach. This results SIBUTRAMINE
in a lower rate of fat absorption by almost 30%. Orli-
stat also reduces total cholesterol and LDL cholester- Sibutramine widely used after its approval by the
ol. This medication could be considered in patients USFDA in 1997. It is a serotonergic and adrenergic
who have the metabolic syndrome. drug – inhibits the re uptake of serotonin and norepi-
nephrine. It is converted into 2 pharmocologically ac-
Contraindication - Pregnancy, chronic malabsorption tive metabolites- N- desmethyl and N- bisdesmethyl
syndromes, cholestasis. sibutramine Sibutramine suppresses appetite, caus-
es satiety,↑thermogenesis mainly through its active
Adverse effects - Oily Spotting, flatus with discharge, metabolites
fecal Urgency, fatty/oily stool, increased defecation,
fecal incontinence. In a 12 month trial in overweight and obese adults
who had BMI of 25kg/m2 or greater weight loss was
LORCASERIN 4.45 kg. There was a decrease in HbA1C level . Waist
circumference was reduced. Sibutramine showed po-
Lorcaserin is a serotonin or 5-hydroxytryptamine (5- tential benefits by improving biochemical risk factors
HT) agonist. Serotonin is involved in the regulation associated with obesity, including plasma glucose,
of appetite and food intake behavior. Lorcaserin is insulin, triglycerides, total cholesterol, LDL and HDL.
metabolized by the liver and excreted renally, cannot
be removed by hemodialysis. Lorcaserin appears to NALTREXONE/BUPROPION
be more beneficial in the first few months and slowly
loses its ability to maintain long-term weight loss. Naltrexone is an opioid receptor antagonist used for
alcohol and narcotic addiction. Bupropion is an anti-
This medication does not reduce LDL cholesterol and depressant that is also beneficial to promoting tobac-
has no effect on HDL cholesterol, but it reduces total co cessation and weight loss. Bupropion is a selective
cholesterol and triglyceride levels. Potential increased reuptake inhibitor of dopamine and noradrenaline; it
rate of cancer remains a concern. reduces cravings for nicotine and food most likely
due to increasing the extracellular dopamine level.
PHENTERMINE/TOPIRAMATE The effect of this combination is to reduce hunger;
it has no effect on energy metabolism.
A nonselective stimulator of synaptic
A) Noradrenaline, The most common reported adverse events were
B) Dopamine, nausea, headache, constipation, dizziness, vomiting,
C) Serotonin release and dry mouth, compared with the placebo group.
Topiramate - Anticonvulsant drug that blocks volt- This medication is a good choice for patients who
age-dependent sodium channels, glutamate recep- smoke and have a mild to moderate level of depres-
tors, and carbonic anhydrase, and augments the ac- sion.
tivity of gaminobutyrate.

Phentermine has been used as an appetite suppres-
sant in the US since 1959. Increased energy expendi-

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Cardio Diabetes Medicine 2017 513

LIRAGLUTIDE Bariatric surgery - Health outcomes

Liraglutide is the only currently available FDA-ap- Surgical group was 5.5 times more likely to have re-
proved injectable weight loss medication. Liraglutide mission. Remission of type 2 diabetes was related
is indicated as an adjunct to a low-calorie diet and to weight loss and lower baseline HbA1c levels. Bar-
increased physical activity for chronic weight man- iatric surgery significantly reduces the likelihood of
agement in adults with obesity or who are over- hypertriglyceridemia and low HDL cholesterol at two
weight (BMI 27 kg/m2) in the presence of at least years follow up.
one weight-related comorbid conditions.

The most common reported side effects are nau-
sea, hypoglycemia, diarrhea, constipation, vomiting,
headache, decreased appetite, dyspepsia, fatigue,
dizziness, abdominal pain and increased lipase. It is
particularly attractive for patients with hyperglycemia.

METFORMIN

Metformin improves insulin sensitivity, has a good
safety profile, and long-term clinical experience. The
weight loss attributable to metformin is small. Hence,
its usefulness as monotherapy for obesity treatment
is limited.

RATIONAL USE OF MEDICATIONS IN
OBESITY MANAGEMENT

The scientific literature on drug treatment for obe-
sity is limited. Obesity requires long term treatment.
Barriers to the initiation or sustained use of obesity
medications include – Costs, Safety concerns, Per-
ception of limited efficacy, reluctance to view obesity
as a disease requiring medical treatment.

SURGICAL MANAGEMENT

Surgical treatment of obesity

Generally, the criteria include:

BMI of over 35 with obesity-related medical compli-
cations, such as high blood pressure, diabetes, ele-
vated cholesterol, or sleep apnea.

BMI of over 40 without medical complications.

Bariatric surgery in adults

Bariatric surgery is an effective weight loss interven-
tion.

In a systematic review, patients predominantly with
BMI ≥35 kg/m2 receiving bariatric surgery had be-
tween 52.5% and 77% excess weight loss at ten years
post surgery.

Laparoscopic banding,

Bilio-pancreatric diversion +/-,

Roux-en-Y gastric bypass

Cardio Diabetes Medicine

514 Cardio Diabetes Medicine 2017

Convertible Visceral Fat As a
Therapeutic Target to Curb Obesity

Dr. P.G. Sundararaman M.D., D.M.

Consultant Endocrinologist

ABSTRACT requirements for thermo genesis. Hypertrophic vis-
ceral adipocytes are characterized by a hyperlipolytic
Obesity worldwide is increasing in epidemic propor- state that is resistant to the anti-lipolytic effect of in-
tion affecting 13 % of the population. Obesity is form sulin. The resulting overload of free fatty acids, glyc-
of inflammation, increasing the risk of various health erol and lactate in the liver adversely affects hepatic
problems. Obesity is associated with poor quality of metabolism, leading to increased liver glucose and
life and premature death. Adults with extreme obesi- triacylglycerol rich lipoprotein production. Moreover,
ty have increased risks of dying at a young age from white adipocytes are endocrine cells that release
cancer and many other causes including heart dis- hormones such as leptin and adiponectin, as well
ease, stroke, diabetes, kidney and liver diseases. The as pro-inflammatory cytokines, including interleu-
researchers found that the number of years of life kin-6 (IL-6) and tumour necrosis factor. The greater
lost for class III obesity was equal or higher than that production and secretion of IL-6, IL-8, plasminogen
of current cigarette smokers among normal-weight activator inhibitor 1 and angiotensinogen by visceral
participants in the same study. In the early 1980s, fat relative to subcutaneous fat may also account for
cross-sectional clinical studies showed a higher in- the harmful effects of visceral obesity.
cidence of hypertension, hypertriglyceridaemia, and
hyperinsulinemia and glucose intolerance in individ- The main target of anti-obesity strategies is the con-
uals with a high waist/hip ratio. version of white adipocytes to brown ones. Evolution
of this transdifferentiation started several centuries
Three types of adipose tissue are present; these are before. Tibetian yoga- means the fierce goddess of
white, brown and beige. The main function of the for- heat and passion in Tibetan Buddhist tradition. Med-
mer is to store excess energy in the form of TAGs itation, Breathing exercises, Extreme cold exposure
(triacylglycerol), whereas the latter is specialized to caused the conversion of white adipocytes to brown
dissipate energy as heat through UCP1 (uncoupling ones
protein 1)-mediated uncoupling of oxidative phosphor-
ylation from ATP synthesis ; Beige adipocytes could Some of the agents, such as PPARγ activator rosigl-
be perceived as the result of ‘transdifferentiation’ of itazone induce the expression of UCP1.Activation of
WAT to BAT in response to appropriate stimuli, a re- PPARγ induces brown adipocyte-like cells in mouse
cent study suggests that beige adipocytes are a new epididymally derived white preadipocytes differentiat-
type of adipocytes derived from progenitors distinct ed to mature adipocytes in vitro. PRDM16 is involved
from WAT and BAT. WAT, which is highly inflamed in in both the induction of BAT genes and the repres-
obese individuals (metainflammation) and is closely sion of WAT genes. PRDM16 induces 200-fold UCP1
involved in the onset of some of the more severe and also strongly induces PGC-1a. PRDM16 functions
medical complications of obesity. In obesogenic synergistically with PPARγ.
conditions, WAT is infiltrated by macrophages that
form crown-like structures around dying adipocytes. C/EBPβ acts in synergy with PRDM16. Inhibition of C/
This phenomenon is highly pro-inflammatory and is EBPβ forces adipocyte precursors to acquire a white
one of the pivotal events leading to insulin resistance phenotype during development. Countering such in-
and type 2 diabetes. Adipocytes therefore have the hibition can promote browning.
distinctive ability to physiologically and reversibly un-
dergo phenotype reprogramming to meet the body’s Empagliflozin Promotes Fat Utilization and Browning.

FXR agonist fexaramine (Fex) Adipocyte MR regu-

GCDC 2017

Convertible Visceral Fat As a 515
Therapeutic Target to Curb Obesity

lates brown remodeling of WAT through a modula-
tion of autophagy

MR antagonists – Spiranolactone increase UCP1 in
visceral and inguinal fat depots, Induced up-regula-
tion of brown adipocyte-specific transcripts and Pre-
vents adipocyte dysfunction.

Obesity is the leading cause for metabolic disorders.
Definition of obesity and overweight for Indians is
more stringent than western counterparts. Over the
past few decades, substantial experimental evidence
shows that adipose organ, morbid obesity reflects a
massive increase in WAT, especially visceral WAT, at
the expense of BAT. Many drugs have been intro-
duced in the market and many got withdrawn due to
AE. Intense basic and pharmacological research work
is under way to discover targets and molecules that
can stimulate mature BAT and/or induce the brown
phenotype in differentiating adipocyte; which will
curb the burden of metabolic morbidity and mortality.

Abbreviations;

WAT: white adipose tissue

BAT: brown adipose tissue

UCP1 (uncoupling protein1)

PPARγ (peroxisome proliferator-activated receptor γ)

PRDM16, PR domain containing 16

References:

1. Turning WAT into BAT: a review on regulators controlling the browning of
white adipocytes Kinyui Alice LO*1 and Lei SUN†‡1 *Institute of Medi-
cal Biology, 8A Biomedical Grove, #06-06 Immunos, Singapore 138648,
Singapore, †Cardiovascular and Metabolic Disorders, Duke-NUS Graduate
Medical School, 8 College Road, Singapore 169857, Singapore, and ‡Insti-
tute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Singapore
138673, Singapore

2. Convertible visceral fat as a therapeutic target to curb obesity Article in
Nature Reviews Drug Discovery · March 2016

3. Jean-Philippe Bastard • Bruno Fève Editors Physiology and Physiopathology
of Adipose Tissue

Cardio Diabetes Medicine

516 Cardio Diabetes Medicine 2017

Inotropes And Heart :
When to Use and When Not to Use

Dr. J. Cecily Mary Majella, DM (Cardio).,

Asst. Prof .Cardiology, Madras Medical College ,Chennai.

Dr. S. Anneprincy, Post Graduate in Cardiology

INTRODUCTION: tricles and reduced ejection fraction who present
with low SBP (<90 mm Hg) or low measured cardiac
Systolic heart failure is a systemic disease due to re- output in the presence of signs of congestion and
duced cardiac contractility. Although it is logical that organ hypoperfusion such as decreased mentation
this condition can be treated by employing therapeu- and reduced urine output. Its benefit are mainly due
tic strategies to directly improve contractility, inotro- to direct increase in cardiac output and reduction in
pic agents in failure patients have universally failed neurohumoral activation.
to live up to their expectations. Paradoxically, favor-
able outcomes can be achieved by administering The conventional agents include adrenergic inotropes
drugs that acutely decrease contractility and block such as dopamine, dobutamine, and norepinephrine,
neurohormonal stimulation. The proven success of non adrenergic inotropes like milrinone, enoximone,
this latter approach, especially in combination with levosimendan and digoxin. The newer and emerg-
implantable cardioverter-defibrillator and cardiac re- ing agents includes omecamtiv mecarbil, istaroxime,
synchronization therapy (ICD-CRT), has drawn our SERCA2a gene therapy. (Table 1)
attention away from addressing the root cause of
the problem: reduced contractility. In this update, Inotropic agents are mainly used for AHF and should
we will discuss current options for inotropic therapy be used with close hemodynamic monitoring and
in HF, when it might be appropriate to employ ino- should be stopped as soon as adequate organ perfu-
tropes in HF patients, and what steps can be tak- sion is restored. This is because all of these agents in-
en to mitigate their risks while maximizing benefit. crease conduction through the atrioventricular node,
causing a rapid ventricular response in patients pre-
These inotropic agents acts via cyclic adenosine senting with atrial fibrillation. Other conditions where
monophosphate (cAMP)-mediated inotropy increas- inotropes prove useful is in cardiogenic shock as a
es the cardiac output and through vasodilatation re- temporary therapy to prevent hemodynamic collapse
duce PCWP. Although these drugs can successfully or as a life-sustaining bridge to more definitive thera-
increase cardiac output, their use has been proved to py for those patients awaiting mechanical circulatory
have excessive mortality due to increased tachycar- support, ventricular assist devices, or cardiac trans-
dia and myocardial oxygen consumption leading to plantation.
arrhythmia and myocardial ischemia.  Even the short
term use (hours to few days) of intravenous inotro- CONVENTIONAL INOTROPES
pes is associated with significant side effects such
as hypotension, atrial or ventricular arrhythmias, and ADRENERGIC AGENTS
an increase in long-term mortality. Thus the need for
new inotropic agents that are devoid of these harmful Dopamine
effects i.e improve systolic performance without nec-
essarily increasing the myocardial oxygen consump- Initiation of dopamine therapy causes a rapid release
tion.Inotropes have beneficial hemodynamic effects of norepinephrine that can precipitate tachycardia,
especially in patients with heart failure with reduced atrial and ventricular arrhythmias. Dopamine has
ejection fraction (HFrEF; also known as systolic HF) complex effects that vary significantly with dose.
and should be limited to patients with dilated ven-
Low-dose dopamine (≤2 μg/kg/min) has been pro-
posed to cause selective dilation of renal, splanchnic,

GCDC 2017

Inotropes and Heart : When to Use and When Not to Use 517

DRUG MECHANISM EFFECT ON MORTALITY

CONVENTIONAL INOTROPES:

ADRENERGIC AGENTS

Dopamine Dose-dependent D1, α1-, and β1-adrender- Increased
gic receptor agonist

Dobutamine β1- and β2-adrenergic receptor agonist Increased

Norepinephrine β1- and α1-adrenergic receptor agonist Increased

NON ADRENERGIC AGENTS

Phosphodiesterase inhibitor

Milrinone PDE inhibitor, raises SR calcium Increased

Enoximone PDE inhibitor Increased

Calcium sensitizing agent

Levosimendan Myofilament calcium sensitizer, PDE-3 Neutral
inhibitor

Digitalis

Digoxin Na-K pump inhibitor, raises SR calcium Neutral, increased mortality if
long-term therapy discontinued

NEWER EMERGING AGENTS

Omecamtiv mecarbil Potentiates the effects of myosin on Unknown
actin to prolong systole

Istaroxime Na-K pump inhibitor, PDE inhibitor Unknown

SERCA2a gene therapy Restoration of SERCA2a to improve calci- Unknown
um release and reuptake from the SR

Pic 1: Intracellular Signaling Cascades Within Cardiomyocytes Altered by Inotropes[1]

Cardio Diabetes Medicine

518 Cardio Diabetes Medicine 2017

and cerebral arteries as well as promoting natriure- dysfunction .Lowest effective dose has to be admin-
sis through direct distal tubular effects. The DAD-HF istered with contibuous BP and rhythm monitoring,
study of 60 patients hospitalized for AHF suggested with a more gradual weaning off. Temporary adjust-
that a combination of low-dose frusemide and low- ments to afterload-reducing agents or diuretics may
dose dopamine resulted in comparable urine output assist in weaning. Concomitant use of beta blocker
and dyspnea relief but improved renal function pro- therapy has a competitive antagonism effects on
file and potassium homeostasis compared with high- dobutamine, and higher doses of dobutamine (10 to
dose frusemide. In contrast, the ROSE trial of 241 pa- 20 μg/ kg/min) may be required to obtain the desired
tients with acute heart failure and renal dysfunction hemodynamic effects.
showed that low-dose dopamine did not enhance
decongestion nor improve renal function when add- Adverse effects: Tachycardia, increasing ventricular
ed to diuretic therapy. If low-dose dopamine therapy response to atrial fibrillation, increased atrial and
is initiated, it should be discontinued in the event of ventricular arrhythmias, myocardial ischemia( direct
no response. toxic effect). It can also cause idiosyncratic adverse
effects like eosinophilia and fever. An eosinophilic
Intermediate-dose dopamine (2 to 10 μg/kg/min) re- hypersensitivity myocarditis has been reported in 2.4
sults in enhanced release of norepinephrine which to 23 percent of patients treated with a prolonged
stimulates the cardiac receptors causing increase in dobutamine infusion. The CASINO (“CAlcium Sensi-
inotropy and mild stimulation of peripheral vasocon- tizer or Inotrope or NOne in low output heart fail-
stricting receptors. Dopamine has poor response in ure”) study significantly demonstrated the increased
patients with severe systolic dysfunction[2,3]. This mortality with dobutamine compared with placebo,
is because the positive inotropic effect of dopamine consistent with the results of other studies of this
is largely dependent on myocardial catecholamine class of agent.
stores, which often are depleted in patients with ad-
vanced heart failure, High-dose dopamine (10 to 20 Although initially short term infusion proved clinical
μg/kg/min) by direct agonist effects on alpha1-ad- benefit and was used for chronic home or outpa-
renergic receptors causes vasoconstriction of the tient infusions the FIRST (Flolan International Ran-
peripheral and pulmonary artery. These doses carry domized Survival Trial), dobutamine was associated
a significant risk of precipitating limb and end-organ with worse survival and poorer clinical outcomes and
ischemia and should be used cautiously. did not improve quality of life during or after the
infusions. However long-term infusions are still used
Dobutamine as a bridge to heart replacement therapy and also
in the palliative care setting.
Dobutamine has a direct agonistic effect on β1- and
β2-adrenergic receptors with no vasoconstrictor prop- Epinephrine
erties and less tachycardia and has multiple actions
with variable effect. Beta receptor stimulation results It also has a balanced vasodilator and vasoconstric-
in increased inotropy and chronotropy. At low dos- tor effects. Synthetically manufactured norepineph-
es(1 to 2 μg/kg/min), stimulation of beta2 and alpha rine is uses in the treatment of severe septic and car-
receptors causes vasodilation, reduction in afterload diogenic shock. Typically, norepinephrine is infused
and systemic vascular resistance thereby increases at 0.2 to 1 μg/kg/min.
cardiac output indirectly. At higher doses, (5 to 10 μg/
kg/min) vasoconstriction can occur with decreased Noradrenaline and dopamine: Similar to high-dose
venous capacitance and increased right atrial pres- dopamine, it has a propensity to cause skin necrosis
sure. Tachyphylaxis may occur with infusions lasting and sloughing of tissue and should be given through
longer than 24 to 48 hours, owing in part to receptor a secure intravenous cannula. A comparator study
desensitization. published in 2010 indicated that a subset of patients
with cardiogenic shock derived more survival benefit
 Advantages over dopamine: It does not increase sym- from norepinephrine than from dopamine. Although
pathetic norepinephrine signaling or peripheral va- the overall mortality rate was similar between dopa-
soconstriction. Whereas dopamine rises blood pres- mine and norepinephrine the adverse effects with
sure through peripheral vasoconstriction dobutamine the use of dopamine was more than with the use of
does it by solely increasing cardiac output. norepinephrine

Uses: Generally used in patients with significant Uses: Occasionally some patients in cardiogen-
hypotension and in the setting of significant renal ic shock may present with vasodilation and hypo-

GCDC 2017

Inotropes and Heart : When to Use and When Not to Use 519

tension and some patients may develop refractory levels in the range of 0.5 to 0.9 ng/ml may be op-
vasodilation following mechanical circulatory assist timal. In general, digoxin levels below 1.0 ng/ml are
device implantation. These patients benefit well from safer and may even be more effective. A post-hoc
norepinephrine (vasoconstriction). Norepnephrine is subgroup analysis of the DIG study indicated that
also an useful agent in the treatment of transplant the effects of digoxin vary between men and women.
recipients with denervated hearts due to its direct Digoxin was associated with an increase in all-cause
effect on increasing cardiac inotropy independent of mortality among women, but not men, with systol-
myocardial catecholamine stores. ic heart failure. This may be explained that women
because of their lower BSA, may be more prone to
Adverse effects: Tachycardia, myocardial ischemia, harmful elevations of digoxin levels (≥1.2 ng/ml)  [4]
and arrhythmia(effects similar to high doses dopa-
mine) Phosphodiesterase Inhibitors

NON ADRENERGIC AGENTS Phosphodiesterase IIIa (PDE IIIa) is compartmen-
talized in the cardiac and vascular smooth muscle,
Digoxin where it terminates the signaling activity of cAMP by
degrading it to AMP. Many specific inhibitors of PDE
Digoxin is the only safe and effective oral positive IIIa, such as milrinone and enoximone, have been de-
inotropic agent. By inhibiting the sarcolemmal Na+/ veloped to provide organ specific improvements in
K+ ATPase pump, digoxin impedes the transport of hemodynamics through increasing myocardial and
sodium from the intracellular to the extracellular vascular smooth muscle cell cAMP concentrations.
space reducing the transmembrane sodium gradient PDEIs cause significant peripheral and pulmonary
further reducing the activity of the Na+/Ca2+ exchang- vasodilation, reducing afterload and preload, while
er, thereby raising the intracellular calcium levels. The increasing inotropy. These effects make them well
increase in the activator calcium is responsible for suited for use in patients with LV dysfunction and
both its inotropic and the arrhythmogenic effects of pulmonary hypertension or in transplant recipients.
cardiac glycosides.Digoxin does not affect heart rate
or blood pressure adversely. It does not increase the Milrinone
myocardial oxygen demand nor reduce coronary per-
fusion. It diminishes neurohormonal activation and Milrinone is a bipyridine, noncatecholamine, positive
improves hemodynamics at rest and during exercise. inotropic agent that can be given intravenously to pa-
Another advantage is that it is available in both in- tients with advanced systolic heart failure to improve
travenous and oral form. Most importantly, digoxin cardiac performance. It inhibits PDE-3, an intracellular
can improve symptoms and tends to reduce hos- enzyme that breaks down cyclic adenosine mono-
pitalization rate and if digoxin is withdrawn from a phosphate (cAMP) and thus increase cAMP, which
stable heart failure patient there is considerable risk increases calcium entry into the cardiac myocytes as
of clinically deterioration. Digoxin is cleared by renal well as the rate of removal, which in turn leads to
excretion, hence must be used cautiously in patients increased myocardial contractility. It is both a posi-
with impaired renal function. tive inotropic agent and a peripheral vasodilator. Mil-
rinone also has lusitropic properties which are mani-
Uses: Atrial fibrillation occurs in roughly 20% to 30% fested by improvement in diastolic function. It raises
of patients with heart failure and digoxin is particu- heart rate, but not to the same extent as dobutamine.
larly useful for patients with heart failure and con-
comitant atrial fibrillation when the uses of other Milrinone is the most commonly used PDEI, but only
rate controlling drugs such as diltiazem or verapamil 3% of patients in ADHERE and less than 1% in EHFS II
may be problematic. Digoxin has been used to wean received it. Patients who have had prolonged admin-
patients dependent on intra-aortic balloon pumps or istration of milrinone may experience delayed dete-
inotropic support. rioration, so they should be observed for at least 48
hours after cessation. Milrinone is renally excreted,
The results from the DIG (Digitalis Investigation Group) necessitating dose adjustment in the presence of
study indicated that digoxin had a neutral effect on renal dysfunction or substitution with dobutamine.
mortality, although reductions were seen in overall
rates of hospitalization and heart failure progression. Adverse effects: Hypotension and atrial and ventric-
The DIG trial also demonstrated the importance of ular arrhythmias.
measuring digoxin levels.
In OPTIMECHF (Outcomes of a Prospective Trial of
Digoxin levels  ≥1.2 ng/ml may be harmful; whereas, Intravenous Milrinone for Exacerbations of Chronic

Cardio Diabetes Medicine

520 Cardio Diabetes Medicine 2017

Heart Failure) patients admitted with exacerbation of and vasodilators to receive either levosimendan or
systolic heart failure not requiring intravenous ino- dobutamine. An early reduction in mortality was not
tropic support were randomly assigned to receive sustained through 180 days, but levosimendan was
milrinone or placebo infusion. No difference was associated with a higher incidence of atrial fibrillation
found in the primary endpoint of days hospitalized and lower incidence of worsening heart failure com-
for cardiovascular causes within 60 days, but signif- pared with dobutamine.
icant increases in sustained hypotension and new
atrial arrhythmias were noted in the milrinone-treated NEWER INOTROPES
patients. In addition, a post hoc subgroup analysis
demonstrated increased mortality in patients with an Omecamtiv mecarbil
ischemic cause of heart failure who received milri-
none. This study reinforces the need for caution in Formerly known as CK-1827452, omecamtiv mecarbil
selecting these agents for the treatment of patients [1]is a new potential therapy for heart failure. Ome-
with AHF. camtiv mecarbil is the first selective cardiac myosin
activator to be studied in humans. The development
Enoximone of omecamtiv mecarbil showed that myocardial per-
formance can be improved by prolonging systole
Enoximone also is a type IIIa PDE inhibitor. Dosing is rather than increasing the velocity of fiber-shorten-
essentially one-tenth that of milrinone. It is extensive- ing, which is the usual mechanism typical of most
ly metabolized by the liver into renally cleared active positive inotropic agents. Omecamtiv mecarbil selec-
metabolites, so doses should be reduced in the set- tively activates the S1 domain of cardiac myosin and
ting of either renal or hepatic insufficiency. increases the rate of ATP turnover by accelerating
actin-dependent phosphate release and by slowing
Levosimendan the rate of adenosine 5′-diphosphate (ADP) release
leading to increased numbers of myosin molecules
Levosimendan is a novel agent that increases myo- bound to actin causing prolongation of the contrac-
cardial contractility and produces peripheral vasodila- tile force without increasing left ventricular pressure
tion. The main mechanism of action includes calcium development (dP/dt). The calcium transient remains
sensitization by calcium-dependent (systolic) tropo- unchanged in contrast to conventional inotropic
nin C binding and activation of vascular smooth mus- agents where there is an increase the calcium tran-
cle potassium channels. It also has some in vitro PDEI sient. By this mechanism, it appears that omecamtiv
activity and at high concentrations, PDE-3 inhibitor mecarbil does not increase the heart’s demand for
activity. Levosimendan has an active, acetylated me- energy; rather, it improves systolic performance by
tabolite with a half-life of over 80 hours, so that it can allowing the myocardium to make more efficient use
continue to exert its effect even days after discontin- of energy.
uation of the infusion. In clinical trials, levosimendan
has been shown to significantly increase cardiac out- The ATOMIC AHF (Acute Treatment with Omecamtiv
put, reduce PCWP and afterload, and decrease dys- Mecarbil to Increase Contractility–Acute Heart Failure
pnea. Initial clinical studies demonstrated reduced ar- showed that the drug appears to avoid the usual
rhythmias and improved survival with levosimendan adverse effects (e.g., tachycardia and arrhythmia) of
compared with placebo and dobutamine. REVIVE-II traditional inotropic agents. Early experience demon-
(Randomized multicenter EValuation of Intra- Venous strated an increase in LV ejection fraction and stroke
levosimendan Efficacy versus placebo in the short- volume with decreased end-systolic and end-diastolic
term treatment of decompensated heart failure), a re- volumes. At high plasma concentrations, chest pain,
cent study, demonstrated significant improvement in tachycardia, and myocardial ischemia were noted. In
clinical status, serial BNP levels, and hospital length a sense, omecamtiv mecarbil may not be an inotrope,
of stay with levosimendan treatment compared with but it does improve myocardial systolic performance.
standard care, but also documented more episodes
of hypotension, atrial fibrillation, and ventricular ec- Sarcoplasmic Recticulum Ca2+- ATPase
topy, as well as a nonsignificant increase in early Modulation
deaths at 14 to 90 days.The SURVIVE (Survival of
Patients with Acute Heart Failure in Need of Intrave- Sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) is
nous Inotropic Support) trial randomly assigned 1327 an enzyme responsible for both myocardial relax-
patients with systolic dysfunction, evidence of low ation(by reuptake of calcium into the SR) and con-
cardiac output, and dyspnea at rest despite diuretics tractility (by controlling the amount of calcium in the
SR). SERCA2a is usually downregulated in the fail-

GCDC 2017

Inotropes and Heart : When to Use and When Not to Use 521

ing heart which results in contractile dysfunction and HOME INOTROPIC SUPPORT
arrhythmia. Experimental models have proved when
SERCA2a expression is increased in cardiomyocytes SELECTION OF PATIENTS :
which can lead to restoration of intracellular calcium
cycling there was demonstrable  improvement in Patient preferences and goals of care should ideally
contractility, cardiac metabolism, and survival The be determined prior to any initiation of intravenous
CUPID (Calcium Up-regulation by Percutaneous ad- inotropic therapy. This should involve direct conver-
ministration of gene therapy In cardiac Disease) trial, sations with the patient and family discussing the
a multicenter open-label study designed to evaluate available treatment options and possible outcomes.
the safety profile and provide first-in-human data for When one is unable to wean patients from inotropic
the gene transfer of SERCA2a cDNA (adeno-associ- support discharging a patient with home inotropic
ated virus [AAV1]/SERCA2a). Three separate dosing therapy [5] and patients should also be instructed
regimens of AAVI/SERCA2a were tested and com- that further hospitalization is likely even with home
pared to a placebo group, with the high-dose group inotropic therapy.
showing improvement or stabilization in each of the
efficacy endpoints for the 6-month primary analysis. INOTROPES IN PATIENTS AWAITING
AAV1/SERCA2a was well tolerated with no reported HEART TRANSPLANT — 
adverse events. Thus The CUPID trial demonstrates
that SERCA2a is a potential therapeutic target in pa- BRIDGE THERAPY :
tients with heart failure and two clinical trials are cur-
rently targeting SERCA2a, one in patients implanted Patients with severe heart failure (HF) with reduced
with left ventricular assist devices and another exam- ejection fraction who are awaiting heart transplanta-
ining the effect on cardiac remodeling. tion constitute a unique population with respect to
the role of therapy for hemodynamic support. In this
Istaroxime setting, the goal of HF management is to maintain
the patient’s clinical stability long enough to enable
Istaroxime is a novel intravenous drug which inhibits the patient to undergo transplantation when a donor
the activity of sodium-potassium ATPase and stimu- heart becomes available. A variety of approaches have
lates sarcoplasmic reticulum calcium ATPase isoform been used to “bridge” a patient to heart transplanta-
2a (SERCA2a). tion, including the use of mechanical ventricular as-
sist devices. Intravenous inotropic agents are another
This dual mechanism of action results in both inotro- option for the temporary hemodynamic support of a
pic action(by allowing the accumulation of cytosolic heart transplant candidate. The clinical improvements
calcium during contraction) and a lusitropic effect(by seen with inotropes (reduced hospitalization, less fre-
sequestering calcium during relaxation) and thus it quent worsening of HF) are beneficial because the
was found improve both systolic and diastolic dys- patient is maintained in an optimal clinical condition
function without an increased incidence of arrhyth- prior to surgery. The increased risk of sudden death
mias. The HORIZON-HF (Hemodynamic, Echocardio- associated with these agents can be mitigated with
graphic, and Neurohormonal Effects of Istaroxime, the use of an implantable cardioverter-defibrillator
a Novel Intravenous Inotropic and Lusitropic Agent: (ICD) and pharmacotherapy (usually amiodarone) for
a Randomized Controlled Trial in Patients Hospital- the suppression of ventricular arrhythmias.
ized with Heart Failure) study, a double-blind, place-
bo-controlled trial in patients hospitalized with acute The benefit of outpatient intravenous inotropic
heart failure, assessed the hemodynamic effects of therapy as a bridge to heart transplantation was
istaroxime which showed that there was reduction in illustrated in a report of 21 patients with severe
the primary end point- reduction in pulmonary cap- HF treated for a mean duration of 146 days. All
illary wedge pressure, was improved for all 3 doses but one of the patients received an ICD prior to
compared to placebo. The distinguishing features hospital discharge. Intravenous inotropic therapy
from conventional agents included, a dose-depen- resulted in significant improvements in functional ca-
dent reduction in heart rate, an increase in systolic pacity, renal function, and hemodynamics as well as
blood pressure but no effect on neurohormones, re- a decrease in the number of hospitalizations.
nal function, or troponin levels. Thus Istaroxime may
be a potential inotrope which avoids the adverse ef- Thus for patients awaiting transplant, inotropes are
fects associated with conventional inotropes. meant to maintain hemodynamics and end-organ
function and alleviate symptoms as a bridge to trans-
plantation. For patients who are not likely to undergo
further advanced therapies, inotropic agents may al-

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522 Cardio Diabetes Medicine 2017

leviate symptoms and should be provided based on awaiting cardiac transplantation
the patient and family’s preferences.
As “palliative therapy” for symptom control in select
WHEN TO USE? patients with stage D HF despite optimal GDMT and
device therapy who are not eligible for either MCS or
TEMPORARY INTRAVENOUS INOTROPIC cardiac transplantation.
SUPPORT
WHEN NOT TO USE?
Patients with cardiogenic shock [6]should receive
temporary intravenous inotropic support to maintain Use of parenteral inotropic agents in hospitalized pa-
systemic perfusion and preserve end-organ perfor- tients is potentially harmful[6] if used
mance.
• without documented severe systolic dysfunction,
Until definitive therapy (eg, coronary revasculariza-
tion, Mechanical Circulatory Support(MCS), heart • without hypotension
transplantation)
• without impaired perfusion and
Until resolution of the acute precipitating problem
• without evidence of significantly depressed cardi-
CONTINUOUS INTRAVENOUS INOTROPIC ac output, with or without congestion.
SUPPORT
Long-term use of either continuous or intermittent,
As a “bridge therapy” in patients with stage D HF intravenous parenteral positive inotropic agents, in
who are refractory to Guidelines Directed Medical the absence of specific indications or for reasons
Therapy and device therapy who are eligible for and other than palliative care, is potentially harmful in
the patient with HF.

GCDC 2017

Inotropes and Heart : When to Use and When Not to Use 523

CONCLUSION

End-stage heart failure is a progressive disease with
high mortality and limited medical therapeutic op-
tions. Long-term use of conventional inotropic agents
has been associated with no improvement or even
increased overall mortality. One would hope that the
next generation of inotropic agents will achieve en-
hanced myocardial performance without altering
the velocity of shortening or promoting excessive
calcium modulation. A better understanding of the
physiology and important adverse effects of these
medications should lead to directed clinical use, with
realistic therapeutic goals. 

REFERENCES:

1. Inotropes: Journal of the American College of Cardiology Vol. 63, No.
20, 2014

2. Braunwald’ s Heart diseases: text book of cardiovascular medicine- 10th
edition

3. Inotropes and Vasopressors: Review of Physiology and Clinical Use in Car-
diovascular Disease Christopher B. Overgaard, MD; Vladimír Dzˇavík, MD

4. Use of vasopressors and inotropes: UPTODATE 2016
5. Allen LA, Stevenson LW, Grady KL, et al. Decision making in advanced

heart failure: a scientific statement from the American Heart Association.
Circulation 2012;125:1928–52.
6. 2013 ACCF/AHA Guideline for the Management of Heart Failure-A Re-
port of the American College of Cardiology Foundation/American Heart
Association

Cardio Diabetes Medicine

524 Cardio Diabetes Medicine 2017

Integrated Management of
Diabetes Through Novel Therapies

Dr. Dina Nagodra, MBBS

MSc Public and Tropical Health, UMST, Sudan
Certified in Regenerative Medicine, Utrecht University, Netherlands

Certified in Diabetes, IDF, Belgium

1.Introduction: • Bring blood glucose levels under control with oral
hypoglycemics
According to the International Diabetes Federation,
diabetes currently affects 7% of the world’s popula- 2.1 Mesenchymal Stem Cells
tion — nearly 250 million individuals worldwide. This
total is expected to rise to 380 million by 2025 as Mesenchymal stem cells (MSCs) harbor differentia-
a result of aging populations, changing lifestyles, tion potential, immunosuppressive properties, and
and a recent worldwide increase in obesity.  DM is anti-inflammatory effects, and they are considered
a major risk factor for ischemic heart disease and an ideal candidate cell type for treatment of DM.
stroke, which collectively account for high rates of MSC-related research has demonstrated exciting
morbidity and mortality among adult patients. In ad- therapeutic effects in glycemic control both in vivo
dition, DM is the most common underlying cause of and in vitro, and these results now have been trans-
chronic kidney disease and blindness among adults. lated into clinical practice. The richest source for
Improvement in glycemic control is the key to pre- MSCs, however, is the bone marrow. MSCs are niche
vention of complications of DM. Type 2 diabetes mel- cells. (2).
litus (T2DM), which accounts for 90–95% of all DM
cases, results from a combination of insulin resis- Several recent studies in rodents have indicated that
tance and dysfunction of insulin-producing pancre- the adult pancreas contains some type of endocrine
atic beta cells. It is the major cause of amputations progenitor cells that can differentiate toward b-cells
in the United States, accounting for 50% to 70% of (3,4).
all nontraumatic amputations, and diabetic neuropa-
thy accounts for more hospitalizations than all other During pregnancy, pancreatic islet cells normal-
diabetic complications combined. ly expand in number to meet increased metabolic
demands. Researchers have found that the protein
2.Why Stem Cells? HNF4-alpha helps increase b-cell mass and also en-
able b-cell proliferation. Furthermore, various reports
As such, stem cell therapy would directly benefit per- have also described putative stem cells in the liver,
sons with diabetes by replenishing b-cells that are spleen, central nervous system, and bone marrow
destroyed by autoimmune processes, although it that can differentiate into insulin-producing cells.
would still be necessary to mitigate the autoimmune
destruction of b-cells (1).  Once a population of these cells has been gener-
ated, they could either 1) be induced to differentiate
Stem Cell Treatment can be used for both, Type 1 into insulin-producing cells in vitro and then be trans-
and Type 2 Diabetes. The long-term goals of are to: planted, or 2) be injected into the circulation along
with stem cell stimulators, which differentiate into a
• Prolong life permanent self-renewing b-cell population.

• Reduce symptoms Even in advanced cases of diabetes mellitus, the hu-
man pancreas retains its ability to restore the func-
• Prevent diabetes-related complications such as tional possibilities of its tissues as well as their re-
blindness, heart disease, kidney failure and am- generation, specifically the insulin-producing β-cells
putation of limbs

GCDC 2017

Integrated Management of 525
Diabetes Through Novel Therapies

of the Islets of Langerhans. MSCs are known to pro- F)-BB, and angiopoietin-1, also play an integral role
mote the regeneration of pancreatic islet beta cells, in the process of cell regeneration.
protect endogenous pancreatic islet beta cells from
apoptosis, and ameliorate insulin resistance of pe- Type 1 Diabetes is characterized by the action of
ripheral tissues by providing a supportive niche mi- b-cell-specific, autoreactive T-cells. Even if the regen-
croenvironment driven by the secretion of paracrine erative properties of the pancreas remain functional,
factors or the deposition of extracellular matrix. the continued presence of these T-cells effectively
counteracts any endogenous repair and would likely
The identification of stem cells that possess the po- decimate populations of newly-regenerated or trans-
tential to differentiate into insulin-producing cells planted insulin-producing cells (5).
(IPCs), improve pancreatic regeneration, and amelio-
rate insulin resistance offers an alternative to islet In addition to their regenerative properties, MSCs
cell transplant. The potential to differentiate into IPCs have also demonstrated an immunoregulatory ca-
was first considered to be the primary mechanism pacity. MSCs are also known as immunoprivileged
by which MSCs ameliorate hyperglycemia in T2DM. cells because of the low intracellular expression of
(Fig 1) class II major histocompatibility (MHC) proteins and
co-stimulatory molecules. MSCs suppress the prolif-
MSCs promote the regeneration of endogenous pan- eration of T lymphocyte by inhibiting the energy me-
creatic islet beta cells by migrating to the injured islet tabolism of the T cell population, promoting T-cell
cells. The MSCs participate in the repair processes tolerance, or by inducing proliferation of regulatory
by secreting a variety of cytokines and growth fac- T-cell populations.  MSCs also inhibited a variety of
tors that have both paracrine and autocrine activi- immune cell functions, including cytokine secretion
ties.  The paracrine factors, such as vascular endo- and cytotoxicity of T and natural killer (NK) cells. Giv-
thelial growth factor (VEGF)-alpha, insulin-like growth en that oxidative stress injury induced by hypergly-
factor (IGF)-1, platelet-derived growth factor (PDG- cemia is recognized as a major etiological factor in

Fig 1: Diagram explaining the mechanism by which MSCs act on type 2 diabetes.
Cardio Diabetes Medicine

526 Cardio Diabetes Medicine 2017

the development of diabetes, MSCs have been re- strategy for the treatment of T2DM.
ported to promote islet survival against hypoxia and
oxidative stress. Autophagy by MSCs is one of ideal A total of 96 registered phase I/II clinical studies
among T2DM patients can be found with the clinical

No Stem cell Randomized Mean dose of Mode of Follow-up Assessment Assessment Publication
type placebo injected injection period of beta-cell of insulin
function sensitivity
control study cells/kg

1. MNCs – – Intrapancreatic 12 month Fasting C-peptide Estrada et al. [69]

2. BM-MNCs – 3.1 × 106 Intra- 6 months Fasting HOMA-IR Bhansali et al. [70]
pancreatic C-peptide,
glucagon
stimulated
c-peptide,
HOMA-β

3. BM-MNCs Yes 3.2 × 108 Intra- 12 months Fasting HOMA-IR Bhansali et al. [71]
pancreatic C-peptide,
glucagon
stimulated
c-peptide,
HOMA-β

4. UC-MSCs – 1 × 106 IV + 12 months Fasting C-peptide HOMA-IR Liu et al. [72]

intrapancreatic and HOMA-β

on day 5

4. BM-MNCs Yes 2.8 × 109 Intra- 33 months Mixed meal Hu et al. [73]
pancreatic tolerance test

6. MNCs – (5–7) × 108 IV or 6 months Fasting HOMA-IR Sood et al. [75]
pancreatic C-peptide,
ar terial glucagon
infusion stimulated
c-peptide,
HOMA-β

7. PD-MSCs – 1.35 × 106 IV 6 months Fasting C-peptide Fasting insulin Jiang et al. [77]

8. MSCs – 1.8 × 106 IV 6 months Fasting C-peptide Kong et al. [78]

9. BM-MSCs – (0.3–2.0) × IV 24 months Fasting C-peptide Fasting insulin Skyler et al. [83]
106

10. BM-MNCs Yes 3.8 × 109 Pancreatic 12 months Fasting C-peptide HOMA-IR Wu et al. [85]
ar terial and OGTT
infusion

11. BM-MNCs – 3.76 × 108 Pancreatic 720 days Mixed meal Wang et al. [86]
ar terial tolerance test
infusion

12. CB-SC – – IV 12 months Fasting C-peptide HOMA-IR Zhao et al. [87]

and HOMA-β

13. BM-MSCs Yes MSCs: 1 Intra- 12 months Fasting HOMA-IR, Bhansali et al. [88]
and MNCs x 106/kg; pancreatic C-peptide, HOMA-S
MNCs:109in glucagon and insulin
total stimulated sensitivity
c-peptide, index during
HOMA- β, hyperglycemic
hyperglycemic clamp
clamp

Table 1: Summary of MSC-based therapies for type 2 diabetes

MSCs mesenchymal stem cells, MNCs mononuclear stem cells, UC umbilical cord, PD placenta-derived, CB-SC cord blood-derived
multipotent stem cells, IV intravenous, HOMA-β homeostatic model assessment of beta cell function, HOMA-IR homeostasis model

assessment of insulin resistance

GCDC 2017

Integrated Management of 527
Diabetes Through Novel Therapies

trials registry. Thirteen papers evaluating the clinical to reduce their existing insulin doses by 75 to 80 %
effects of MSC treatment in the management of to just minimum necessary. These difficult cases as
T2DM have been published (2). a rule were having diabetes of more than 22 years
duration and/or with severe obesity. Complications
As the clinical efficacy of MSC treatment for T2DM due to diabetes, such as various pain syndromes,
is a major concern, HbA1c  reduction and insulin re- diabetic cardiomyopathy, nephropathy, neuropathy,
quirements are frequently used as measures to as- diabetic foot with ulcers and angiopathic changes,
sess the efficacy of MSC treatment for T2DM. Fast- as well as obesity disappeared practically completely
ing C-peptide is the most convenient and effective and even impaired erectile function was restored up
indicator, it was evaluated in all 13 published clini- to the male patient’s satisfaction. Those having high
cal studies HOT can promote stem cell mobilization blood pressure could see their blood pressure come
and endothelial progenitor cell release by increasing down towards normal levels and accordingly blood
the concentration of carbon monoxide synthase. It pressure medications were either stopped or doses
was hypothesized that the combination of HOT and decreased. Obese patients experienced an average
MSC transplantation can have a synergistic effect. weight loss of between 6 to 13 kgs. (7)
In 2008, Estrada et al. first found that combination
therapy with BM-MSC transplantation and hyperbaric 2.Importance of Nerve Growth Factor and
oxygen therapy (HOT) effectively reduced HbA1c lev- Insulin like Growth Factor -1
els in patients with T2DM for up to 1 year (6).
Alternation in NGF levels has been correlated with
On the other hand, more studies have proved that various microvascular complications including reti-
biological activity factors, such as VEGF, IGF-1, and nopathy, nephropathy, and neuropathy. 
β-FGF, secreted by MSCs can regulate the local mi-
croenvironment of the damaged tissue, inhibit cell In Diabetic Neuropathy, there is a reduction in the
apoptosis, improve the immune defense system, availability of nerve growth factor (NGF) and neurotro-
and promote tissue regeneration and revasculariza- phin family of peptides, required for the maintenance
tion. Systemic infusion of MSCs was believed to be of the neurons, the ability to resist apoptosis and
superior to local injection because the therapeutic regenerative capacity. There is increasing evidence
effects of MSCs were mainly derived from their se- that there is a deficiency of NGF in diabetes, as well
cretory effects rather than their differentiation effect. as the dependent neuropeptides substance P (SP)
The best homing of MSCs in the pancreas was ob- and calcitonin gene-related peptide (CGRP) that may
served when cells were infused in the superior pan- also contribute to the clinical symptoms resulting
creaticoduodenal artery. Multiple injections of stem from small fiber dysfunction. Similarly, Neurotrophin
cells results in a further reduction of insulin dose 3 (NT3) appears to be important for large fiber and
requirements . In current clinical studies, the mean Insulin like Growth Factor for autonomic neuropathy.
dose of injected cells ranges from 1 × 106 to 2.6 × 107/
kg of bodyweight due to the use of different cell Since the identification of insulin-like growth factor-I
types and counting methods. In a randomized, pla- (IGF-I) as one of the proteins responsible for the “non-
cebo-controlled, dose-escalation study, patients with suppressible insulin-like activity”, there is large-scale
type 2 diabetes inadequately controlled with oral an- production of recombinant hIGF-I for use in the treat-
tidiabetic agents received allogeneic BM-MSCs at a ment of DM. Florida conducted a study where they
dose of 0.3 × 106, 1.0 × 106, or 2.0 × 106/kg. At week 12, looked at several areas. They divided the volunteers
the target HbA1c <7 mg/dL was achieved by 33% of into three groups, one group received IGF-1 alone,
the patients who received the 2.0 × 106/kg dose and one group received IGF-1 and prednisone, and one
13.3% of those who received the 0.3 × 106/kg dose. (2). group received prednisone alone.The study found
that IGF-1 at 100 mcg per kilogram of body weight
Why Integrative approach? given twice daily enhanced the body’s protein me-
tabolism in the same way as human growth hormone
Integrated treatment of Diabetes consisting of stem did. Instead, the test subjects who received IGF-1 and
cells, IV Laser blood irradiation, IV ozone thera- prednisone had normal glucose metabolism.  These
py, Post treatment personalized low carbohydrate researchers believe IGF-1 offers much promise in the
diet and orthomolecular supplements have shown treatment of protein catabolic states.
tremendous decrease in consumption of oral hy-
poglycemic and insulin. (95%) could stop all their NGF, brain-derived neurotrophic factor (BDNF), NT-3
anti-diabetic medications, (70%) could stop their in- and neurotrophin-4 (NT-4) are known to be essential
sulin injections, In remaining (30%) it was possible for growth, differentiation and survival of neurons

Cardio Diabetes Medicine