Download The Glycemic Pentad: Role Of Insulin Analogues

Article ID: WMC00562
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The Glycemic Pentad: Role Of Insulin Analogues
Corresponding Author:
Dr. Sanjay Kalra,
Endocrinologist, Bharti Research Institute of Diabetes and Endocrinology, 132001 - India
Submitting Author:
Dr. Sanjay Kalra,
Endocrinologist, Bharti Research Institute of Diabetes and Endocrinology, 132001 - India
Article ID: WMC00562
Article Type: Review articles
Submitted on:08-Sep-2010, 02:28:27 PM GMT
Published on: 08-Sep-2010, 06:34:10 PM GMT
Article URL: http://www.webmedcentral.com/article_view/562
Subject Categories:ENDOCRINOLOGY
Keywords:Diabetes, Glycemic Control, Insulin, Insulin Analogues, Modern Insulins, Quality of Life
How to cite the article:Kalra S , Kalra B . The Glycemic Pentad: Role Of Insulin Analogues . WebmedCentral
ENDOCRINOLOGY 2010;1(9):WMC00562
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The Glycemic Pentad: Role Of Insulin Analogues
Author(s): Kalra S , Kalra B
Introduction
Achieving glycemic control is the main aim of diabetes
care, and near euglycemic levels are targeted to
minimize the risk of developing chronic complications
of the condition. Large trials have demonstrated the
benefits of glycemic control in both type 1 and type 2
diabetes (1,2).Good glycemic control means effective
targeting of fasting plasma glucose (FPG),
postprandial plasma glucose (PPPG) and glycated
hemoglobin (HbA1c), together known as ‘the glucose
triad’(3). Inspite of adequate control of the triad,
however, diabetic complications do occur, and recent
trials have shown an increase in mortality inspite of
good HbA1c (4).
This has led to the emergence of a fourth aspect of
glycemic control, i.e, glycemic variability, which needs
to be minimized for effective diabetes care (3). This is
included in the concept of the ‘glycemic tetrad
A fifth angle, however, which has emerged recently, is
quality of life. Just as it is important to target glucose
levels, it is necessary to ensure good quality of life
with any anti-diabetic medication (5).
These concepts can be unified as a ‘The Glycemic
Pentad,’ and need to be kept in mind while planning
any diabetes management strategy. This article
reviews current information regarding the role, utility
and importance of modern insulin analogues with
respect to all angles of the Glycemic Pentad.
Table 1: The Glycemic Pentad
Fasting plasma glucose.
Postprandial plasma glucose.
HbA1c
Glycemic variability.
Quality of life.
Fasting Plasma Glucose
Fasting hyperglycemia is mediated by excessive
hepatic insulin resistance, normal muscle insulin
sensitivity, a decrease in first phase (0-10 min) insulin
secretory response to intravenous glucose, a reduced
early phase (0-30 min) response to oral glucose, and
normal late –phase (60- 120 min) insulin response to
oral glucose(3).
High FPG has been shown to increase the risk of
retinopathy, microalbumuria, renal failure, as well as
cardiovascular death, heart failure, coronary artery
disease, stroke, and all cause mortality (6-9).
Variability of FPG (measured as variation coefficient
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(CV) of FPG) is an independent risk factor for
proliferative retinopathy, and is inversely related to
survival of patients with type 2 diabetes (10,11).
FPG of 110 mg% has been shown to increase the risk
of cardiovascular events by 1.33 (1.06 -1.67) with
respect to an FPG of 75 mg% (12).
An effective anti- diabetes regime, therefore, should
target FPG, while reducing the variability of FPG as
well. While choosing of an oral drug or insulin, one
should take these factors into account.
Post Prandial Plasma Glucose
Postprandial hyperglycemia is linked with normal or
slightly reduced hepatic insulin sensitivity, severe
muscle insulin resistance, defective early phase insulin
secretion in response to oral glucose, and a severe
deficit in late –phase insulin response to glucose load
(3).
Many epidemiological and interventional studies have
shown an independent link between high PPG and
cardiovascular disease, retinopathy, neuropathy, and
nephropathy (13,14). The role of PPG as an
independent risk factor is less clear for microvascular
complications than macrovascular ones (3).
A 2 hour glucose level of 140 mg% is associated with
a relative risk of cardiovascular events of 1.58 (12).
The importance of controlling post-prandial
hyperglycemia, thus, can not be ignored, and modern
diabetes management should focus on this as well.
HbA1c
HbA1c is the stable adduct of glucose at the Nterminal amino group of the ß- chain of HbA1c, formed
by a post –translational modification which forms an
unstable Schiff base, and later, a stable ketoamine.
Total glycohemoglobin refers to HbA1c as well as
products of glycation at certain lysine residues on the
Hb a and ß–chains (15,16).
HbA1c is the gold standard for assessment of
glycemic control. Many trials have shown the
correlation between reduction in HbA1c and reduction
of micro-as well as macro vascular complications
(1,2).
The UK Prospective Diabetes Study (UKPDS) in type
2 diabetes, and the Diabetes Complications and
Control Trial (DCCT) in type 1 diabetes patients, have
shown reduction in risk of chronic complications with
improvement in HbA1c (1,2).
HbA1c correlates with the average glycemia over the
preceding 8-12 weeks. Hence, all anti –hyperglycemic
drugs, new or old, are measured by their ability to
reduce HbA1c, and this is often taken as a measure of
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efficacy. However, variability is noted in individual
mean glucose concentrations for a given HbA1c. At
the same time, the mean glycemic value (MGV) is
determined not only by the various FPG and PPG
values, but also by glycemic swings.
To give a simple example, a person with PG values of
100 and 200 will have an MGV of 150 while another
individual with PG values of 50 and 250 will also have
an MGV of 150. Taking HbA1c alone as a therapeutic
target, therefore, is not enough.
Variability
The limitations of HbA1c and point glucose estimation
as markers for glycemic control has led to the
emergence of glycemic variability as a fourth target for
therapy.
The acceptance of variability as an endpoint for
treatment has spawned the term ‘glycemic tetrad’ (3).
Authors of the DCCT have hypothesized that mean
HbA1c is not the most complete expression of degree
of glycemia. Complication risk might be linked to
glycemic excursions, which generate reactive oxygen
species (ROS) and lead to oxidative stress.
Apoptosis is markedly increased and the production of
protein kinase C enhanced in human umbilical vein
endothelial cells exposed to periodic hyperglycemia
(17), and cells cultured in a medium with glycemic
fluctuations produce larger amounts of markers of
oxidative stress (18).
In vivo studies have revealed direct relationship
between mean amplitude of glycemic excursion
(MAGE) and urinary excretion of 8-iso –PGF2a, a
marker of oxidative stress (19). Glycemic swings have
shown to be more harmful to the endothelium,
measured by flow –mediated dilation, than stable
hyperglycemia (20). A retrospective analysis of DCCT
data has demonstrated that glycemic variability is
linked to development of microvascular complications
(21).
This body of evidence, therefore, means that variability
of action, or predictiveness, should be an important
consideration when deciding the pros and cons of a
particular therapy (3).
One should search, therefore, for a therapy with
minimal intra-and inter-individual variability.
Quality Of Life
Quality of life forms the fifth angle of the Glycemic
Pentad, along with FPG, PPG, HbA1c variability. Any
diabetes medication should be assessed with regards
not only to physician - reported outcomes, such as
blood glucose or HbA1c, but also by patient – reported
outcomes (PROs).
Patient reported outcomes are gaining ground as a
therapeutic target in diabetes and other chronic
disease, as they reflect the patient’s opinion about
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disease state or health status. PROs include various
measures, including quality of life (QoL), as well as
indices related to treatment satisfaction, mental health,
social life, and diabetes management and well being.
A recent tool is the MIND Youth Questionnaire (MK-Q)
(5). Which is used to assess psychosocial health in
pediatric diabetes.
Other tools include the Diab Met Sat questionnaire
(22). The Diab Met Sat questionnaire has 21 items
which can be assessed a an overall score or as three
subscales : burden (11 items), symptoms (5 items)
and efficacy (5 items) and efficacy (5 items).
Modern Insulins And The Glycemic Pentad
Traditional anti- diabetic therapy, including oral drugs
and the older insulins had some shortcomings,
including the risk of hypoglycemia, high intra individual
and inter individual variability, high index of intrusion
(e.g. having to take a tablet or injection 30 minutes
before meals), poor quality of life, and poor
satisfaction with medical therapy.(23)
The poor acceptance of traditional insulins was in part
because of their unphysiological action profile, which
did not match with food absorption patterns, and
therefore, led to unacceptable post –meal
hyperglycemia, and pre-meal hypoglycemia.
The risk of hypoglycemia and the glycemic swings to
the variability of control achieved with these drugs.
Modern insulins, or insulin analogues, such as insulin
detemir, aspart and lispro, have a more physiological
time –action profile, and less variability. These
attributes, combined with good efficacy, safety and
tolerability, ensure better quality of life with these
drugs. The freedom and flexibility of time of
administration means a lower index of intrusion into
the patient’s lifestyle.
Modern Insulins And Variability
Insulin analogues have been shown to be associated
with lower risks of hypoglycemia, lower levels of
postprandial glucose excursions, better patient
adherence, greater quality of life, and higher
satisfaction with treatment. The long-acting basal
analog insulin detemir has the additional advantage of
producing less weight gain, which has been
considered until now an almost inevitable
consequence of insulin replacement.(23)
In a study, nine healthy male volunteers received
subcutaneous injections of soluble insulin (0.2 U/kg) in
the abdominal region on each of the four study days.
Another 10 volunteers received an injection of insulin
aspart four times. Glucose infusion rates necessary to
neutralize the blood glucose-lowering effect of the
administered insulin were registered during
euglycemic glucose clamps (blood glucose 5.0 mmol/l;
basal intravenous insulin infusion 0.15 mU x kg(-1) x
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min(-1) over the subsequent 600 min. In comparison
to soluble insulin, subcutaneous injections of insulin
aspart led to a more rapid onset of action and a
shorter duration of action. Subcutaneous injection of
the insulin preparations resulted in intraindividual CVs
of the summary measures between 10 and 30%
(soluble insulin vs. insulin aspart: maximal metabolic
activity 15+/-7 vs. 16+/-10%, time to maximal
metabolic activity 14+/-10 vs. 11+/-6%; NS between
the preparations [means +/- SD]). The decline to
half-maximal activity after maximal activity showed a
lower intraindividual CV with insulin as part (19+/-9 vs.
11+/-5%; P = 0.018). The interindividual CVs were
higher than the intraindividual CVs (26 vs. 28, 23 vs.
19, and 26 vs. 17%). Generally, the pharmacodynamic
variability was higher than the pharmacokinetic
variability. For the pharmacokinetic measures, the
intra- and interindividual variability in t(max) was lower
for insulin aspart than for soluble insulin. (24)
In another treatment study, glucose excursions
evaluated from 24-hour glucose profiles showed less
variability with insulin aspart compared with human
insulin.(25)
Similar results have been noted for insulin detemir,
which exhibits much lower variability, and is more
predictive in its action, than glargine or NPH.(26)
Modern Insulins And Quality Of Life
Analysis of a cohort of Indian patients enrolled in the
improve study, receiving biphasic aspart, showed
higher patient satisfaction, with a mean overall score
of 79.03 at final visit vs. 52.33 at baseline visit. Overall
number of extremely satisfied patients increased from
5.4 % to 26%.
Improvement was noted in all subscales, with
symptoms score improving from 58.12 to 77.82,
burden score improving from 49.77 to 77.56, and
efficacy score from 48.98 to 81.79.(27)
Conclusion(s)
All aspects of the Glycemic Pentad, including quality of
life and glycemic variability, should be kept in mind
while prescribing therapy to a person with diabetes.
Modern insulins, or insulin analogues, combine
efficacy with safety and tolerability., This makes them
superior to, and better accepted, as management
strategies, as compared to traditional insulin
preparations.
The favourable data related to variability and quality of
life encourages use of modern insulins for
management of hyperglycemia.
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