68 Journal of The Association of Physicians of India ■ Vol.

65 ■ July 2017

CONSENSUS STATEMENT

Glycemic Pentad
Glycemic Pentad Forum

strategies has been recommended

Abstract in several guidelines aims at
Background: Conventionally, diabetes management involved targeting controlling the triumvirate of
FPG, PPG, and HbA1c, which are
the triad of FPG, PPG, and HbA1c. However, several studies have
conventionally referred as glycemic
suggested the quintessential need for a paradigm shift to incorporate
triad.1 The American Diabetes
glycemic variability and quality of life in the holistic diabetes control
Association recommends targeting
regimen.
HbA1c levels to <7.0% (53mmol/
Aim: To generate a consensus and ratify the position of Glycemic mol), pre-prandial glucose levels to
Variability (GV) and Quality of Life (QOL), along with the traditional 80 - 130 mg/dl (4.4 – 7.2 mmol/l) and
triad, in diabetes management in India. To evaluate whether the triple peak postprandial plasma glucose
fixed dose combination of metformin, glimepiride, and voglibose can levels to < 180 mg/dl (10.0 mmol/l)
accomplish the goals of glycemic pentad. in order to achieve better glycemic
Methodology: Glycemic pentad forum was instituted comprising of control. 2 However, “one size fits
55 experts from different regions of India in the field of diabetology all” concept is NOT suitable for
who discussed various evidences related to the topic and shared their the management of diabetes and
therefore individualized treatment
experiences and expressed their opinion on the relevance of glycemic
based on the patient’s status is
pentad in the present diabetes management and whether triple fixed
recommended.2 For instance, higher
dose combination of metformin, glimepiride, and voglibose is able to
HbA1c target might be appropriate
achieve glycemic pentad targets.
in people with co-morbidities and
Results: Forum has come to a consensus that the conglomerate of who are prone to hypoglycemia or
quintuple elements – FPG, PPG, HbA1c, glycemic variability and quality when there is a high risk associated
of life to be termed as glycemic pentad and these milestones to be with possible hypoglycemia. 3
considered for any antidiabetic therapy. Experts opined that combination Importance of PPG Control in Diabetes
therapy is required to achieve the Glycemic Pentad, as monotherapy Even though control of fasting
might not address all the five arms of Glycemic Pentad. Group also agreed hyperglycemia is essential,
that the diabetes management in Indians require separate attention due obtaining optimal glycemic
to their distinct dietary habits (high carbohydrate content) and socio- control requires regulation of
economic status (economically weak and poorly educated). Therefore, additional parameters. 4 Growing
mild adjustments to the standard practices in the western countries body of evidence indicates that
are suggested. After evaluating various drugs in the current market to reducing postprandial glucose
identify candidates that could regulate the elements of Glycemic Pentad, excursions is equally or perhaps
the forum assume that a triple fixed dose combination of metformin, more important for achieving
glimepiride, and voglibose could be a better choice in Indians as the HbA1c goals. 1 Contribution of
combination is safe, affordable and effective in attaining optimal glucose PPG relative to fasting glycemia
levels and reducing the complications. is predominant when the
Conclusions: Glycemic pentad deserves a prominent position in the HbA1c levels are approximately
diabetes management in India. The triple fixed dose combination of below 7.5% in people with non-
insulin-treated type 2 diabetes
metformin, glimepiride, and voglibose has essential commodities to
and the contribution decreases
achieve glycemic pentad targets.
p r o g r e s s i ve l y w i t h i n c r e a s i n g
HbA1c levels.5 Convincing evidence
suggest that oxidative stress and
Introduction characterized by decreased insulin
sensitivity and hyperglycemia

D iabetes is one of the lifestyle

oriented, metabolic diseases
ultimately causing aberrant glucose
homeostasis. Diabetes management
Glycemic Pentad Forum (see page no. 79)
Received: 29.05.2017; Accepted: 04.06.2017
 Journal of The Association of Physicians of India ■ Vol. 65 ■ July 2017 69

HbA1C complications and recent studies

have shown that mortality rate
increased even after maintaining
good HbA1c 13 and HbA1c derived
information is insufficient to explain
all of the risk associated with
Glycemic Quality of
Variability Life complications of diabetes. 14 High
frequency glycemic excursions in
GLYCEMIC
PENTAD
conventionally treated patients
could be an explanation for this
observation. 9 Subsequent studies
established a relation between
o s c i l l a t i n g g l u c o s e l e ve l s a n d
oxidative stress and corroborated
the hypothesis that HbA1c
FPG PPG together with glycemic variability
might be a superior indicator
Fig. 1: Geo mapping of case clusters in neighbouring districts of glucose control than mean
excessive protein glycation might diabetic population demands a HbA1c alone. 6,9 Oscillating blood
occur as harmful consequences of separate attention. glucose levels rather than chronic
sustained chronic hyperglycemia. 6 hyperglycemia has been shown to
The IDF guidelines on controlling Glycemic Pentad: have harmful effects on parameters
of cardiovascular (CV) risk such as
post-meal glucose recommends Emerging Concept
that postprandial hyperglycemia is endothelial dysfunction. 15,16 This
harmful and should be lowered by Traditionally, diabetes control led to the emergence of new aspect
incorporating a variety of both non- strategies mainly targeted to reduce in glycemic control, i.e., glycemic
pharmacologic and pharmacologic the triad of fasting and postprandial va r i a b i l i t y 1 7 a n d wa s i n c l u d e d
therapies. 4 blood sugars and HbA1c. However, in the concept of the ‘glycemic
optimal glycemic control in UKPDS tetrad. 18
Diet and Postprandial Hyperglycemia
in Indian Context and ADVANCE trials failed to Glycemic variability (GV)
prevent macrovascular events and can be simply defined as the
Asian Indian diabetic patients
death. 10,11 Importance of factors degree of daily blood glucose
are different from other ethnicities.
other than average blood glucose fluctuations (peaks and nadirs)
Carbohydrate content in Indians
in causing diabetes complications in an individual. 19 It comprises of
diet constitutes about 65%, which
have been consistently debated both postprandial glucose spikes
is more than that is recommended
a n d t h e a d va n c e s i n r e s e a r c h as well as the hypoglycemic
for diabetic patients. 7 Of the whole
h a s p a ve d t h e wa y t o i n c l u d e episodes. Glycemic variations are
ingredients in an individual’s diet,
two more variables, i.e. glycemic of two types: Variations measured
carbohydrates has the greatest
variability and quality of life, to within a day are called as intraday
influence on blood glucose
the existing components. These five glycemic variations and the glucose
level, and both the amount and
elements are collectively referred variations measured at the same
type of carbohydrate intake
as “glycemic pentad”. Different t i m e o n t w o c o n s e c u t i ve d a y s
are the important determinants
components of glycemic pentad are are called as inter day glucose
of postprandial glucose.8
shown in Figure 1. va r i a t i o n s . D e f e c t i ve g l y c e m i c
Consumption of such imbalanced
diet with high carbohydrates could regulation and reduced insulin
Glycemic Variability availability are presumptive
cause increased insulin resistance,
metabolic syndrome, and type 2 etiological factors of GV. 20 Even
It was observed in the Diabetes
DM. The amount of carbohydrates though certain degree of glycemic
Control and Complications Trial
consumed affects blood glucose variations is observed in normal
(DCCT) that in spite of similar
levels and insulin responses and individuals, it increases in people
HbA1c levels, patients treated with
a clear link between carbohydrate with diabetes and impaired blood
c o n ve n t i o n a l m e t h o d s s h o we d
intake and post-prandial glucose glucose tolerance. 19
a remarkable progression to
level exists in diabetic population. 9 retinopathy over a period of time Several studies attribute
Since Indians consume diet with when compared to intensively hyperglycemia and dysglycemia
high glycemic index and load, treated subjects. 12 Furthermore, (peaks and nadirs) to the occurrence
postprandial glucose control and controlling glycemic triad does not o f va r i o u s m i c r o va s c u l a r a n d
overall glycemic control in Indian prevent the occurrence of diabetic macrovascular complications
70 Journal of The Association of Physicians of India ■ Vol. 65 ■ July 2017

in diabetes. 19 Excessive protein that regulating glycemic variability In general patient compliance
glycation end products and is necessary to achieve proper is poor in diabetes irrespective
a c t i va t i o n o f o x i d a t i v e s t r e s s glycemic control in diabetes of the treatment regimen (oral
are suggested to be underlying patients. Collectively, GV and antidiabetic agents or insulin). 30
pathophysiological mechanisms CGMS could help in redefining Moreover, physicians should
causing these vascular reasonable interventions in the notice that failure to achieve target
complications. Hypoglycemia resource limited healthcare glycemic levels could be because
along with glycemic variations can environment of countries such as of inadequate self-management
influence the onset and progression India. rather than less effectiveness of
of diabetes complications and can the prescribed medication. In
be troublesome in patients treated Quality of Life such cases, patient counseling
in intensive care units (ICUs) for to improve treatment adherence
Of late quality of life (QOL)
clinical conditions other than should be preferred rather than
has emerged as an important
diabetes. 21 increasing the dose or changing
parameter in the general disease
Several methods to effectively the medication. Insulin-based
management routine. The QOL
measure postprandial therapy is generally associated
is defined as a multidimensional
hyperglycemia and GV are with decreased QOL, therefore,
construct incorporating an
available currently. Ambulatory it should be carefully considered
individual’s subjective perception
glucose profiling (AGP) is one such before various combinations of oral
of physical, emotional, and social
technique which retrospectively medications are used. 31 To sum up,
wellbeing. 25 It includes both a
analyze blood glucose levels from QOL in diabetes is affected by two
cognitive component (satisfaction)
the data collected with flash glucose categories of factors: the disease
and an emotional component
monitoring (FGM). The FGM and derived factors such as duration and
(happiness). In general, QOL is
continuous glucose monitoring complications and therapy derived
low in diabetes patients and it is
(CGM) provides information that factors such as adverse events,
positively correlated with duration
could not be obtained with periodic cost, life style restrictions imposed
of the disease. 26 Past research on
capillary blood glucose monitoring, by the treatment. Therapeutic
QOL in diabetes has revealed that
provides all-over the day coverage factors generally influence the
patients desired to improve the
and alerts and alarms for actual compliance to treatment and
way they feel. 27 Complications
or looming hypo- and hyper- when the compliance is decreased,
associated with diabetes affects
glycemia. 22 This information can be diabetic complications increase
the QOL of patients. 28 Moreover,
used to educate, motivate, and alert resulting in the deterioration of
acute and bothersome side effects
people with diabetes. The FGM or QOL in a cyclic process. Hence,
and lifestyle restrictions prevent
CGM is medically recommended for medications used to treat diabetes
the patients from motivating to
patients with frequent, severe, or should reduce the complications
comply with the treatment even
nocturnal hypoglycemia, especially and also contain the features to
though it promises long-term
in those who are unaware of it. 22 enhance adherence.
benefits. 27 Therefore therapeutic
S e ve r a l s t u d i e s i n d i c a t e d t h a t policies should aim at reducing International diabetes guidelines
consistent use of CGMS results in the complications and also has mentioned the importance
better glycemic control. A meta- i m p r o ve t r e a t m e n t a d h e r e n c e of QOL during the course of
a n a l y s i s o n f o u r t e e n R C Ts b y and compliance. Benefits of t r e a t m e n t . 2,3 T h e A m e r i c a n
Floyd et al. showed a significant diabetes therapy could be properly d i a b e t e s a s s o c i a t i o n ( A D A)
reduction in HbA1c and duration reaped through the maximum recommends to use a patient-
of hypoglycemia with CGMS use. 23 convenience of the dosing regimen centered communication style that
Similarly, a cochrane review of 22 a n d m a x i m a l Q O L b e n e f i t s . 27 incorporates active listening, elicits
RCTs revealed a reduction in HbA1c Martinez et al suggest that QOL patient preferences and beliefs,
with higher compliance to CGMS in patients could be enhanced by and assesses literacy, numeracy,
when compared to self-monitoring including interventions that could and financial barriers. 2 They also
of blood glucose (SMBG). 24 overcome the negative attitude suggest that a successful medical
In the end, proper biological towards treatment adherence and evaluation depends on beneficial
rationale and enough evidence by promoting medical prescription interactions between the patient
convince us to endorse the concept knowledge. 29 Furthermore, balance and the care team. Individualization
of GV as an important risk factor between treatment burden of treatment based on patients’
that is directly involved in the an d healt h out comes could b e preferences, values, and goals is
p a t h o g e n e s i s o f t h e va s c u l a r achieved with the wide variety also recommended.
complications of diabetes. Overall, of interventions available in the QOL is generally assessed
it is persuading enough to propose current market. 27 using a broad questionnaire that
 Journal of The Association of Physicians of India ■ Vol. 65 ■ July 2017 71

translates an individual subjective To summarize, QOL should be inhibitors function at the level of
perception into numerical scores. considered en route to achieve glucose absorption and excretion
Accuracy and reliability of a QOL optimal glycemia in a diabetes respectively. While AGIs delay the
tool depends on the extent to patient. From this viewpoint, intestinal glucose absorption by
which it addresses the factors following are some of the important inhibiting enzymes responsible for
pertaining to the local population attributes of any antidiabetic complex carbohydrate breakdown,
such as language, socio-economic therapy: it should be simple to SGLT-2 inhibitors prevent glucose
elements, culture, race and religious follow and affordable, it should reabsorption in the kidney by
b e l i e f s . 3 2 S e ve r a l i n s t r u m e n t s / have convenient dosing regimen regulating the activity of glucose
questionnaires are available to and least side effects, it should transporters.
assess QOL. While instruments n o t i m p o s e t o o m a n y l i f e s t yl e Attaining optimal glucose levels
such as World Health Organization restrictions and overall, it should is the foremost objective of any
– BREF (WHO-BREF), EuroQol improve the way an individual antidiabetic therapy. Decision to
f i ve d i m e n s i o n s q u e s t i o n n a i r e feels about oneself. begin or alter a therapy is based
(EQ-5D) and Short Form – 6D Collectively, the glycemic on the prevailing glycemic levels. 34
(SF – 6D) are used for general pentad as a new concept deserves When monotherapy fails to produce
QOL assessment, questionnaires to have its position in the diabetes ambient glycemic levels, multiple
such as Diabetes Quality Of Life management course. It is imperative drugs with different modes of action
Measure (DQOL), Diabetes-Specific that a global antidiabetic strategy can be considered. 34 Factors such as
Quality Of Life Scale (DSQOLS) should be aimed at reducing the safety, efficacy, additional benefits
and Diabetes – 39 (D - 39) are four components of glycemic in reducing complications, ease of
specifically used to measure QOL pentad i.e., FPG, PPG, HbA1c, and use, and expense are important
in diabetes. As India is a diverse glucose variability and improving considerat ions whi l e c h o osi n g
country with enormous cultural the fifth element, quality of life. an OAD. 35 Furthermore, HbA1c
and socio-economic disparities, levels also provide a direction
QOL assessment tools created for Achieving Goals of towards decision making; while
other ethnic populations might Glycemic Pentad with Anti- high HbA1c levels (≥8.5%) desire
not derive complete and proper to be treated with fast acting agents
information. Therefore, India Diabetic Therapy
or combination therapy, levels
specific QOL measurement tool is Anti-diabetic agents close to target indicate the use of
the need of the hour. In this regard, agents with lesser potential and/
Several varieties of antidiabetic
Nagpal J et al. has developed Quality or slower onset of action. 35 Overall
agents are currently available. On
Of Life Instrument for Indian the treatment regimen should be
the basis of mode of administration,
Diabetics (QOLID), to assess the planned in such a way that all of the
anti-diabetic therapy can be
QOL of Indian diabetes patients. 33 five goals of glycemic pentad are
broadly categorized into injectable
It comprises of eight domains and attained both at the convenience of
and non-injectable or oral therapy.
34 items (questions) evaluating the physician and patient.
Insulin and its analogues and
physical health, socio-economic
glucagon like peptide 1 (GLP-1) The list of different antidiabetic
and psychological status of a
receptor agonists (GLP-1 RAs) agents, their mode of action
patient. The first three domains role
belong to the injectable category. and ability to reduce different
limitation due to physical health,
Oral antidiabetic (OADs) category components of glycemic triad is
physical endurance, and general
is overwhelming, with a variety of listed in Table 1. Regardless of
health could be classified as health
drugs that have different modes the mode of administration or
related quality of life (HRQOL);
of action. Insulin secretagogues action, sole aim of any anti-diabetic
they evaluate the general health
such as sulphonylureas therapy is to maintain glucose
and wellbeing of an individual.
(SU), meglitinides and DPP-4 homeostasis with minimal adverse
The remaining five domains
inhibitors stimulate the β-cells events and maximal convenience
treatment satisfaction, symptom
of pancreas to secrete insulin. or ease. Since Indians constitute
botherness, financial worries,
Insulin sensitizers including a special category of diabetes
emotional/mental health and diet
biguanides, thiazolidinediones, population with distinct dietary
advice tolerance reflect the diabetes
a n d D P P - 4 i n h i b i t o r s p r e ve n t habits and socio-economic and
specific quality of life (DSQOL).
hepatic glucose production and cultural backgrounds, choice of
Further work is mandated to
increase glucose uptake in the antidiabetic therapy should not
validate this instrument across
peripheral tissues such as muscle only rely on the effectiveness of
a wider geographical and socio-
and adipose tissue. Two other the agent but also on the cost,
economic spectrum and in different
classes of drugs, alpha-glucosidase ease of administration and other
community settings.
i n h i b i t o r s ( A G I s ) a n d S G LT - 2 confounding factors.
72 Journal of The Association of Physicians of India ■ Vol. 65 ■ July 2017

Table 1: Summary of antidiabetic agents. List of different antidiabetic agents with their glucose homeostasis and have the
mode of action, abilities to reduce components of dysglycemia and cost** tendency to enhance adherence
Class of drugs Mode of action HbA1c (%) FPG PPG Cost and persistence to therapy. 43 Use
reduction reduction reduction of FDCs could effectively overcome
Sulphonylureas Insulin secretagogue 0.8 – 2.0 +++ ++  s e ve r a l b a r r i e r s f o r t r e a t m e n t
Meglitinides Insulin secretagogue 0.5 – 2.0 + +++  adherence such as pill burden,
GLP-1 receptor agonists Insulin secretagogue 0.5 – 1.0 +++ +++  dosage frequency, flexibility
Biguanides Insulin sensitizer 1.5 – 2.0 +++ +  and ease during administration
Thiazolidinediones Insulin sensitizer 1.4 – 2.6 +++ +  and medication costs. 43 Optimal
DPP-4 inhibitors Insulin secretagogue and 0.5 – 0.8 + +++  glycemia can be obtained with
insulin sensitizer triple FDCs in a safe, well-tolerated
Alpha-glucosidase Delay carbohydrate 0.5 – 0.7 0 +++  and economic manner. 44
inhibitors absorption in intestine
SGLT-2 inhibitors Prevent glucose re- 0.7 – 1.0 ++ ++  Landmark trials such as
absorption in kidney DCCT and the United Kingdom
**References:35,73,74,75; 0 = neutral; + = mild; ++ = moderate; +++ = moderate to marked; ++++ = Prospective Diabetes Study
marked;  = cheap;  = quite cheap;  = expensive;  = very expensive (UKPDS) has proven that intensive
Insulin vs. Oral Antidiabetic Agents homeostasis helps in delaying the glucose lowering from the early
initiation of insulin therapy and stages of diabetes is associated with
It is an undisputed fact that lesser risk of diabetes associated
insulin is the effective therapeutic therefore could increase a patients’
quality of life. Particularly, complications. 11, 45 In many cases,
agent for the control of diabetes this requires using fixed dose
which cannot be re-placed by any triple fixed combination therapy
involving agents with different combinations as monotherapies
other antidiabetic agents in critical are not effective at regulating all
cases (i.e.HbA1c > 9.0%). However, modes of action could help in
achieving target glycemic goals aspects of dysglycemia. Current
several factors hinder the routine guidelines also propose a paradigm
use of insulin in diabetes patients. when mono and dual therapy
have failed. However, it has to shift in the treatment approach,
Inconvenience to life-style caused where combination therapy is
due to strict timings and multiple be strictly noticed that OADs
are not replacement for insulin recommended when HbA1c levels
d o s e s , 36 f e a r o f h y p o g l y c e m i c are elevated in the initial stages of
episodes, 37 concerns over weight treatment and insulin should be
appropriately prescribed as and diagnosis. 46 As discussed above,
gain 37 and mitogenic potential, 38 achieving the targets of all variables
fear of injections and needles 39 are when necessary.
in glycemic pentad is important in
perceived as some of the barriers Fixed Dose Combination Therapy
the holistic diabetes management.
for insulin use. Mandatory regular Increasing body of evidence However, such goals can only be
monitoring of blood glucose suggest that glycemic targets attained with combination therapy.
levels during insulin therapy is in patients not taking insulin For instance, metformin could
also one of the reasons for less could be effectively attained only control fasting glucose levels.
t r e a t m e n t a d h e r e n c e . 36 M a j o r with a combination of different Sulphonylureas could regulate
drawbacks of insulin treatment antidiabetic agents with distinct FPG effectively and to some extent
include negative perception and modes of action. 42 Apart from that, PPG. It has to be noted that in
noncompliance. 40 Furthermore, high dose monotherapy could cause Indian scenario agents effectively
patient self-management during more side effects than low dose downsizing postprandial glucose
insulin therapy requires adequate combination therapy. 42 Usually, excursions are also crucial.
knowledge on storage, syringe guidelines recommend the use Therefore a combination therapy
a n d v i a l c o m pa t i bility, n eed le of combination therapy of two or cont rolling fast ing , int er- mea l
size, injection site and technique more OADs with distinct modes and postprandial hyperglycemia
and dosing. 41 All of this could of action when glycemic goals are is essential for obtaining optimal
h a ve si g n i f i c a n t i m p ac t in th e not achieved with metformin. 2 glucose levels in the Indian
Indian population where majority Fixed dose combinations (FDC) population; in fact, this is true in all
of patients don’t give adequate or polypill(s) have emerged those people who consume heavy
emphasis on health care awareness. as important players in the meals containing high amount of
When QOL and patient- management of not only diabetes carbohydrates and in people with
perceived difficulties are but also other diseases. They contain high PPG levels.
considered, OADs score better fixed doses of more than one active
S e v e r a l F D C s a r e a va i l a b l e
over insulin treatment. 31 Ample pharmaceutical ingredient. The
in the market. The FDC of
a va i l a b i l i t y o f di fferen t OA Ds FDCs are simple to use, can be
metformin and sulphonylurea is
that can effectively attain glucose effective in controlling aberrant
a established combination among
 Journal of The Association of Physicians of India ■ Vol. 65 ■ July 2017 73

the Indian market. The FDCs with less hypoglycemic episodes could be effective in combination
of metformin or sulphonylurea when compared to other SUs with metformin or sulphonylurea. 3
with other antidiabetic agents are except glipizide. 48 Furthermore, Therefore, addition of voglibose
also routinely available. Of the glimepiride is associated with to metformin and glimepiride
contextual interest is the triple fixed weight neutralizing/reducing combination would effectively
dose combination of metformin, effects and therefore it might be reduce the postprandial glycemic
glimepiride, and voglibose. This advantageous. 48,49 When compared excursions along with FPG and
combination has different drugs to various other sulphonylureas, HbA1c. As a result, the overall
optimizing glucose levels through glimepiride has highest extra glycemic variability could also
distinct mechanisms; metformin is pancreatic activity and lowest ratio be reduced significantly. GV
an insulin sensitizer, glimepiride of increase in plasma insulin and parameters such as mean amplitude
is an insulin secretagogue and decrease in blood glucose activity.50 of glycemic variations (MAGE) and
voglibose delays glucose absorption Combination of metformin standard deviation (SD) around
in intestine. a n d g l i m e p i r i d e wa s f o u n d t o t h e m e a n g l u c o s e l e ve l s we r e
Fixed Dose Combination of Metformin, be effective when compared to found to be similar or better with
Glimepiride, and Voglibose Might be metformin plus DPP-4 inhibitors metformin use when compared to
Appropriate to Achieve all Goals of in a systematic review and meta- insulin or meglitinides. 59,60 In an
Glycemic Pentad analysis of safety and effectiveness open label prospective study on
Glycemic pentad acknowledges variables. 51 Efficiency of voglibose T2D patients, Matsumoto et al have
a multidimensional approach in is far bigger and its tolerability demonstrated that voglibose is
treating diabetes. It suggests that is also high when compared to able to effectively reduce the daily
the therapy should not only aim at other AGIs including acarbose and glycemic excursions and functional
clinical features (FPG, PPG, HbA1c, miglitol.52 Furthermore, voglibose is burden of the β cells.61 Furthermore,
and GV) but also consider the able to improve insulin sensitivity, when compared to sitagliptin,
socio-economic and psychological increase high-density lipoprotein voglibose significantly reduced
status of the patients. Among the ( H D L) a n d a p o l i p o p r o t e i n A - I the slope of postprandial elevation
clinical aspects, the major factor l e ve l s a n d r e d u c e i n s u l i n a n d of glucose after every meal and
that sets Indians (Asians) apart is triglyceride levels in the body. 53 In also increased the time taken to
the postprandial hyperglycemia addition, voglibose administration a t t a i n m a x i m a l g l u c o s e l e ve l s
which is due to intake of high elicits changes in the intestinal post dinner. 62 All these evidences
carbohydrate content in the diet. microbiota and reduces body clearly suggest that metformin and
Hence, an antidiabetic agent that weight, total cholesterol and voglibose are effective at managing
c o u l d e f f e c t i ve l y r e d u c e t h e s e .
triglyceride levels 54 Voglibose glycemic excursions.
excursions and therefore reduce is also associated with increase The Diabetes Prevention
the GV is essential. The antidiabetic in GLP-1 levels in the circulation Program (DPP) and its Outcomes
therapy has to be affordable and 55
which could furt her help in Study (DPPOS) revealed that
it should be relatively simpler to attaining glucose homeostasis. the investment made on lifestyle
follow. The FDCs have repeatedly Apart from controlling PPG and interventions and metformin to
proven their effectiveness in hyperlipidemia, voglibose is prevent diabetes in high-risk adults
attaining these elements of disease known to reduce oxidative stress is highly beneficial.63 Long-term use
management. Therefore, an FDC markers and soluble intercellular of metformin stabilized body mass
of metformin, glimepiride, and adhesion molecule 1, which is an index (BMI) and improved body
voglibose appear to have all the inflammatory marker. 56 Moreover, composition in adolescent obese
necessary characteristics to fulfill voglibose is equally effective as and insulin resistant subjects. 64
this criterion. sitagliptin at improving endothelial Evaluation of overall treatment
Metformin and glimepiride are dysfunction in type 2 diabetes satisfaction with Diabetes
the most commonly prescribed p a t i e n t s . 57 P h a r m a c o k i n e t i c Treatment Specific Questionnaire,
diabetic agents in India. 47 Safety properties of metformin, status version (DTSQs) revealed
and efficacy of these molecules glimepiride, and voglibose are no significant differences between
wa s p r o v e d r e p e a t e d l y . T h e y provided in Table 2. combination of metformin plus
are known to reduce the fasting Combined use of voglibose and glimepiride or empagliflozin. 65
glucose levels and HbA1c and to sulphonylureas might be effective Furthermore, though a population
some extent postprandial glucose. in controlling postprandial plasma based mathematical model Zhang
Hypoglycemia and weight gain glucose and delay the onset of et al has found that the use of
are the usual adverse events vascular complications in patients SUs as second line of therapy
associated with SUs. However, with type 2 diabetes. 58 Even IDF resulted in similar outcomes such
glimepiride use is associated guidelines suggest that the AGIs as life years (LYs) and quality
74 Journal of The Association of Physicians of India ■ Vol. 65 ■ July 2017

Table 2: Pharmacokinetic parameters of metformin, glimepiride and voglibose Pentad forum, consisting of 51
PK Parameters Metformin Glimepiride $
Voglibose@ leading medical experts from
Half life ~5 hrs* 5-8 hrs 1 to 1.5 hours different regions of India in the
Mean renal clearance (CLr) 510±130 ml/min* Negligible field of diabetology were convened
Total clearance (CL) 1140 ± 330 mL/min*** 47.8 mL/min Negligible into 5 groups to bring a consensus
Oral bioavailability 50–60%** 100% Poorly absorbed on the position of glycemic pentad
Peak plasma concentrations (Cmax) IR- 1-3 hrs 2-3 hrs Undetectable in diabetes control and the FDC
ER- 4-8 hrs# of metformin, glimepiride and
Plasma protein binding Negligible# > 99.5%. voglibose in the management of
Volume of distribution (Vd) 300–1000 L# 8.8 L diabetes in India. Each group met
Elimination half-life 6.2 hrs** 3-6 hrs independently in different cities
IR: Immediate release; ER: Extended release; References: *76; **77; ***78; #79; $80; @52 of India, reviewed the relevant
literature, expressed their opinions
adjusted life years (QALYs) as headache, diarrhea, flatulence,
on the position of glycemic
DPP-4 inhibitors or GLP-1 RAs sweating and hot flushes. 72
pentad and shared their personal
or insulin. 66 In addition SU based
Consensus Statement on experiences with the use of triple
therapies incurred significantly
FDC of metformin, glimepiride,
low cost per QALY and prolonged the Position of Glycemic and voglibose in clinical practice.
the time required for insulin
Pentad in Diabetes Control A final consensus statement is
treatment. Similarly, voglibose
and the FDC of Metformin, generated after the key points in
along with standard care resulted
different meetings were shared
in cost saving and prolonged life Glimepiride, and Voglibose among the forum and an approval
expectancy in glucose intolerant in the Management of is given by all members of the
Japanese patients. 67 Together these
evidences suggest a beneficial
Diabetes In India forum.
role of metformin, glimepiride, Objectives Key Points from the
and voglibose in improving
the QOL. Considering all these
Research on diabetes has been Consensus Meetings
endorsing the importance of GV and
facts, it is rationale to put the Consensus on the position of glycemic
QOL in the management of diabetes
triple combination of metformin, pentad in the management of diabetes
along with FPG, PPG, and HbA1c.
glimepiride, and voglibose at the in Indians
E ve n t h o u g h s o m e g u i d e l i n e s
forefront of diabetes management Recent advances in the field of
h a ve b e e n a c k n o wl e d g i n g t h e
in India. diabetology incited a further leap
significance of QOL in diabetes
Summary of safety and efficacy control, GV has been largely to diabetes management and added
studies on the combination of ignored. Furthermore, Indian two more dimensions - glycemic
metformin, glimepiride, and diabetes patients are different variability (GV) and quality of
voglibose is available in Table 3. from western people due to their life (QOL) - to already existing
Availability of limited number varied dietary and cultural habits. glycemic triad and the composite of
of studies assessing the safety So diabetes management there these 5 elements is now identified
and efficacy of this triple FDC require slight modifications, a s G l y c e m i c Pe n t a d . G l y c e m i c
demands the necessity for further particularly in regulating variations are the physiological
high quality studies. However, postprandial hyperglycemia consequences of circadian rhythms
it is evident from the already through a cost-effective and easy of hormones involved in glucose
available information that this to follow regimen. Various OADs control and also due to postprandial
triple combination is safe to use are available in the market. Even spikes in glucose levels. Clinical
and effective at reducing FPG, t h o u g h t h i s g i ve s q u i t e m a n y evidences suggest that patients
PPG, and HbA1c (Table 2). Pankivn opportunities to physicians, often it with high GV are prone to high
VI et al. also reported a significant creates confusion among health care risk of retinopathy. Patients with
weight reduction in the group of professionals working at primary painful neuropathy had high GV
patients treated with this FDC when health care centers where most of when compared to patients with
compared to the dual combination the Indian diabetes population is painless neuropathy. Also, high
of metformin and glimepiride. 68 treated. Therefore, there is a need GV is associated with increased
This combination is well tolerated for a simple medication which c a r o t i d m e d i a t h i c k n e s s . E ve n
in general, 69,70,71 yet, some patients could offer easy and economical though the fluctuation reduction
might experience temporary side alternative to treat diabetes. with insulin and GLP-1 added
effects such as abdominal pain, together (FLAT-SUGAR) study
Methodology
has provided some evidences on
An expert group, Glycemic the benefits of controlling GV,
 Journal of The Association of Physicians of India ■ Vol. 65 ■ July 2017 75

Table 3: Efficacy and safety studies on metformin, glimepiride and voglibose combination. A list of safety and efficacy studies
that were carried out on the combination of metformin, glimepiride, and voglibose either as FDC or as triple therapy
Author et al., Type of No. of subjects (n); Drug dosage Efficacy and safety results
study duration of study
Hari K. et al., 2014;69 n = 20; 4 months Metformin 500mg (SR#) + Significant reduction in FPG (181±10.2 mg/dl to 116±2.97 mg/
Non-randomized, Glimepiride 1/2mg + Voglibose 0.2mg ml; P < 0.0001), PPG (239±11.2 mg/dl to 140±4.42 mg/dl; P <
open, non-comparative, OD. (FDC) 0.0004), and HbA1c (9.07 ±0.346 to 6.51±0.129; p < 0.0001).
mono-centric study. All of the patients tolerated the drug and no adverse events
were reported.
Faruqui AA, 2016;70 n = 50; 3 months Metformin 500mg (SR#) + Significant decrease in HbA1c value 10.6 ± 1.3 vs. 6.6 ± 0.4 (P<
Non-randomized, Glimepiride 0.5 mg + Voglibose 0.0001), FPG levels 208.33mg/dl vs. 118.06 (P< 0.0001), and
open, non-comparative, 0.2mg BD. (FDC) PPHG levels 360.14 mg/dl vs. 168.36, (P< 0.0001).
mono-centric study. None of the patients complained about adverse events
including nausea, vomiting, and headache at the given doses
of medication.
Rao C. et al., 2013;71 n = 20; 3 months Metformin 500mg (SR#) + Significant decrease in HbA1c (8.86 ± 0.7111 gm/dl vs. 8.0 ±
Non-randomized, Glimepiride 1/2mg + Voglibose 0.2mg 0.66 gm/dl), fasting (137±17.64 mg/dl vs. 116.8 ± 6.129 mg/
open, non-comparative, BD. (FDC) dl, P < 0.0001) and post prandial blood glucose level ((237.8
mono-centric study. ± 59.22 mg/dl vs.173.4 ± 27.6 P < 0.0004) was observed from
baseline.
This triple combination was well tolerated.
Jindal A. et al., 2014;72 n = 30; 6 months Metformin 500mg BD + Glimepiride Significant reduction (p<0.001) in FPG, PPG and HbA1c over
Open label study 2mg BD + Voglibose 0.2mg TDS a period of 6 months.
Side effects such as abdominal pain, headache, diarrhea,
flatulence, sweating, and hot flushes are observed.
Murti K. et al., 2016;81 n = 75; 10 months Dual therapy group: Metformin Even though significant reduction in FPG, PPG, and HbA1c
Prospective, open-label, 500mg + Glimepiride 1mg Triple was observed from baseline to end of study in both dual and
comparative study therapy group: Metformin 500mg + triple therapy groups, it was larger in triple therapy group.
Glimepiride 1mg + Voglibose 0.3mg
Pankivn VI et al., n = 45; 12 weeks Group I: Metformin + Glimepiride + Decrease in HbA1c was high in group I (1.5 [1.1; 1.9] %
201668 Prospective, Voglibose 0.2mg (p < 0.05) than group II (0.1 [0.09; 0.6] % (p > 0.05) after 12
comparative study TDS. weeks of treatment.
Group II: Metformin + Glimepiride + Body weight reduced significantly by 2.1 kg in group I while
no response was observed in group II.
Safety was proven in terms of functional states of liver and
kidney.
FDC: Fixed dose combination; # SR: sustained release; OD: Once daily; BD: Twice daily: TDS: Three times in a day

further high quality research is health and well-being. Poor QOL could score well in regulating all
recommended to strongly establish worsens the life of an individual five domains of glycemic pentad.
these facts. GV is of two types: in a positive feedback loop. In Consensus on the role of triple FDC of
1. Intra-day variations which are diabetic patients, poor QOL leads metformin + glimepiride + voglibose
ve r t i c a l g l y c e m i c f l u c t u a t i o n s to diminished self-care which in regulating glycemic variability
within a day. 2. Inter-day variations results in deregulated glycemic Post meal hyperglycemia,
which are observed as time wise control. This leads to increase in particularly post breakfast
glycemic fluctuations between the risk of diabetes associated hyperglycemia is the major factor
different days. Several evidences complications which in turn affect influencing the glycemic excursions
suggest that GV is an important the QOL of an individual again. in Indian diabetes patients and
predictor of hypoglycemia whereas Therefore, it is sensible to address are important in regulating
HbA1c could not provide any the issue of QOL of a patient during glycemic variation and the overall
such information. Therefore, it is the diabetes treatment. glycemic control and quality of life.
imperative to acknowledge the Considering all these facts, it is Furthermore, for the same amount
importance of controlling glycemic convincing to incorporate glycemic of carbohydrate intake, Asians have
variations in diabetes patients. variation and quality of life as higher postprandial glucose values
Off late QOL has emerged new dimensions in the overall when compared to Caucasians.
as an important element in the diabetes management program and Even though the carbohydrate
management of diabetes and therefore glycemic pentad as a fresh content in the breakfast is lower than
also in the overall health care concept has utmost significance in lunch and dinner, post breakfast
of an individual. It predicts an the holistic control of diabetes. glucose spikes are observed to
individual’s capacity to manage Hence, it is rational to identify the be higher in the Indian diabetes
disease and maintain long-term better combination therapy that patients (personal experience from
76 Journal of The Association of Physicians of India ■ Vol. 65 ■ July 2017

experts) than that of post lunch or dose (0.3 mg) after the patient This combination provides an
post dinner. is acclimatized to the treatment. extended temporal window for
Continuous glucose Voglibose should be restricted the patients and the physician
measurement is important to in patients with active hepatic before an insulin dose is initiated.
understand the dynamics of blood disease. However, it is not a substitute for
glucose levels. Since this technique Metformin and glimepiride has insulin therapy. Patients who have
is expensive to some individuals, been a successful combination in the very high HbA1c or PPG levels and
7 point glucose measurements are diabetes management scenario of require insulin therapy should be
recommended to be performed Indian setup. On the similar note, it given appropriate treatment.
routinely with intermittent AGP. is also a well-accepted fact that the Effective treatment regimens
Choice of any antidiabetic drug effect of this combination reduces should include GLP-1 receptor
should be individualized based on after sometime due to various agonists and DPP-4 inhibitors
the patients’ phenotype, history, physiological consequences and along with voglibose in order to
affordability, and acceptance. therefore it compels the inclusion achieve over all good glycemic
of a new agent. control. Gliptins are a good option
Changing the timing of
Triple fixed dose combination when patients have both high FPG
medication based on AGP is more
(FDC) of metformin, glimepiride, and PPG values whereas when only
beneficial in improving the glycemic
and voglibose is effective in PPG values are more, voglibose is
control rather than increasing the
r e d u c i n g g l y c e m i c va r i a b i l i t y a better choice.
dosage of the medications.
and HbA1c in Indian diabetic Overall the triple FDC of
In the Indian scenario, where
p a t i e n t s . T h e r e s u l t s a r e ve r y metformin, glimepiride, and
consumption of carbohydrates is
conspicuous when data from triple voglibose is effective in attaining
high, alpha glucosidase inhibitors
FDC are compared to metformin + good glycemic control in diabetic
are the best choice of drugs after
glimepiride dual combination. patients. While glimepiride controls
metformin and glimepiride.
In order to control post dinner FPG and to some extent PPG,
Alpha glucosidase inhibitors metformin regulates nocturnal
hyperglycemia in patients who
c o u l d b e p r e f e r r e d o ve r b o l u s glucose levels and voglibose
h a ve n o c t u r n a l h y p o g l y c e m i a
insulin in controlling post meal majorly prevents PPG excursions.
after sulphonylurea (SUs) use it is
hyperglycemia when hypoglycemic As a result, this combination
recommended to down titrate the
episodes are considered. This is could effectively regulate overall
SU dose and incorporate voglibose
mainly because it is very difficult glycemic levels. However, high
into the treatment regimen. This
to the patient to plan their quality studies comparing the
combination can also be prescribed
carbohydrate intake based on the efficacy of triple fixed dose
as up-titration to the ongoing
insulin dose on a daily basis. combination with dual therapy
medication or as a replacement
Voglibose could decrease therapy in the patients who are of metformin and glimepiride or
glycemic variations by controlling already on a different triple drug any other antidiabetic therapies
postprandial glucose excursions combination. are recommended so as to fairly
and also effectively reduce the risk demonstrate the additive benefits
Twice daily dose of this FDC after
of hypoglycemia. Voglibose (alpha of this triple combination in the
breakfast and dinner is sufficient to
glucosidase inhibitors) is under control of diabetes.
prevent the glycemic excursions
used in Indian population when Consensus on the role of metformin,
in a day. However, as and when
compared to other Asian countries. glimepiride and voglibose FDC in
required, elevated blood glucose
Voglibose can be prescribed to achieving good QOL scores in Indian
levels post lunch or evening snack diabetic patients
regulate uncontrolled postprandial could be handled with voglibose
glucose peaks in those patients alone. Use of the triple drug combination
who are already on metformin, of metformin, glimepiride, and
The ideal time to take the triple voglibose could result in the overall
glimepiride, and basal insulin.
drug is 15 - 30 minutes before the improvement of QOL in diabetes
Moreover, addition of voglibose
meal. However, when practical in- patients. However, compelling
at night could reduce the need
convenience is considered, it can evidences that substantiate this
for SU or bolus insulin who have
also be taken just before the meal, concept has to be generated in the
the tendency to cause nocturnal
at the time or after the consumption due course through systematically
hypoglycemia.
of a meal. Even if the patients designed QOL studies.
In patients who are predisposed miss the appropriate timing, it is
to gastroparesis or bloating, start recommended that they take it Triple FDC of metformin,
with low dose of voglibose (0.2 sometime rather than missing the glimepiride, and voglibose is
mg) and up-titrate it to maximal dose completely. associated with improving overall
glycemic control, increasing
 Journal of The Association of Physicians of India ■ Vol. 65 ■ July 2017 77

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