Download The Importance of Postprandial Plasma Glucose Control

Issue 1
Clinical Use of Incretin-Based Therapies to
Promote PPG Control In Type 2 Diabetes
Term of Approval
Release date: April 2009
Expiration date: April 30, 2010
The Importance of
Postprandial Plasma
Glucose Control
IN THIS ISSUE:
Page
2
Measures of glycemic control: Interpretation
and use in clinical practice
2
Monitoring plasma glucose levels for
diabetes management
4
The challenge of meeting glycemic targets
5
PPG and the pathophysiology of type 2 diabetes
7
Incretin-based therapies: Addressing PPG and
filling a therapeutic need
11 Current treatment guidelines regarding PPG
12 Literature summaries
Sponsored by the Institute for Medical and Nursing Education, Inc.
and brought to you by the Caring for Diabetes Educational Forum
Editor
David D’Alessio, MD
Professor of Medicine
Director, Division of Endocrinology
University of Cincinnati College of Medicine
Chief, Endocrinology and Diabetes Clinic
VA Medical Center
Cincinnati, Ohio
This activity is partially supported by an educational grant from
Takeda Pharmaceuticals North America, Inc.
1
Program Overview
Several landmark clinical studies have demonstrated the relationship
between type 2 diabetes and increased risk of both microvascular
and macrovascular complications. Optimal glycemic control is vital
to managing these risks in patients with type 2 diabetes. However,
recent estimates indicate that only 57% of type 2 diabetes patients
reach the American Diabetes Association glycemic target of A1C < 7%.
Historically, glycemic control efforts have emphasized achievement of
A1C and fasting plasma glucose (FPG) targets. It has recently become
increasingly evident that postprandial increases in blood glucose levels
also contribute significantly to overall glycemic control and to the
development of diabetes complications. Consequently, postprandial
plasma glucose (PPG) control is receiving recognition as an essential
therapeutic target for optimizing glycemic control in patients with type
2 diabetes. This publication series will explore the science of PPG and
its contribution to glycemic control, and highlight recent and emerging
therapies that address this important target.
Intended Audience
This program is intended for endocrinologists, diabetologists, and other
healthcare professionals (HCPs) who frequently treat patients with type
2 diabetes.
Learning Objectives
After completing this issue, participants should be able to:
• Describe the relative contribution of FPG and PPG to overall
glycemic control among patients with type 2 diabetes, and explain
how this relationship changes at different levels of glycemic control
• Explain the pathophysiologic defects that precede the development
of type 2 diabetes, and indicate when elevated PPG begins to play a
contributing role
• Discuss the available evidence suggesting that elevated PPG leads
to increased macrovascular complications
Accreditation and Credit Designation Statements
The Institute for Medical and Nursing Education, Inc (IMNE) is accredited
by the Accreditation Council for Continuing Medical Education (ACCME)
to provide continuing medical education (CME) for physicians.
IMNE designates this educational activity for a maximum of 2.0 AMA
PRA Category 1 Credit(s)™. Physicians should only claim credit
commensurate with the extent of their participation in the activity.
Disclosures
In compliance with the ACCME’s Standards for Commercial Support, it
is the policy of IMNE to ensure fair balance, independence, objectivity,
and scientific rigor in all programming. All individuals involved in
planning (eg, CME provider staff, faculty, and planners) are expected
to disclose any significant financial relationships with commercial
interests over the past 12 months. IMNE also requires that faculty
identify and reference off-label or investigational use of pharmaceutical
agents and medical devices.
In accordance with ACCME Standards for Commercial Support,
parallel documents from other accrediting bodies, and IMNE policy,
identification and resolution of conflict of interest have been made in
the form of external peer review of educational content. The following
disclosures have been made:
Faculty
David D’Alessio, MD
Formal Advisor: Takeda Pharmaceuticals North America, Inc;
Merck & Co, Inc
Research Activities: Amylin Pharmaceuticals, Inc; Eli Lilly and Company;
ETHICON, Inc
Consultant: Amylin Pharmaceuticals, Inc; MannKind Corporation
2
CME and Educational Partner Staff
Steve Weinman, RN
Executive Director
IMNE
Disclosures: Nothing to disclose
Amy Groves
Director, Program Development
IMNE
Disclosures: Nothing to disclose
Katie Fidanza
Program Development Executive
IMNE
Disclosures: Nothing to disclose
Kim McFarland, PhD
Senior Medical Writer
IMNE
Freelance Writer: MediTech Media, Ltd
Stock Interests: Pfizer Inc; Procter & Gamble
Robert Hash, MD
Texas A&M Health Science Center
College of Medicine
College Station, Texas
Dr Hash has nothing to disclose.
Martin Quan, MD
David Geffen School of Medicine
University of California, Los Angeles
Los Angeles, California
Dr Quan has nothing to disclose.
Disclaimer
This activity is designed for HCPs for educational purposes. Information
and opinions offered by the faculty/presenters represent their own
viewpoints. Conclusions drawn by the participants should be derived
from careful consideration of all available scientific information.
While IMNE makes every effort to have accurate information presented,
no warranty, expressed or implied, is offered. The participant should
use his/her clinical judgment, knowledge, experience, and diagnostic
decision-making before applying any information, whether provided here
or by others, for any professional use.
Commercial Support Acknowledgment
This activity is partially supported by an educational grant from Takeda
Pharmaceuticals North America, Inc.
Method of Obtaining CME Credit
CME credit/verification is offered upon successful completion of a
posttest with a minimum passing score of 70%. CME certificates will
be issued to participants after receipt of the CME registration form,
evaluation form, and successfully completed posttest. For those taking
the test and completing the evaluation online at www.webbasedCME.
com, a printable certificate will be made available upon successful
completion of the posttest.
Questions or comments can be addressed to [email protected].
If you choose to apply for CME credit by mail or fax, please allow up to
12 weeks for issuance of CME credit.
Introduction
Diabetes can be defined as a state of chronic hyperglycemia that increases the risk of microvascular
complications, namely retinopathy, nephropathy, and neuropathy.1 However, diabetes is also associated with
increased risk of macrovascular complications including ischemic heart disease, stroke, and peripheral vascular
disease, and in fact these are the leading causes of mortality in patients with diabetes.1,2 Type 2 diabetes
is characterized by progressive β-cell failure and decreased production of the β-cell-derived glucoregulatory
hormones, insulin and amylin.3-6 Compounding the insulin deficiency is a diminished responsiveness to insulin
action, or insulin resistance, in peripheral tissues.5-7 The combined effect of these 2 physiologic abnormalities is
hyperglycemia, both in the fasting state and after eating.5,6
Landmark studies have demonstrated that therapies designed to lower average blood glucose (BG) to levels
approaching the normal range reduce the risks that microvascular complications will develop or progress.8-10 The
results of these studies have prompted the development of treatment guidelines for type 2 diabetes emphasizing
goals for glycemic control that have been demonstrated to prevent the development of diabetes complications
or limit their progression.4,5,11
The pathophysiology of type 2 diabetes is complex and includes more than abnormalities of glucose metabolism.
Patients with diabetes also have additional metabolic abnormalities such as hyperlipidemia and hypertension,
and interventions that correct these abnormalities are also recommended to reduce microvascular and
macrovascular complications in these patients.4,5,11 Moreover, while a substantial reduction in insulin action is
central to diabetes, it is likely that other hormonal abnormalities contribute to the
clinical picture of this condition.3,5
Macrovascular disease has a multifactorial etiology, and the
role of hyperglycemia in this process has been difficult to
define. Several large, randomized, controlled trials
failed to demonstrate that intensive treatment of BG
reduced macrovascular complications associated
with diabetes.8,12-14 Nonetheless, the increased
risk of vascular complications shared by persons with
types 1 and 2 diabetes suggests that dysregulated
glucose contributes to this important complication, and
dismissing treatment of hyperglycemia as unhelpful to limit
macrovascular disease is an overly rigid interpretation of
current evidence. For example, a recent meta-analysis of
randomized trials comparing conventional treatment
with interventions targeted to improve glycemic
control demonstrated that improved glycemic control
was associated with a decreased incidence of
macrovascular events.15
Peak Issues is a publication series that focuses on
glycemic control in patients with type 2 diabetes, with
an emphasis on the regulation of postprandial plasma
glucose (PPG) levels through the use of incretin-based
therapies and the potential benefits of this approach.
1
Measures
of glycemic
control:
Interpretation
and use in
clinical practice
Plasma glucose (PG) levels can be assessed using several
different measures that have specific uses and can provide
insights into pathophysiology. For example, PG levels
measured after an overnight fast have become the standard
for diagnosing diabetes. Fasting glucose levels are a function
of endogenous, mostly hepatic, glucose production, and
elevated concentrations reflect some combination of insulin
deficiency, glucagon excess, and hepatic insulin resistance.16-18
PG levels measured after consumption of a standardized
meal or a fixed quantity of liquid glucose provide information
as to how the glucose homeostatic system can respond to
a challenge and give insights into the adequacy of insulin
secretion and the degree of insulin sensitivity. The following
sections describe and explain the use of several glycemic
indicators that are commonly used in diabetes diagnosis and
management: fasting plasma glucose (FPG), postchallenge
plasma glucose (PCPG), glycosylated hemoglobin (glycated
hemoglobin, hemoglobin A1C, HbA1c, or A1C), and PPG.
Measuring plasma glucose for diabetes
diagnosis
Diagnostic criteria for diabetes may be based on FPG, oral
glucose tolerance test (OGTT), or casual PG levels.1,4,5 FPG
is measured after an extended period (eg, 8-12 hours) with
no caloric intake.4,5 FPG is the measure preferred by the
American Diabetes Association (ADA) for the diagnosis of
diabetes because of its ease, relatively low cost, and extensive
standardization.4 FPG levels ≥ 126 mg/dL (7 mmol/L) on 2
separate occasions constitute a diagnosis of diabetes. A BG
level ≥ 200 mg/dL (11.1 mmol/L) 2 hours after the ingestion
of 75 g liquid glucose solution, an OGTT, is also diagnostic
of diabetes.1,4,5 OGTTs are more sensitive than FPG for
diagnosing abnormalities of glucose metabolism, including
diabetes, but are time consuming and more variable.4 Both of
these diagnostic criteria are based in part on their association
with microvascular complications.1,4,5,11 A third diagnostic
indicator of diabetes is a random, or casual, glucose level
≥ 200 mg/dL (11.1 mmol/L) with symptoms of
hyperglycemia (primarily polyuria and polydipsia).4,5
PPG is the BG level measured 1-2 hours after eating.7 Similar
to an OGTT, PPG is a measure of PG level after glucose intake
and indicates the patient’s ability to use glucose over time.
However, because administration of a standardized glucose
load is not required, PPG can be readily determined through
self-monitoring of blood glucose (SMBG) and can therefore
be used as an end point in the management of type 2
diabetes.4,5,19
2
The World Health Organization (WHO), ADA, and American
Association of Clinical Endocrinologists (AACE) diagnostic
criteria based on FPG and OGTT levels are provided in
Table 1.1,4,5 Patients meeting 1 criterion receive the
corresponding diagnosis, with the exception that patients
must fulfill both criteria to receive a diagnosis of prediabetes
according to WHO guidelines.1,4,5 In addition, ADA and AACE
criteria provide for diagnosis of diabetes based on the
presence of diabetes/hyperglycemia symptoms (polyuria,
polydipsia, unexplained weight loss) and a casual PG level
of ≥ 200 mg/dL.4,5 Table 1 also includes criteria for the
diagnosis of impaired fasting glucose (IFG) and impaired
glucose tolerance (IGT), conditions that are also referred to
as prediabetes and are associated with increased risk for
developing diabetes.1,4,5
Table 1. Diagnostic criteria for
diabetes and prediabetes1,4,5
WHO
ADA
AACE
FPG (mg/dL)
≥ 126
≥ 126
≥ 126
PCPG (mg/dL)
≥ 200
≥ 200
≥ 200
< 126†
100-125
100-125
≥ 140 & < 200†
NVI
NVI
110-125‡
NVI
NVI
< 140‡
140-199
140-199
Diabetes
IFG*
FPG (mg/dL)
PCPG (mg/dL)
IGT*
FPG (mg/dL)
PCPG (mg/dL)
WHO, World Health Organization; ADA, American Diabetes Association; AACE,
American Association of Clinical Endocrinologists; FPG, fasting plasma glucose;
PCPG, postchallenge plasma glucose; IFG, impaired fasting glucose; IGT, impaired
glucose tolerance; NVI, no value indicated.
*Prediabetes; †FPG and PCPG criteria must both be met; ‡FPG and PCPG criteria
must both be met if both tests are performed.
Monitoring plasma glucose levels for
diabetes management
A number of studies have revealed the importance of glycemic
control in patients with type 2 diabetes. In the Kumamoto
study, intensive glycemic control prevented and delayed the
progression of retinopathy, nephropathy, and neuropathy
in patients with type 2 diabetes.10 Based on analysis of the
combined primary prevention and secondary intervention
cohorts in this study, intensive glycemic control reduced
the risks of worsening retinopathy and nephropathy by 69%
and 70%, respectively.10 The United Kingdom Prospective
Diabetes Study (UKPDS) similarly reported that lower glycemic
exposure was associated with a 25% reduction in the risk of
microvascular complications.8 Additional analyses of the data
demonstrated that the risk of microvascular complications
decreases 37% for each 1% reduction in A1C level.20
Current evidence regarding the general benefits of tight
glycemic control on cardiovascular outcomes in patients
with type 2 diabetes is not as convincing as the case for
limiting microvascular disease. Among patients in the UKPDS
who were allocated to sulfonylurea or insulin treatment,
reduction in the risk of myocardial infarction (MI) was of
borderline significance, while a significant 30% reduction
in cardiovascular risk was reported for overweight patients
treated with metformin.8,21 A subsequent analysis of UKPDS
data revealed a 14% decrease in the risk of MI associated with
each 1% decrease in A1C level.20
Subsequent studies have yielded results that do not support
the hypothesis that tighter glycemic control improves
cardiovascular risk.12-14 The Action to Control Cardiovascular
Risk in Diabetes (ACCORD) trial was designed to demonstrate
whether intensive diabetes treatment that targeted a
hemoglobin A1C of less than 6% would reduce cardiovascular
events compared with standard therapy.12 The ACCORD trial
was terminated early due to an increased rate of death from
any cause in the intensive therapy group compared with the
standard therapy group.12 Analysis of the study data also
revealed an increased death rate due to cardiovascular causes
in the intensive therapy group compared with the standard
group.12,22 There was no difference between the intensive
and standard therapy groups in the primary composite
cardiovascular outcome.12
Like the ACCORD trial, the Action in Diabetes and Vascular
Disease: Preterax and Diamicron Modified Release Controlled
Evaluation (ADVANCE) study and the VA Diabetes Trial (VADT)
were large, long-term studies designed to determine whether
intensive glycemic control improves cardiovascular outcomes
compared with standard glycemic control in patients with
established type 2 diabetes.23 The ADVANCE study and VADT
were completed in 2008.23 Intensive glycemic control was not
associated with a significant decrease in cardiovascular events
in either study.13,14 The number of cardiovascular events
was lower than expected for both the standard and intensive
therapy groups in the VADT, but this may have been due to
better control of hyperlipidemia and hypertension in both
groups.14,24 In contrast with ACCORD, tighter glycemic control
was not associated with increases in cardiovascular-related
death or death due to any cause in the ADVANCE study and
VADT.13,14
While recent clinical trials of the effects of tight glycemic
control on macrovascular disease have not demonstrated
a benefit over the course of the study, recently published
results from the UKPDS indicate a legacy effect of tight
glycemic control.25 Ten years after the end of this study, the
intensive glycemic control group had a lower risk of MI than
the standard control group despite the fact that differences in
glycemic control between the 2 groups were lost as early as
1 year after the end of the study.25 This observation serves
to highlight the complexity of macrovascular disease, the
potential for interventions to have different effects at different
points in the natural history of this condition, and the need to
be circumspect in the interpretation of specific trials.
In addition to the ACCORD and UKPDS findings, a metaanalysis of randomized controlled trials to compare glycemic
interventions demonstrated that tight glycemic control
decreased the incidence of macrovascular events, particularly
stroke and peripheral vascular events, in patients with type
2 diabetes.15 The effect was most pronounced among
younger patients with shorter disease duration, emphasizing
the importance of individualizing interventions based on the
patient’s clinical characteristics.15
In light of the existing evidence, the ADA recommends
glycemic goals that are near normal and acknowledges the
importance of individualizing diabetes management so that
glycemic goals can be safely achieved.4,23 Glycemic goals
from treatment guidelines developed by the International
Diabetes Federation (IDF), ADA, and AACE are presented in
Table 2.4,5,11
Table 2. Therapeutic
glycemic targets4,5,11
IDF
ADA
AACE
A1C
(%)
< 6.5%
< 7.0%
≤ 6.5%
PrePG
(mg/dL)
< 110 mg/dL
70-130 mg/dL
< 110 mg/dL
PPG
(mg/dL)
< 145 mg/dL*
< 180 mg/dL*
< 140 mg/dL†
IDF, International Diabetes Federation; ADA, American Diabetes Association;
AACE, American Association of Clinical Endocrinologists; A1C, glycated
hemoglobin; PrePG, preprandial plasma glucose; PPG, postprandial plasma
glucose.
*Measured 1-2 hours after start of meal; †measured 2 hours after start of
meal.
Hemoglobin molecules inside red blood cells are glycosylated,
covalently bound to glucose, in proportion to circulating
glucose levels.26 There are several assays of glycosylated
hemoglobin that have been used to monitor glycemic control in
diabetic patients. The best established assay method, referred
to as hemoglobin A1C or simply A1C, has become the gold
standard because of its use in major clinical trials and because
it has been widely standardized.27
Hemoglobin molecules are removed from circulation with aged
red blood cells, so their lifespan is about 120 days.26 The
degree of glycosylation increases over the red cell lifespan so
that conditions that affect red cell lysis or production, such
as hemolytic anemia or erythropoetic stimulation, can falsely
reduce A1C.4 However, for most patients, A1C measurements
provide a record of average PG levels over the previous 2 to 3
months.26
Because it provides an integrated estimate of glycemia
over time and has been the primary end point for the major
diabetes intervention trials, A1C has become the primary
clinical target for monitoring glycemic control.27 However,
it is not currently recommended for diabetes diagnosis.4,5,11
Practice guidelines recommend measuring A1C every 2 to
6 months.4,5,11 Clinicians should have access to A1C results
during a patient’s office visit to promote timely and appropriate
therapy adjustment.4,5
3
Results of a recent study affirmed a linear relationship between
A1C and estimated average glucose (eAG).27 A list of A1C
values and their corresponding eAG levels is presented in
Table 3.27
Table 3. Correlation between
A1C and estimated average
plasma glucose levels27
A1C (%)
eAG (mg/dL)*
eAG (mmol/L)*
5
97 (76-120)
5.4 (4.2-6.7)
6
126 (100-152)
7.0 (5.5-8.5)
7
154 (123-185)
8.6 (6.8-10.3)
8
183 (147-217)
10.2 (8.1-12.1)
9
212 (170-249)
11.8 (9.4-13.9)
10
240 (193-282)
13.4 (10.7-15.7)
11
269 (217-314)
14.9 (12.0-17.5)
12
298 (240-347)
16.5 (13.3-19.3)
eAG, estimated average glucose. *Data in parentheses are 95% CIs.
The IDF, ADA, and AACE treatment guidelines also include
target PG levels that correspond with the target A1C
values.4,511 Preprandial plasma glucose (PrePG) and PPG levels
are measured before and after a meal, respectively, and are
applicable in the context of patient self-management.4,5,11,19
PrePG levels may be used interchangeably with FPG levels.5,19
SMBG can provide patients with information to assess
their therapeutic response and adjust their treatment
regimen.4 Results from SMBG also can complement A1C
measurements.4,11 Because A1C is an average measure and
does not reflect glycemic variability, a combination of SMBG
and A1C may be appropriate to judge glycemic control in
patients who experience glucose fluctuations.4 Timing and
frequency of SMBG are generally determined by the patient’s
needs.4 For example, an individual who is not reaching A1C
goals despite good FPG levels may be advised to assess PPG
levels to determine whether postmeal glucose fluctuations are
high enough to be treated in order to improve overall glycemic
control.4
diabetes and to avoid the associated rise in health care
costs.30 Historically, glycemic control efforts have emphasized
achievement of A1C and FPG targets.31,32 However, it is
becoming increasingly evident that postprandial increases
in PG levels (also referred to as PPG excursions) also
contribute significantly to overall glycemic control and to the
development of diabetes complications.5,32,33 Consequently,
PPG control is receiving recognition as an essential
therapeutic target for optimizing glycemic control in patients
with type 2 diabetes.4,5,32-34 Acceptance of PPG control as a
therapeutic goal for type 2 diabetes has been facilitated by the
introduction of agents that specifically target PPG.33
Relative FPG and PPG contributions to A1C
Both FPG and PPG contribute to A1C, but the specific
relationship among these glycemic indicators remains
unclear.33 In a study of patients with good glycemic control
(A1C < 7.0%) who were not treated with insulin, Bonora et
al observed that A1C levels correlated most closely with
mean plasma glucose (MPG) levels and less so with PrePG/
FPG levels. The poorest correlation was between A1C
and PPG levels.34 In contrast, a study of patients receiving
insulin therapy (mean A1C = 7.83%) demonstrated that A1C
correlated better with PPG than FPG levels.35 In fact, the
strongest correlations with A1C were noted for PPG levels
measured after breakfast and dinner.
In a study of patients with type 2 diabetes treated with diet
and/or metformin, Monnier et al demonstrated that PPG levels
make a greater relative contribution to A1C in patients with
good glycemic control, and FPG levels have a greater impact
on A1C in patients with poor glycemic control (Figure 1).36
The study by Monnier et al specifically excluded patients
receiving acarbose or insulin because these treatments affect
PPG excursions.36 For patients with poor glycemic control,
PPG contributed approximately 30% to A1C, but the PPG
contribution was 70% in patients with A1C values < 7.3%.36
The observations of Monnier et al suggest that achieving PPG
control may be important to achieving near-normal glucose
levels because of a disproportionate contribution of PPG to
overall glycemic control as A1C levels approach the normal
range.36
The challenge of PPG levels make a
meeting glycemic
greater relative
targets
contribution to
Despite evidence supporting the benefits of tight glycemic
control for patients with type 2 diabetes, a large number of
patients do not meet recommended glycemic targets. Recent
estimates indicate that 57% of type 2 diabetes patients reach
the ADA glycemic target of A1C < 7%, and only 33% reach the
AACE glycemic target of A1C ≤ 6.5%.28,29
It is essential to identify treatment approaches to improve
glycemic control in order to prevent complications due to
4
A1C in patients
with good
glycemic control.
Figure 1. Relative contributions
of FPG and PPG to A1C36
80
a,b
FPG
Contribution (%)
60
c
PPG
It is now evident that a large number of patients with type
2 diabetes experience significant PPG excursions, even
in the context of good control according to A1C and FPG
measurements. A study by Bonora et al revealed that > 60%
of patients with type 2 diabetes experienced PPG excursions
higher than 160 mg/dL.34 This was true even in patients
with A1C levels < 7.0. Erlinger and Brancati reported similar
findings, with 74% of patients experiencing postchallenge
hyperglycemia in response to an OGTT.37
c
a
40
b
a
20
0
There is currently support for using all 3 glycemic measures
— A1C, FPG, and PPG — to direct therapy necessary to
achieve the glucose targets that have been demonstrated to
reduce the risk of complications due to diabetes.4,5,19 This is
particularly true for patients who are not meeting A1C goals or
who are treated with multiple daily insulin injections.
1
2
3
4
5
(<7.3)
(7.3-8.4)
(8.5-9.2)
(9.3-10.2)
(>10.2)
A1C Quintiles
A1C
a, significant difference between FPG and PPG; b, significant difference from
all other A1C quintiles; c, significantly different from highest A1C quintile
Although PPG control is likely to improve overall glycemic
control, a case can be made for targeting FPG first because
PPG levels are elevated, in part, due to increased FPG levels.33
In addition, FPG is subject to fewer variables than PPG, which
is affected by factors such as nutrient content of the meal
and gastric emptying.33 According to this rationale, monitoring
and correcting PPG levels would be considered appropriate
for patients who have discrepant A1C and FPG measures.4 In
these scenarios, monitoring and correcting PPG levels may
have benefit on glycemic control in specific patients.
Data generated to date suggest that the relative contributions
of FPG and PPG to overall glycemic control depend, to some
extent, on a patient’s clinical characteristics. Consistent
with these observations, treatment guidelines for type 2
diabetes include recommendations for personalizing diabetes
management plans to include SMBG and PPG control as
necessary.4,5,19
PPG and the
pathophysiology
of type 2
diabetes
The importance of managing PPG to meet
lower glycemic targets
There is general consensus that, for many patients,
IGT is an early stage in diabetes pathogenesis.1,4,5,38,39 IGT is a
specific instance of postprandial hyperglycemia, defined by a
BG level of 140 to 200 mg/dL (7.8-11 mmol/L) 2 hours after
oral glucose ingestion in persons who have normal fasting
glucose concentrations.1,4,5 The risk for subjects with IGT to
progress to diabetes is about 30% over 3 years.40 The state
of IGT, an abnormality in PPG but not FPG, suggests that
monitoring glycemia after a glucose challenge may be more
sensitive than after a period of fasting. According to ADA
criteria, IFG is defined by a BG concentration of 100 to 125
mg/dL (5.6-6.9 mmol/L) and can accompany IGT.4 Together,
IGT, IFG, and IGT/IFG are considered to be prediabetic states.4
Arguments can be made for measuring both FPG and PPG to
achieve optimal glycemic control.33 Rationale supporting the
use of each are listed in Table 4.33
Table 4. Reasons to Target
FPG or PPG Values33
FPG
•Contributes to A1C
•Determinant of PPG
•Poor glucose control
(A1C > 8.4%)
•Contributes ≈ 70%
when A1C > 10.2%
•More reproducible
PPG
•Contributes to A1C
•Better glucose control (A1C < 8.4%)
•Contributes ≈ 70% when A1C < 7.3%
•Is frequently the earliest abnormality
of type 2 diabetes
•May represent an independent risk for
cardiovascular disease
•Preprandial, but not A1C, at goal
•Gestational diabetes
•For patients using medications
targeting PPG
•If postprandial hypoglycemia
is expected
Even in instances where PPG elevation is not measured
prior to a diabetes diagnosis, it is detectable early in the
progression of the disease, and elevated PPG levels are
considered to be a sensitive indicator for diagnosis.1,4,38 The
progressive loss of β-cell function, insulin secretion, and insulin
sensitivity contributes to the development of postprandial
hyperglycemia (Figure 2).32,41
5
% β-Cell Function
Figure 2.41 β-Cell Dysfunction Begins
10 Years Prior To Type 2 Diabetes Diagnosis
100
75
DIAGNOSIS
50
25
Postprandial
Hyperglycemia
T2DM
IGT
0
–12 –10
–6
–2
0 2
6
10 12 14
Time
Consequences of poor PPG control
Individuals with diabetes have increased cardiovascular
risk. Heart disease death rate and the risk for stroke are
2 to 4 times higher in adults with diabetes than adults
without diabetes.2 In fact, recommendations of the National
Cholesterol Education Program (NCEP) include diabetes as a
coronary heart disease (CHD) risk equivalent because patients
with diabetes have the same risk of experiencing major
coronary events as individuals with CHD.42 The cardiovascular
mortality rate among patients with type 2 diabetes has been
estimated at 52%, making cardiovascular disease the leading
cause of death in patients with type 2 diabetes.43
Poor PPG control has been associated with development
of surrogate markers for cardiovascular disease and has
recently been proposed as a risk factor for cardiovascular
disease.32 A number of studies have demonstrated an
association between poor PPG control and the development of
cardiovascular disease. The IDF Guideline for Management of
Postmeal Glucose provides a good review of these studies.32
In particular, the Diabetes Epidemiology Collaborative Analysis
of Diagnostic Criteria in Europe (DECODE) study is 1 key study
that demonstrated that PPG glucose levels better predicted
excess mortality due to all causes and cardiovascular events
than FPG levels.44
Several mechanisms have been hypothesized to explain the
increased cardiovascular risk that has been attributed to
postprandial hyperglycemia, such as oxidative stress and
free radical generation, inflammation, endothelial dysfunction,
and hypercoagulability.45 For example, in a study comparing
patients with type 2 diabetes and normal controls, Monnier
et al measured excretion of urinary 8-iso=PGF2 to assess
oxidative stress over 24 hours.46 Oxidative stress was higher
for patients with type 2 diabetes and correlated most strongly
with the amplitude of postprandial glucose excursions.46
Perhaps the most convincing evidence that elevated PPG
contributes to cardiovascular risk in patients with type
2 diabetes comes from studies in which amelioration
of postprandial hyperglycemia improves cardiovascular
6
outcomes. Although no completed studies have demonstrated
that controlling PPG levels decreases the risk of macrovascular disease in patients with type 2 diabetes, data
suggest that this may be the case.32 For example, treatment
with acarbose, an α-glucosidase inhibitor that decreases
PPG excursions, has been associated with decreased risk of
MI, improved lipid profiles, decreased blood pressure, and
slower progression of intima-media thickness (a surrogate
marker for atherosclerosis) compared with placebo.47,48
Esposito et al compared the effects of repaglinide, an agent
that targets PPG control, with glyburide, an agent that has
greater effects on FPG.49 Both groups generated the same
decrease in A1C, but carotid intima-media thickness (CIMT)
decreased to a greater extent in the repaglinide group than
the glyburide group. In addition, repaglinide treatment was
associated with greater decreases in several markers of
inflammation, namely interleukin-6 (IL-6), IL-18, and C-reactive
protein (CRP).49 Findings such as these raise the possibility
that the use of interventions to target PPG levels can achieve
cardiovascular benefits in addition to better glycemic control.
However, it is important to note that this hypothesis has not
been conclusively established in well-controlled trials or widely
accepted into clinical medicine.
Intervening to address PPG fluctuations
Consumption of foods that are low in dietary fiber content and
contain higher proportions of readily digestible carbohydrates
are associated with development of type 2 diabetes and
CHD.45 In addition, physical inactivity increases insulin
resistance, which in turn exacerbates PPG excursions.45
Diet and exercise can improve PPG and A1C levels and are
recommended as first-line therapeutic approaches for patients
with type 2 diabetes.4,45,50,51 However, even compliant patients
with an initial positive response to diet and exercise are unable
to maintain glycemic control with lifestyle modification alone
and will require therapeutic intensification using a combination
of pharmacologic antihyperglycemic agents.52 Because a
majority of patients with type 2 diabetes will eventually require
pharmacologic agents, and in the interest of space limitations,
this review will focus on pharmacologic agents that target PPG
control. Specifically, incretin-based therapies are reviewed in
depth because they are the newest agents to address PPG.
In type 2 diabetes, postprandial hyperglycemia is the
consequence of a collection of physiologic abnormalities,
including:3,32
• Insulin resistance, which impedes glucose uptake by
peripheral tissues like skeletal muscle and fat.
• Decreased β-cell function with insufficient insulin
secretion to compensate for insulin resistance. In
patients with diabetes, insulin secretion is lower in
absolute terms and delayed in response to eating or
hyperglycemia.
• Impaired suppression of glucagon and endogenous
hepatic glucose production.
• Faster glucose delivery due to more rapid gastric
emptying, a characteristic of many patients with early
diabetes.
Because insulin and amylin have multiple roles in glucose
regulation, replacing these hormones addresses several
physiologic abnormalities. For example, exogenous insulin
can promote peripheral glucose uptake and utilization, even
in insulin-resistant patients, and suppresses endogenous
glucose production by the liver directly and by reducing
glucagon release.3 Amylin replacement slows gastric
emptying, suppresses glucagon secretion, and increases
satiety to reduce food intake.3,32 The intestinal hormone
glucagon-like peptide 1 (GLP-1) also has multiple activities
that promote glycemic regulation. GLP-1 enhances glucosedependent insulin secretion, suppresses glucagon secretion,
slows gastric emptying, and reduces food intake.3 Similar
to therapies that replace insulin and amylin, incretin-based
therapies address multiple physiologic deficits.
Incretin-based
therapies:
Addressing PPG
and filling a
therapeutic need
The studies of Bonora et al and Erlinger and Brancati revealed
that the majority of patients with type 2 diabetes experience
postprandial hyperglycemia.34,37 Most outpatients in the
Bonora study had a PPG level > 160 mg/dL (8.9 mmol/L) with
average levels ≥ 180 mg/dL (10 mmol/L).34 In the Erlinger
and Brancati study, 74% of patients with type 2 diabetes
experienced a 2-h postmeal glucose level ≥ 200 mg/dL
(11 mmol/L).37 Even among patients with A1C < 7%,
the percent of patients who experienced postprandial
hyperglycemia ranged from 39% to nearly 100%, depending
on the particular study group.34,37 Evidence suggests that
improving PPG control is useful for achieving therapeutic
targets, and it has been hypothesized that minimizing
wide swings in BG may reduce the damaging vascular
effects of hyperglycemia.32 As concerns about the negative
consequences of PPG excursions have been raised, practice
guidelines that provide recommendations for the management
of PPG have been developed, including the use of therapeutic
agents that target PPG.4,5,19,50
What are incretin-based therapies?
It has long been known that ingestion of glucose causes a
greater insulin response than intravenous administration of
glucose.53 This enhancement of glucose-stimulated insulin
secretion is due to the release of gastrointestinal hormones
during nutrient ingestion and is called the incretin effect. In
particular, 2 hormones, glucose-dependent insulinotropic
peptide (GIP) and glucagon-like peptide-1 (GLP-1), are thought
to account for most of the incretin effect.53 The incretins, GIP
and GLP-1, are essential for normal glucose regulation, and
interference with either GIP or GLP-1 action causes glucose
intolerance.53
The incretin effect is abnormal in patients with type 2 diabetes
who have been shown to have only a small enhancement of
insulin secretion with oral compared to intravenous glucose.54
While the explanation for an impaired incretin effect in diabetes
is not clear, there is good evidence that the insulinotropic
action of GIP is reduced in diabetic patients.55 GLP-1 remains
a potent β-cell stimulus in persons with type 2 diabetes,
although compared with subjects without type 2 diabetes,
sensitivity to GLP-1 is decreased.55 While some studies
have demonstrated that plasma GLP-1 levels are reduced in
persons with diabetes, this finding has not been consistent.56-59
Moreover, where decrements of GLP-1 secretion have been
demonstrated in patients with diabetes, the absolute decrease
is relatively modest.57,58 Based on current evidence, it seems
unlikely that a deficiency of circulating GLP-1 contributes to the
pathogenesis of type 2 diabetes.
Administration of pharmacologic amounts of GLP-1 to diabetic
subjects has impressive effects on PG. Intravenous infusion
of GLP-1 reduced fasting glucose to near-normal levels
and resulted in PPG similar to individuals without diabetes
(Figure 3).60,61 In a 6-week study, continuous subcutaneous
administration of GLP-1 to poorly controlled subjects with type
2 diabetes improved glycemia by increasing insulin secretion
and reducing plasma glucagon and also caused weight loss.62
Together, these studies demonstrated the potential for GLP-1
signaling to effectively lower glucose in type 2 diabetes, both
acutely and over extended treatment, and to engage multiple
mechanisms to have these effects.
Figure 3. GLP-1 normalizes
postprandial hyperglycemia in
patients with type 2 diabetes 61
T2 diabetes
No diabetes
T2 diabetes + GLP-1
16
14
Glucose (mmol/L)
Agents that target postprandial glycemic control affect 1 or
more of these underlying pathophysiologic characteristics.32
Classes of agents available for managing PPG levels include
fast-acting insulin analogs, glinides, α-glucosidase inhibitors,
amylin analogs, and incretin-based therapies.32 Fast-acting
insulin analogs have rapid onset, peak, and short duration of
action. They were developed to provide insulin replacement in
a manner that is more physiologic, and more convenient for
patients. The glinides are rapid-acting insulin secretagogues
that stimulate β-cell activity. The α-glucosidase inhibitors inhibit
a key enzyme in carbohydrate digestion to slow carbohydrate
absorption and decrease the PPG peak.
12
10
8
6
4
2
0
Breakfast Lunch Snack
22
24
2
4
6
8
10
12
14
16
7
Because GLP-1 is rapidly degraded by the ubiquitous enzyme
dipeptidyl peptidase-4 (DPP-4), continuous infusion of the
native peptide, which is both expensive and impractical,
is required to achieve clinical efficacy in patients with type
2 diabetes.56,63 To overcome this key limitation of GLP-1,
alternative strategies have been employed to utilize GLP-1
receptor signaling in the treatment of diabetes. Two general
approaches have been pursued. The first is development of
DPP-4-resistant GLP-1 receptor agonists that have an extended
half-life after injection. The second is the synthesis of orally
available small molecules that inhibit DPP-4 and increase levels
of endogenous GLP-1 by preventing its degradation.56,63
GLP-1 receptor agonists available or in advanced stages of
clinical development include exenatide, exenatide long-acting
release (LAR)*, liraglutide*, taspoglutide*, and AVE0010*.56,63-66
Each of these therapies is administered by subcutaneous
injection.56,67,68 Exenatide is a synthetic version of a naturally
occurring reptilian peptide, exendin-4, that has considerable
homology with GLP-1 but is resistant to degradation by DPP-4,
and is a potent GLP-1 receptor agonist.56,63 Exenatide is
approved for twice-daily dosing and has been in wide usage for
more than 3 years.68 Exenatide LAR, a microsphere formulation
with delayed release after subcutaneous injection, has a
pharmacokinetic profile consistent with once-weekly dosing
and is in phase 3 clinical trials.56,63,69 Phase 3 clinical trials
also have begun for AVE0010, another exendin-based GLP-1
receptor agonist that is administered 1 to 2 times daily.65,67
Unlike exenatide and AVE0010, liraglutide and taspoglutide are
synthetic versions of human GLP-1 with amino acid changes
that confer resistance to degradation.63,67 Liraglutide, which
has demonstrated benefit with once-daily administration in
clinical trials, is now being considered for regulatory approval
in the US, Europe, and Japan.70-72 Taspoglutide is formulated
for once-weekly administration and is currently in phase 3
clinical trials.64,67
There are currently 5 DPP-4 inhibitors either on the market or
in late-stage clinical development.63,73-75 Sitagliptin has been
available in the US for 2 years and is approved for use as
monotherapy or in combination with other antidiabetic drugs
to lower BG in adults with type 2 diabetes.76 Although it has
not received regulatory approval in the US, vildagliptin* is
approved for use in the European Union, and in other countries
outside the US.77 Discussions continue regarding steps needed
for US approval, but resubmission is not planned at this time.77
Alogliptin* is also awaiting regulatory approval, and phase 3
clinical trials are under way for saxagliptin* and BI-1356*.78-80
As listed in Table 5, GLP-1 engages a range of physiologic
systems that counter the pathophysiology of type 2 diabetes.
Consistent with its release after meals and role in postprandial
metabolism, many of the effects of GLP-1 promote PPG
normalization. The information in Table 5 also indicates that, in
general, both classes of incretin-based therapies share some
of the beneficial actions of GLP-1.56 Unlike the GLP-1 receptor
agonists, the DPP-4 inhibitors appear to have minimal effects
on deceleration of gastric emptying and do not promote
weight loss, but all of the incretin-based therapies counter
multiple pathophysiologic characteristics of type 2 diabetes
that contribute to postprandial hyperglycemia.56
Table 5. Actions of GLP-1 and incretin-based therapies in
correcting postprandial hyperglycemia56
Characteristic of type 2 diabetes
GLP-1 action
GLP-1 receptor agonists?
DPP-4 inhibitors?
Defective β-cell glucose sensing
Improved insulin response to
increased BG
Yes
Yes
Delayed and attenuated insulin
secretion after meals
Improved postprandial insulin
release
Yes
Yes
Hyperglucagonemia
Suppression of glucagon secretion
Yes
Yes
Normal, decelerated, or accelerated gastric emptying
Deceleration of gastric emptying
Yes
No81,82
Hyperphagia/obesity
Satiety/anorexia/weight loss
Yes
No83
Inappropriate HGP
Suppression of HGP
Possibly
Possibly
Impaired glucose disposal
Increased glucose utilization
Possibly84
Possibly85
HGP, hepatic glucose production.
8
*Agent is not yet approved for clinical use.
Incretin-based therapies improve PPG control
There is now ample evidence from clinical trials that demonstrate the efficacy of incretin-based therapies for improving glycemic
control. A summary of clinical trial data published in 2007-2008, which includes PPG control as an outcome, is summarized in
Table 6. Studies with fewer than 100 participants are not included, with the exception of the trial by Covington et al,86 which was
the only study that was identified as having information regarding the effects of alogliptin on PPG.
Table 6. Selected clinical study results: effects of
incretin-based therapiesa on PPG levels in patients with
type 2 diabetes
Trial
PPG (mg/dL, unless otherwise
indicated)
A1C (%)
Cardiovascular risk factors or
surrogate markers
(Change from BL to EOS)
5 mcg EXE: −0.7*
10 mcg EXE: −0.9*
PBO: −0.2
Improved systolic and
diastolic BP for EXE*
GLP-1R Agonists
Exenatideb
Moretto 200887
N = 232c
EXE mono vs PBO
24 weeks
Brodows 200888
N = 414
26 weeks
Barnett 200789
N = 138c
EXE 10 mcg vs GLAR
+ MET or SU
Crossover study
2 × 16-week periods
Nauck 200790
N = 501c
EXE 10 mcg vs ASPART
+ MET and SU
52 weeks
Daily mean PPG excursions
(Change from BL to EOS)
5 mcg EXE: −21.3*
10 mcg EXE: −24.7*
PBO: −8.3
PPG excursions
(AUC calculation)
EXE:
BL:17.7 ± 1.1 mmol∙h/L
End:8.8 ± 0.7 mmol∙h/L‡
GLAR:
BL:15.4 ± 0.9 mmol∙h/L
End:16.4 ± 1.0 mmol∙h/L
2-h PPG excursions
(Mean differences
EXE – GLAR)
−39.6† (morning)
−9† (midday)
−37.8† (evening)
EXE:
BL: 8.2 ± 0.9
End: 7.1 ± 1.1
GLAR:
BL: 8.3 ± 0.9
End: 7.1 ± 0.9
(Change from BL to EOS)
10 mcg EXE: −1.36‡
GLAR: −1.36‡
None reported
None reported
Lower daily mean glucose excursion
for EXE vs GLAR (mean diff. = −30.6†)
PPG excursions
Larger reductions in PPG vs ASPART
(values not reported)†
(Change from BL to EOS)
10 mcg EXE: −1.04
ASPART: −0.89
Smaller increase in HDL for EXE†
Improvement in BP for EXE‡
Systolic: −5 mm Hg, P < 0.001
Diastolic: −2±10 mm Hg,
P = 0.03
Exenatide LARd
Drucker 200891
N = 295
EXE LAR vs EXE
30 weeks
Greater reduction in LDL for EXE
LAR group†
2-h PPG
(Change from BL to EOS)
EXE LAR: −95.4†‡
EXE: −124.2‡
(Change from BL to EOS)
2 mg EXE LAR: −1.9†‡
10 mcg EXE: −1.5‡
Mean PPG
(Change from BL to EOS)
0.6 mg LIR: −30.6*
1.2 mg LIR: −41.4*
1.8 mg LIR: −46.8*
4 mg GLIM: −45*
PBO: −10.6
(Change from BL to EOS)
0.6 mg LIR: −0.7*
1.2 mg LIR: −1.0*
1.8 mg LIR: −1.0*
4 mg GLIM: −1.0*
PBO: 0.1
Fasting triglycerides reduced in
both groups
Similar improvements in systolic
and diastolic BP for both groups‡
Liraglutide
Nauck 200871
N = 1087c
LIR, GLIM, and PBO
+ MET
26 weeks
Greater reduction in systolic BP
for 1.2 and 1.8 mg LIR
compared with GLIM†
9
Trial
PPG (mg/dL, unless otherwise
indicated)
A1C (%)
Cardiovascular risk factors or
surrogate markers
(Change from BL to EOS)
100 mg SIT: −1.0*
PBO: 0
No significant treatment differences in fasting lipid levels
2-h PPG
(Change from BL to EOS)
100 mg SIT: −69.3*
PBO: 12.0
(Change from BL to EOS)
100 mg SIT: −0.65*
PBO: 0.4
None reported
2-h PPG
(Change from BL to EOS)
50 mg VILDA - PBO: −34.2
100 mg VILDA - PBO: −46.8*
(Adjusted mean change)
50 mg VILDA: −0.8*
100 mg VILDA: −1.0*
PBO: −0.3
No significant between-group
differences in lipid measurements
(Change from BL to EOS)
25 mg ALO: −0.22*
100 mg ALO: −0.40*
400 mg ALO: −0.28*
PBO: 0.05
None reported
DPP-4 Inhibitors
Sitagliptin
Raz 200892
N = 190c
SIT vs PBO
+ MET
18 weeks
Nonaka 200893
N = 151
SIT vs PBO
12 weeks
2-h PPG
(Change from BL to EOS)
100 mg SIT: −68.4*
PBO: −14.4
Vildagliptin
Garber 200794
N = 398c
VILDA vs PBO
+ PIO
24 weeks
Alogliptin
4-h PPG
(Change from BL to EOS)
Covington 200886
N = 56
ALO mono vs PBO
2 weeks
Breakfast
25 mg ALO: −32.5*
100 mg ALO: −37.2*
400 mg ALO: −65.6*
PBO: 8.2
Lunch
25 mg ALO: −15.8*
100 mg ALO: −29.2*
400 mg ALO: −27.1*
PBO: 14.3
Dinner
25 mg ALO: −21.9*
100 mg ALO: −39.7*
400 mg ALO: −35.3*
PBO: 12.8
Saxagliptin
Rosenstock 200873
N = 338 (low-dose cohort)
N = 85 (high-dose cohort)
SAX mono vs PBO
12 weeks (low-dose cohort)
6 weeks (high-dose cohort)
1-h PPG
(Change from BL to EOS)
Low dose
2.5 mg SAX: −24.42
5 mg SAX: −35.30
10 mg SAX: −41.04
20 mg SAX: −27.54
40 mg SAX: −33.98
PBO: −1.41
High dose
100 mg SAX: −44.58
PBO: −17.22
(Change from BL to EOS)
Low dose
2.5 mg SAX: −0.72*
5 mg SAX: −0.90*
10 mg SAX: −0.81*
20 mg SAX: −0.74*
40 mg SAX: −0.80*
PBO: −0.27*
None reported
High dose
100 mg SAX: −1.09
PBO: −0.36
ALO, alogliptin; ASPART, biphasic insulin aspart; BL, baseline; BP, blood pressure; EOS, end of study; EXE, exenatide; GLAR, glargine; GLIM, glimepiride; LAR,
long-acting release; LIR, liraglutide; MET, metformin; mono, monotherapy; PBO, placebo; PIO, pioglitazone; SAX, saxagliptin; SIT, sitagliptin; SU, sulfonylurea;
VILDA, vildagliptin.
a
Published trial results for taspoglutide were not available for inclusion; bEXE administered twice per day; cintent-to-treat population; dEXE LAR administered
once per week.
*Significant difference vs PBO; †significant difference vs comparator; ‡significant difference vs baseline.
10
Current
treatment
guidelines
regarding PPG
Recent practice guidelines from the ADA, AACE, and IDF all
reflect increased awareness of the importance of PPG control,
although their recommendations differ slightly. Glycemic
targets, according to each set of guidelines, are presented in
Table 2.
The ADA guidelines acknowledge that PPG levels contribute to
overall glycemic control, measured by A1C, and that elevated
PPG levels have been associated with increased cardiovascular
risk.4 However, because studies demonstrating the relationship
between A1C and diabetes complications have relied heavily
on FPG levels, the ADA recommends that FPG levels should be
measured routinely. According to the ADA guidelines, though,
it is reasonable to include PPG measurements if a patient
achieves PrePG/FPG levels but does not meet A1C goals.4
The AACE guidelines place more emphasis on addressing
PPG levels.5,51 The authors of these guidelines propose
that approaches addressing both FPG and PPG levels are
prudent because of the potential increased cardiovascular
risk associated with elevated PPG levels.5 They were also
considered appropriate because the relative contribution of
PPG to overall hyperglycemia increases as a patient nears
target glucose level. At A1C levels between 7.3% and 8.0%,
FPG and PPG levels each contribute equally (50%) to overall
glycemia, and the FPG contribution drops to 30% as the A1C
decreases below 7.3%.5 The validity of these assumptions will
need to be reconsidered in light of the results of the ACCORD
and ADVANCE trials. However, to facilitate the treatment of
both FPG and PPG by clinicians, the AACE guidelines include
practical recommendations for combinations of agents that
achieve both pre- and postprandial glucose targets based on
the A1C level.5 Furthermore, the appropriate target, FPG or
PPG, relative to A1C level, is specifically indicated on the ACE/
AACE Diabetes Road Map, which provides a diagrammatic
algorithm for treating patients with type 2 diabetes.51
Summary
Improving glycemic control to an A1C of at least 7.0%,
and perhaps lower, has clear benefits in decreasing the
risk of microvascular complications in patients with type 2
diabetes. There is also a growing body of evidence indicating
that intensive glycemic control may decrease the risk of
macrovascular complications, although this position is under
revision given the results of recent clinical trials. Overall
glycemic control, assessed by A1C levels, is determined by
FPG and PPG. As patients with type 2 diabetes achieve nearnormal glucose levels, the contribution of PPG to A1C levels
is greater. Postprandial hyperglycemia also appears to be a
prominent characteristic of glycemic dysregulation in patients
at early stages of diabetes progression.
The majority of patients with type 2 diabetes will require
pharmacologic intervention to maintain glucose control.
Medications like metformin and long-acting insulins are proven
to be effective in controlling FPG and are the cornerstones of
pharmacologic therapy for type 2 diabetes. However, it is now
possible to augment these traditional treatments using several
classes of agents with enhanced effects on PPG. These
include fast-acting insulin analogs, glinides, α-glucosidase
inhibitors, amylin analogs, and incretin-based therapies. In
recognition of growing evidence regarding the importance
of PPG control, clinical practice guidelines from the ADA and
AACE have been revised to address PPG control and to include
recommendations for the use of the relatively new categories
of incretin-based therapies.5,50,51 Subsequent issues of the
Peak Issues series will address the clinical use of incretinbased therapies to achieve near-normal glycemic control and
improve outcomes for patients with type 2 diabetes.
The IDF has developed a specific approach for the
management of postmeal glucose with the stated
understanding that to achieve A1C goals, controlling PPG
excursions is at least as important, and perhaps more
important, than lowering FPG levels.32 The IDF guidelines
provide a rationale for treating PPG, a summary of PPG
targets, a discussion of therapies such as diets with low
glycemic load, and recommendations for pharmacologic
agents that specifically target PPG levels. The list of agents
includes α-glucosidase inhibitors, amylin analogs, glinides,
insulins, GLP-1 receptor agonists, and DPP-4 inhibitors. The
IDF guidelines state, in conclusion, that, “…optimal glycaemic
control cannot be achieved without adequate management of
postmeal glucose”.32
11
Literature
Summaries
Esposito K, Ciotola M, Carleo D, et al. Post-meal
glucose peaks at home associate with carotid
intima-media thickness in type 2 diabetes. J Clin
Endocrinol Metab. 2008;93:1345-1350.
The 2-hour postprandial glucose (2-h PPG) level is
currently used to describe postmeal glycemic peaks
and has been associated with macrovascular outcomes.
The incremental glucose peak (IGP), another measure
of PPG, is defined as the maximal incremental increase
in blood glucose (BG) obtained at any point after the
meal. Because IGP is defined as a difference and does
not reflect premeal glucose levels as 2-h PPG does, it
may be a good measure of postmeal glycemic spikes.
The authors set out to assess the size and timing of
postmeal glucose peaks in everyday life of patients
with type 2 diabetes and to determine the relationship
with carotid atherosclerosis. In addition, they compared
2-hour PPG and IGP in the context of PPG monitoring.
The observational study included 644 patients with type
2 diabetes who attended diabetes clinics in the vicinity
of Campania County, South Italy. Study participants had
disease durations of 6 months to 10 years, A1C levels
≥ 6.5%, and were treated with oral antidiabetic agents or
diet. Patients treated with insulin were excluded from the
study.
Participants were requested to follow their normal
therapeutic regimen and diet for the month of their study
involvement. Study participants completed specified
home BG measurements over the course of 1 month.
All participants were provided with the same model
of glucose monitor and were instructed to measure
BG around their main meal (just before and every 30
minutes after for 2 hours) for 3 nonconsecutive days.
Participants were also asked to measure fasting plasma
glucose (FPG) on 2 nonconsecutive days. Carotid
intima-media thickness (CIMT) was assessed by B-mode
ultrasound. The following glucose parameters were
examined: IGP, A1C, FPG, premeal glucose, 2-h PPG,
and absolute glucose peak (the highest glycemic peak
recorded at any time after the meal). Statistical analyses
included only results from those patients with 3 complete
BG profiles and CIMT measurements.
A summary of glycemic and CIMT results, by IGP
quintiles, is presented in the accompanying table.
Home BG profiles were reproducible for each patient. In
addition, 95% of patients experienced IGP within 1 hour
from the start of the meal, regardless of their therapeutic
regimen. Results are summarized in the table below and
indicate that all examined measures of glycemic control
correlated with IGP, although the correlation with premeal
glucose level was negative. A positive correlation
between IGP and triglyceride level was also reported.
Glycemic and CIMT Outcomes by IGP Quintile
IGP Quintiles (mg/dL)
P value
0–40
41–70
71–100
101–129
>130
Entire Group
129
129
129
129
128
644
IGP
29
(12)
55
(16)
88
(15)
111
(18)
164
(17)
89
(56)
< .001
Fasting
142
(40)
144
(51)
146
(46)
158
(53)
160
(59)
148
(35)
.035
Premeal
147
(42)
140
(40)
140
(39)
136
(30)
129
(32)
137
(29)
.028
2-h PPG
160
(40)
164
(44)
175
(46)
282
(59)
212
(60)
177
(53)
< .001
Absolute peak
179
(35)
189
(40)
209
(41)
235
(51)
295
(61)
220
(61)
< .001
A1C (%)
6.7
(0.8)
7.0
(0.9)
7.6
(1.2)
8.1
(1.2)
9.0
(1.3)
7.6
(1.3)
.01
CIMT (mm)
0.82
(0.2)
0.84
(0.2)
0.86
(0.2)
0.92
(0.2)
0.94
(0.2)
0.88
(0.2)
.01
n
Glucose (mg/dL)
Data are expressed as mean (SD) unless otherwise specified.
IGP, impaired glucose response; PPG, postprandial plasma glucose; CIMT, carotid intima-media thickness
12
Of the glycemic control markers, IGP had the strongest
positive, statistically significant, linear correlation with CIMT
(r = .40; P = .006). Correlations were also observed for
absolute glucose peak (r = .35; P = .01), 2-h PPG
(r = .24; P = .02), and A1C (r = .21; P = .03). Age also
demonstrated a strong correlation with CIMT (r = .38;
P = .001). Levels of fasting insulin, FPG, total cholesterol,
HDL-cholesterol, and triglycerides did not correlate with CIMT.
When results were considered by A1C level (< 7.0,
7.0-8.5, > 8.5), significant trends for increase in CIMT
with increasing IGP were observed for each level (see
accompanying figure).
P<.01
P<.05
0.95
CIMT (mm)
0.9
P<.01
P<.01
0.85
0.8
>8.5
7.0-8.5
0.75
<7.0
0.7
>120
51-120
HbA1c
0-50
IGP (mg/dL)
The results of this study demonstrate that postchallenge
hyperglycemic spikes measured at home correlate more
strongly with CIMT than 2-h PPG, A1C, and FPG levels. In
addition, based on the timing of the IGP, 2-h PPG should not
be considered equivalent with IGP. The correlation between
IGP and CIMT exists regardless of A1C level. These findings
suggest that home monitoring of postmeal glucose peaks may
provide additional benefits in managing patients with type 2
diabetes.
Woerle HJ, Neumann C, Zschau S, et al. Impact of
fasting and postprandial glycemia on overall glycemic
control in type 2 diabetes: Importance of postprandial
glycemia to achieve target HbA1c levels. Diabetes Res
Clin Pract. 2007;77:280-285.
Woerle et al reported the results of a prospective interventional
study performed to assess the relative contributions of fasting
plasma glucose (FPG) and postprandial plasma glucose (PPG)
control in reaching target A1C levels. The trial included 164
patients with unsatisfactory glycemic control as indicated by
A1C levels ≥ 7.5%.
Prior to beginning the 3-month interventional portion of
the study, participants provided 7-point diurnal PG profiles,
including 3 preprandial measurements (7 AM, 1 PM, 7 PM),
3 PPG measurements 90 minutes after completion of each
meal, and 1 bedtime measurement. Participants then entered
a 2-week assessment period to titrate, intensify, and optimize
their therapeutic regimens. Therapeutic optimization followed
a stepwise process, beginning with treatment intensification to
achieve FPG levels < 100 mg/dL, followed by further titration
to achieve PPG levels < 140 mg/dL. The target A1C level was
≤ 7.0%.
Treatments were individualized for each patient and included a
range of regimens, including:
• Diet
• Metformin (MET)
• Sulfonylurea (SU)
• MET + SU
• Neutral protamine Hagedorn insulin (NPH)
• NPH twice daily
• NPH + short-acting insulin
• NPH + MET
• NPH + SU
• NPH + short-acting insulin + MET
• NPH + short-acting insulin + MET + SU
Following the 2-week therapeutic titration period, participants
entered a 3-month study period. A second set of diurnal
measurements was obtained at the end of this study period.
By the end of the 3-month study period, participants did not
experience significant weight change, and there were no
cases of severe hypoglycemia. Significant decreases in mean
A1C, FPG, PPG, and daylong glucose levels were measured
following the intervention phase of titrated therapy and are
summarized in the accompanying table.
Glycemic Parameters Before
and After Titrated Therapy
Glycemic
Parameter
Preintervention
Postintervention
P Value
A1C (%)
8.7 (0.1)
6.5 (0.1)
< .001
FPG (mg/dL)
174 (4)
117 (2)
< .001
PPG (mg/dL)
Daylong glucose
(mg/dL)
224 (4)
159 (3)
< .001
199 (4)
141 (2)
< .0001
Data are expressed as mean (SD) unless otherwise specified.
The target A1C of ≤ 7.0% was achieved by 73% of
participants. Among participants achieving the FPG target
(< 100 mg/dL), 64% also reached the A1C target. By
comparison, 94% of patients achieving the PPG target (< 140
mg/dL) reached the A1C target.
13
FPG was nearly identical for patients who did and did not
achieve A1C targets. However, all other measurements on
diurnal glucose curves were significantly higher for those who
did not achieve A1C. Diurnal plasma glucose curves revealed
that, for patients who did not achieve A1C ≤ 7.0%, PG levels
did not return to premeal levels following meals, resulting in a
progressive, stepwise increase in PG levels throughout the day
(see accompanying figure).
220
HbA1c > 7 N=44
HbA1c ≤ 7 N=120
200
mg/dL
180
160
140
120
100
6
8
10
12
14
Hours
16
18
20
22
24
Multiple linear regression analysis, with A1C level changes as
the dependent variable and FPG and daylong hyperglycemia as
independent variables, revealed partial regression coefficients
of 0.22 and 0.40 for FPG and daylong hyperglycemia,
respectively. This indicates that daylong hyperglycemia
contributed nearly twice as much to A1C as FPG. In addition,
PPG contribution was estimated at ≈ 90% for A1C levels
< 6.2% and ≈ 40% for A1C levels > 9.0%.
Results of this study confirm earlier findings regarding the
relative contributions of FPG and PPG to overall hyperglycemia.
In particular, PPG contributes more to A1C as A1C levels
decrease. Sequential optimization of FPG and PPG control
permitted investigators to demonstrate that control of PPG, in
addition to FPG, is needed to achieve A1C targets specified
in current treatment guidelines. Furthermore, good glycemic
control, using individualized treatment plans targeting FPG
and PPG, can be attained without weight gain or severe
hypoglycemia. The results of this study underscore the
importance of attention to PPG goals when A1C targets are
not achieved despite optimal FPG control.
Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA.
10-year follow-up of intensive glucose control in type 2
diabetes. N Engl J Med. 2008;359:1577-1589.
The United Kingdom Prospective Diabetes Study (UKPDS)
compared outcomes following conventional glucose control
(dietary restriction) or intensive glucose control (either
sulfonylurea or insulin [SU-insulin] or, in overweight patients,
14
metformin [MET]) in patients newly diagnosed with
type 2 diabetes. Compared with the conventional therapy
group, the UKPDS revealed significantly decreased risks for
microvascular complications in the SU-insulin group and for
any diabetes-related end point, myocardial infarction (MI),
and death from any cause in the MET group. In the Diabetes
Control and Complications Trial/Epidemiology of Diabetes
Interventions and Complications (DCCT/EDIC) study of patients
with type 1 diabetes, macrovascular risk was not reduced
for the intensive glucose therapy group compared with the
conventional group at the end of the study, but decreased
cardiovascular risk became evident during the 8-year
postintervention follow-up period. Posttrial monitoring was
also conducted for the UKPDS to ascertain whether glycemic
control was maintained and to determine macrovascular
outcomes.
A subset of 3277 UKPDS participants entered posttrial
monitoring. The posttrial participants were asked to attend
annual UKPDS clinics for 5 years and complete annual
questionnaires in years 6 to 10. Posttrial monitoring examined
7 aggregate clinical outcomes prespecified by the UKPDS
according to previous randomization categories. The
outcomes included:
• Any diabetes-related end point (sudden death, death
from hyperglycemia or hypoglycemia, fatal or nonfatal
MI, angina, heart failure, fatal or nonfatal stroke,
renal failure, amputation, vitreous hemorrhage, retinal
photocoagulation, blindness in 1 eye, or cataract
extraction)
• Diabetes-related death (sudden death or death from
MI, stroke, peripheral vascular disease, renal disease,
hyperglycemia, or hypoglycemia)
• Death from any cause
• MI (sudden death or fatal or nonfatal MI)
• Stroke (fatal or nonfatal)
• Peripheral vascular disease (amputation of at least 1
digit or death from peripheral vascular disease)
• Microvascular disease (vitreous hemorrhage, retinal
photocoagulation, or renal failure)
Posttrial follow-up continued for a median of 8.5 years for
participants in the SU-insulin group and 8.8 years for those
in the MET group. Overall mortality across both groups was
the leading cause of death. Baseline differences in A1C levels
between intensive- and conventional-therapy groups were
no longer evident after 1 year. Results related to aggregate
outcomes are summarized in the accompanying table.
Aggregate Outcomes for Patients During Follow-up
Aggregate Outcome
Intensive Therapy
SU-insulin group
Any diabetes-related end point
Diabetes-related death
Death from any cause
Myocardial infarction
Stroke
Peripheral vascular disease
Microvascular disease
MET group
Any diabetes-related end point
Diabetes-related death
Death from any cause
Absolute Risk*
Conventional Therapy
P Value
48.1
14.5
26.8
16.8
6.3
2.0
11.0
52.2
17.0
30.3
19.6
6.9
2.4
14.2
.04
.01
.007
.01
.39
.29
.001
45.7
14.0
25.9
53.9
18.7
33.1
.01
.01
.002
Myocardial infarction
14.8
21.1
.005
Stroke
6.0
6.8
.35
Peripheral vascular disease
2.3
3.4
.19
Microvascular disease
12.4
13.4
.31
MET, metformin; SU, sulfonylurea.*The absolute risk is the number of events per 1000 patient-years.
In the SU-insulin group, significant risk reductions for any
diabetes-related end point (relative risk reduction [RRR], 9%)
and for microvascular disease (RRR, 24%) were maintained.
Significant risk reductions emerged for diabetes-related
death (RRR, 17%), MI (RRR, 15%), and death from any cause
(RRR, 13%). No risk reductions were observed for stroke or
peripheral vascular disease. Significant reductions for any
diabetes-related end point (RRR, 21%), diabetes-related death
(RRR, 30%), MI (RRR, 33%), and death from any cause (RRR,
27%) were maintained in the MET group. No additional risk
reductions emerged; there was no observed risk reduction for
stroke, peripheral vascular disease, or microvascular disease.
The data indicate a legacy effect for intensive glycemic
control such that earlier periods of intensive glucose control
result in long-standing risk reduction. Ten years after the end
of the UKPDS, participants who received intensive control
experienced benefits beyond those who received conventional
control, even though the gap in A1C levels between groups
was closed soon after the study ended. These data support
implementing intensive glycemic control as early as possible in
the progression of type 2 diabetes to prevent the development
of microvascular and cardiovascular complications.
15
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91. Drucker DJ, Buse JB, Taylor K, et al. Exenatide once weekly versus twice daily
for the treatment of type 2 diabetes: A randomised, open-label, non-inferiority
study. Lancet. 2008.
92. Raz I, Chen Y, Wu M, et al. Efficacy and safety of sitagliptin added to
ongoing metformin therapy in patients with type 2 diabetes. Curr Med Res
Opin. 2008;24(2):537-550.
93. Nonaka K, Kakikawa T, Sato A, et al. Efficacy and safety of sitagliptin
monotherapy in Japanese patients with type 2 diabetes. Diabetes Res Clin
Pract. 2008;79(2):291-298.
94. Garber AJ, Schweizer A, Baron MA, Rochotte E, Dejager S. Vildagliptin in
combination with pioglitazone improves glycaemic control in patients with type
2 diabetes failing thiazolidinedione monotherapy: A randomized, placebocontrolled study. Diabetes Obes Metab. 2007;9(2):166-174.
17
Posttest
Questions
1. A patient’s ______ level provides a record of
average blood glucose levels over several
months, but it is not a good indicator of
glycemic variability.
a. A1C
b.fasting plasma glucose (FPG)
c.postprandial plasma glucose (PPG)
d.preprandial plasma glucose (PrePG)
2. PPG is typically measured _______ following a
meal.
a.immediately
b.1-2 hours
c.5-6 hours
d.7-8 hours
3. PPG levels have a relatively __________
influence on overall glycemic control at nearnormal plasma glucose levels and contribute
approximately _________ when A1C is < 7.3%.
a.small, 10%
b.small, 30%
c.large, 50%
d.large, 70%
4. The American Diabetes Association (ADA)
recommends a therapeutic PPG target of
_________, and the American Association of
Clinical Endocrinologists (AACE) recommends
_____________.
a.< 200 mg/dL, < 180 mg/dL
b.70-130 mg/dL, < 110 mg/dL
c.< 180 mg/dL, < 140 mg/dL
d.< 160 mg/dL, < 120 mg/dL
5. A study by Bonora et al revealed that _______
of patients with type 2 diabetes experience PPG
levels > 160 mg/dL.
a.< 10%
b.< 50%
c.> 60%
d.> 90%
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6. Postprandial hyperglycemia in the range of
140 to 200 mg/dL is referred to as impaired
glucose tolerance (IGT) and is considered to be
a prediabetic state with a risk of progression to
diabetes of ________.
a.30% over 1 year
b.10% over 3 years
c.30% over 3 years
d.30% over 5 years
7. Agents that ameliorate PPG excursions
may provide cardiovascular benefits as
demonstrated by their ability to _________.
a.slow the progression of atherosclerosis
b.increase inflammation
c.increase blood pressure
d.decrease A1C
8. Postprandial hyperglycemia is a consequence
of several physiologic abnormalities including
insulin resistance, decreased β-cell function,
and ________________.
a.increased insulin secretion
b.slowed gastric emptying
c.impaired glucagon suppression
d.decreased hepatic glucose production
9. Which of the following is not an agent or class
of agents that targets PPG levels?
a.α-glucosidase inhibitors
b.fast-acting insulin analogs
c.incretin-based therapies
d.metformin
10. Incretin-based therapies improve PPG control by
__________________.
a.suppressing glucagon secretion
b.accelerating gastric emptying
c.decreasing postprandial insulin release
d.inhibiting α-glucosidase
cme demographic and evaluation form
Release Date:
Expiration Date:
April 2009
April 30, 2010
Participant Information
Please print clearly; illegible forms will delay your receiving credit/verification:
First Name
MI
Last Name
Address 1
Address 2
City
Country
State
ZIP
Daytime Telephone
Fax
E-mail Address
Physicians: Are you licensed in the US?
What is your professional title?
MD
Yes No
DO RN PA Other
Specialty:
Posttest Answers
Please fill in the posttest answers here:
1.______ 2.______ 3.______ 4. ______ 5.______ 6. ______ 7. ______ 8. ______ 9. ______ 10. ______
Cme Credit Attestation
The Institute for Medical and Nursing Education, Inc. (IMNE) designates this educational activity for a maximum of 2.0 AMA PRA Category 1
Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.
I certify that I completed this CME activity. The actual amount of time I spent in this activity was:
____hours _____minutes. (Not to exceed 2.0 hours.)
Signature: Date: ___________________
(without a signature, credit cannot be issued)
Please send completed forms to:
Institute for Medical and Nursing Education, Inc.
57 LaGrange Street
Raritan, NJ 08869
Or fax to: 609 207 7032
Please keep a copy for your records. Forms must
be received no later than April 30, 2010 to
receive credit.
19
FACULTY AND CONTENT
Rating Scale: 1=Poor 2=Fair 3=Good 4=Very Good 5=Excellent
Please rate the publication authors with respect to:
• Knowledge of subject
• Article content was orderly and understandable
1
1
2
2
3
3
4
4
5
5
LEARNING OBJECTIVES
Rating Scale: 1=Poor 2=Fair 3=Good 4=Very Good 5=Excellent
Please evaluate how well the following learning objectives were met:
•Describe the relative contribution of fasting plasma glucose (FPG) and
postprandial plasma glucose (PPG) to overall glycemic control among patients with
type 2 diabetes, and explain how this relationship changes at different levels of glycemic control
1
2
3
4
5
•Explain the pathophysiologic defects that precede the development of type 2 diabetes,
and indicate when elevated PPG begins to play a contributing role
1
2
3
4
5
•Discuss the available evidence suggesting that elevated PPG leads to increased
macrovascular complications
1
2
3
4
5
BALANCE
AND OBJECTIVITY
Yes No
•Were all data reported objectively and with appropriate referencing?
•Was the overall content of this educational activity presented objectively and free of bias?




If you answered “No” to any of the above questions, please explain:
____________________________________________________________________________________________________________
____________________________________________________________________________________________________________
OVERALL
ACTIVITY
Yes No
•Was the subject matter relevant to your clinical practice? 
•Was the educational format an effective learning method?
 
If you answered “No” to any of the above questions, please explain:
____________________________________________________________________________________________________________
____________________________________________________________________________________________________________
ACTIVITY PLANNING AND NEEDS ASSESSMENT
What one question remains unanswered after having participated in this activity?
____________________________________________________________________________________________________________
____________________________________________________________________________________________________________
Cite one new piece of information learned from this activity.
____________________________________________________________________________________________________________
____________________________________________________________________________________________________________
What related topics would you like to have offered as future CME activities?
____________________________________________________________________________________________________________
____________________________________________________________________________________________________________
What are your preferred learning methods? (check as many as applicable)
 Live conferences CD-ROM  Print materials; eg, monographs  Internet/Web-based
 I do not want to receive further information regarding CaringForDiabetes activities
Additional comments:
____________________________________________________________________________________________________________
____________________________________________________________________________________________________________
OUTCOMES ASSESSMENT
To assess impact on clinical behavior, outcomes surveys are conducted at 3 months following and 1 year following educational activities.
Surveys are issued to a convenience sampling of activity participants. We appreciate your feedback to these surveys, as it assists us in
identifying and meeting additional educational needs.
20
Thank you for participating in this educational activity.
21
Clinical Use of Incretin-Based Therapies to
Promote PPG Control In Type 2 Diabetes
c/o the Institute for Medical and Nursing Education, Inc.
57 LaGrange Street
Raritan, NJ 08869