Gilles Dagenais, MD, Laval
University Heart and Lung Institute, Quebec City, Quebec, Canada, and Ambady
Ramachandran, MD, India Diabetes Research Foundation, Chennai, India, presented
an overview of the Outcome Reduction With an Initial Glargine Intervention
Trial [ORIGIN; NCT00069784].
ORIGIN was a large, international,
randomized, controlled trial that lasted >6 years in people with new or
recently diagnosed diabetes, impaired fasting glucose (IFG), impaired glucose
tolerance (IGT), and additional cardiovascular (CV) risk factors.
ORIGIN is the longest investigation
of the effect of insulin treatment on CV outcomes and cancer incidence in this
population to date. The relationship between long-term supplementation with n-3
fatty acids and the rate of CV events was also studied [Gerstein H et al. N
Engl J Med 2012].
ORIGIN TRIAL DESIGN
ORIGIN was a double-blind study with
a 2-by-2 factorial design. It was designed to test the effect of titrated basal
insulin glargine versus standard care, and it also investigated n-3 fatty acid
supplements versus placebo on CV outcomes [Gerstein H et al. Am Heart J2008].
A total of 12,537 participants (mean
age, 63.5 years; 35% women) were enrolled from 573 clinical sites in 40
countries. Patients were randomly assigned by region. The median follow-up was
6.2 years (interquartile range, 5.8 to 6.7 years). At the conclusion of the
study, the primary outcome status was known for 99% of participants.
Coprimary outcomes in the glargine
trial were the first occurrence of nonfatal myocardial infarction (MI) or
nonfatal stroke or CV and the first occurrence of nonfatal MI or nonfatal
stroke or CV death or hospitalization for heart failure or revascularization.
Other outcomes and measures included new or recurrent cancers, angina,
ischemia-related amputation, hypoglycemia, and CV and other hospitalizations.
n-3 FATTY ACID TRIAL RESULTS
Jacqueline Bosch, MSc, McMaster
University, Hamilton, Ontario, Canada, presented results from the n-3 fatty
acid portion of the ORIGIN trial.
Baseline intake of n-3 fatty acids
was 210 mg/day versus 209 mg/day for placebo. At the end of the study, it was
257 mg/day versus 253 mg/day for placebo. The primary outcome of the trial was
CV death. Secondary outcomes were MI, stroke or CV death, all-cause mortality,
presumed arrhythmic death, or cardiac arrest.
Patients were randomized to
receive a daily supplement of n-3 fatty acid (1g per day) or placebo. The
primary outcome of the trial was CV death. Secondary outcomes were MI, stroke
or CV death, all cause mortality, presumed arrhythmic death, or cardiac arrest.
Omega-3 fatty acids did not reduce
the rate of CV events in high-risk patients with diabetes or prediabetes. The
rate of CV death was 9.1% in patients who were treated with placebo and 9.3% in
patients who were treated with omega-3 fatty acids. Supplementation with n-3
fatty acids did not have a significant effect on major vascular events (16.5%
versus 16.3%) or all-cause death (15.1% versus 15.4%), nor did it make a
difference in fatal or nonfatal MI, fatal or nonfatal stroke, heart failure
hospitalization, revascularization, limb or digit amputation, or hospitalization
for any CV cause.
Except for a significant decrease of
14.5 mg/dL (0.16 mmol/L; p<0.001) in triglycerides in the group that took
fish oil supplements, there was minimal difference in blood pressure, heart
rate, and cholesterol.
Kaplan-Meier curves were virtually
indistinguishable between arms for death from CV cause (HR, 0.98; 95% CI, 0.87
to 1.10; p=0.72); MI, stroke, or CV death (HR, 1.01; 95% CI, 0.93 to 1.10;
p=0.81); all-cause death (HR, 0.98; 95% CI, 0.89 to 1.07; p=0.63); or death
from arrhythmia (HR, 1.10; 95% CI, 0.93 to 1.30; p=0.26).
Previous randomized, double-blind,
placebo-controlled trials have reported conflicting results on the efficacy of
n-3 fatty acid supplements in the secondary prevention of CV disease.
Aldo P. Maggioni, MD, ANMCO Research
Center, Florence, Italy, explained that these differences may be due to
differences in background clinical conditions, risks, or therapies. In patients
with dysglycemia and additional CV risk factors, 1 g of n-3 fatty acids daily
over a period of 6 years does not reduce CV deaths or other CV outcomes.
The different risks of these
patients and optimized background therapies may explain the neutral results of
ORIGIN versus those of other trials that have been conducted in higher-risk
populations. Additional large trials will provide important information that is
related to n-3 fatty acids at various stages of CV disease. These include
ASCEND [NCT00135226], the Rischio and Prevenzione study, and VITAL
INSULIN GLARGINE MAIN TRIAL RESULTS
Hertzel C. Gerstein, MD, MSc,
McMaster University, Hamilton, Ontario, Canada, presented the main results from
the insulin glargine trial.
The intervention (added to lifestyle
change) for the insulin glargine group used the same approach for subjects with
or without type 2 diabetes: add evening glargine to 0 or 1 oral agent;
self-titrate at 1 to 2 units twice a week to target capillary fasting plasma
glucose (FPG) ≤95 mg/dL (5.3 mmol/L); and add metformin if needed to mitigate
hypoglycemia. The nondiabetes standard care group was screened for type 2
diabetes annually. Those with the disease received treatment, based on
guidelines and physician’s judgment.
During the study, insulin use in the
glargine group dropped from 100% to 83% at Year 6, while it rose from 0% to 10%
in the standard care group (Figure 1). At the end of the study, median FPG in
the glargine group was 95 mg/dL (5.3 mmol/L) versus 123 mg/dL (6.8 mmol/L) in
the standard care group. At 6 years, median HbA1C levels were 6.2% for glargine
and 6.5% for standard care.
Figure 1. Insulin Use.
Rates of incident CV outcomes were
similar in the glargine and the standard care groups: 2.94 and 2.85 per 100
person-years, respectively, for the first coprimary outcome (MI, stroke, or CV
death; HR, 1.02; 95% CI, 0.94 to 1.11; p=0.63) and 5.52 and 5.28 per 100
person-years, respectively, for the second coprimary outcome (MI, stroke, CV
death, revascularization, heart failure; HR, 1.04; 95% CI, 0.97 to 1.11; p=0.27).
Differences in the incidence of any cancer were not significant (HR, 1.00; 95%
CI, 0.88 to 1.13; p=0.97).
Dr. Gerstein concluded that basal
insulin glargine that is titrated to a normal FPG has a neutral effect on CV
outcomes and on cancer compared with standard care.
Jeffrey L. Probstfield, MD,
University of Washington School of Medicine, Seattle, Washington, USA,
discussed diabetes prevention, asking the question: "Could insulin prevent
The predefined outcome of new diabetes
that developed from the time of randomization up to and including an oral
glucose tolerance test (OGTT) that was done approximately 1 month after all
glucose-lowering therapies were stopped occurred in 24.7% versus 31.2% of 1456
participants without baseline diabetes (OR, 0.72; 95% CI, 0.58 to 0.91;
p=0.006). A consistent but attenuated effect size was noted when the results of
a second OGTT (done 3 months later in people without diabetes, based on the
first OGTT) were included (OR, 0.80; 95% CI, 0.64 to 1.00; p=0.05) [Gerstein H
et al. N Engl J Med 2012].
Dr. Probstfield concluded that
although the durability of the effect is unclear, in people who are at risk for
future diabetes, approximately 6 years of basal insulin glargine that is
titrated to a normal FPG reduces the incidence of diabetes compared with
SAFETY: HYPOGLYCEMIA AND WEIGHT
Lars E. Rydén, MD, PhD, Karolinska
University Hospital, Stockholm, Sweden, noted that insulin therapy has been
known to cause hypoglycemia for 90 years and that it is also linked to CV
outcomes. Whether or not the relationship is causal is controversial. To
estimate benefits and risks of insulin glargine, ORIGIN sites collected
information about severe and nonsevere episodes of clinical hypoglycemia at each
Severe hypoglycemia was defined as:
a) signs and/or symptoms of hypoglycemia; b) required assistance (unable to
help self); and c) spontaneous recovery with carbohydrate/glucagon or any
measured glucose ≤36 mg/dL (2 mmol/L). Nonsevere hypoglycemia was defined as
signs and/or symptoms of hypoglycemia.
According to Dr. Rydén, there were
significant differences between the two groups in all categories of
hypoglycemia. Rates of severe hypoglycemia were 1.00 versus 0.31 per 100
person-years (p<0.001). Median weight increased by 1.6 kg (95% CI, 2.0 to
5.5; p<0.001) in the glargine group and decreased by 0.5 kg (95% CI, 4.3 to
3.2; p<0.001) in the standard care group during 6.2 years.
IMPLICATIONS FOR INSULIN THERAPY
Compared with standard glycemic care
of people with early diabetes, IGT, and/or IFG, using once-daily basal insulin
glargine to an FPG ≤95 mg/dL (5.3 mmol/L) for a median of 6.2 years maintains
near-normal glycemic control; has a neutral effect on CV outcomes and on
cancers; slows the progression of dysglycemia; and modestly increases
hypoglycemia and weight.
The implications of these findings
are that supplementing endogenous insulin with basal insulin injections slows
progression of dysglycemia. Although later benefits or harms can not be ruled
out, exogenous basal insulin’s main effect over 6 to 7 years is to flexibly
Despite lower glucose levels,
routine early use of basal insulin glargine is not better than guideline-based
standard care in limiting important health outcomes. Basal insulin glargine is
now the best-studied glucose-lowering drug that is available, and no new safety
concerns limit its early use when needed.
Glycemic control is difficult to maintain in
children with diabetes aged <7 years for several reasons. Children of this
age are at increased risk of hypoglycemia (particularly at night), and there is the potential for hypoglycemia-related neurocognitive outcomes. In
addition, at this age, children often have unpredictable eating patterns and
variable levels of activity. Closed-loop insulin delivery is a recent medical
innovation that aims to achieve tight glucose control while reducing the risk
of hypoglycemia, but it has not been tested in young children. Andrew Dauber,
MD, Boston Children’s Hospital, Boston, Massachusetts, USA, presented data from
the Closed-Loop Insulin Delivery in Children <7 years of Age Study that
showed how closed-loop therapy (CLT) has the potential to improve diabetes care
in young children [NCT01421225].
CLT combines glucose-sensing and
insulin-delivery components with real-time glucose-responsive insulin
administration. A disposable sensor measures interstitial glucose levels, which
are fed automatically into an algorithm that is used to control the delivery of
a rapid-acting insulin analog into the subcutaneous tissue by an insulin pump.
This was a randomized crossover trial that compared CLT with standard
(open-loop) pump therapy (SPT) in children aged <7 years who were diagnosed
with type 1 diabetes for more than 6 months and had been treated with insulin
pump therapy for more than 6 weeks. Study participants (n=10) had a mean age of
5.1 years (range 2.0 to 6.8 years) with a mean duration of diabetes of 2.1
years (range 0.5 to 4.7 years). Mean HbA1C was 8.1% (range 7.1% to 8.9%), and
the average daily insulin dose was 0.72 units/kg (range 0.61 to 1.0 units/kg).
All subjects had fasting c-peptide levels <0.1 ng/mL.
In this study, glucose values were
transmitted from 2 Freestyle Navigator® sensors (one placed in each
thigh) to a bedside receiver. The values were retrieved from the receiver and
entered manually into a control algorithm to calculate insulin recommendations.
The control algorithm was a physiological insulin delivery algorithm, developed
by one of the investigators, that utilized proportional-integral-derivative
terms that were modified by insulin feedback. All recommendations generated by
the algorithm were approved by the physician and then entered into the Animus
OneTouch® Ping® insulin pump remote, which transmitted
the insulin order to the insulin pump attached to the patient. There were 2
periods of control: overnight (10:00 PM to 8:00 AM) when basal rates were
adjusted every 20 minutes based on sensor readings, and daytime (8:00 AM to
noon), when mini-boluses of insulin in increments of 0.05 units were given up
to every minute, based on sensor readings. Target blood sugars were 150 mg/dL
during the night and 120 mg/dL during the day.
Subjects were admitted to the clinic for 48
hours. Meals and snacks were provided on a regular schedule. Participants were
free to choose from a standardized menu but received the identical meals/snacks
on Days 1 and 2. All meals were weighed pre- and post-consumption. The
Freestyle sensors were placed on the morning of admission. That afternoon
patients were switched to the study insulin pump. An intravenous line was also
placed to allow for frequent blood sampling. The study period began at 10:00 PM
and ran until noon the following day. During that time, subjects were
randomized to receive either CLT or SPT. From noon until 10:00 PM, subjects
received their standard therapy. At 10:00 PM on the second evening, subjects
were randomized to the opposite therapy from the prior night.
Time at overnight target was increased with
CLT but was not significantly different from SPT; however, time in extreme
hyperglycemia was significantly reduced as was the total glycemic excursion
overnight. There was no difference in the number of interventions for hypoglycemia
or in daytime peak postprandial glucose (despite the absence of a pre-meal
bolus), while the pre-lunch was significantly decreased (Table 1).
Table 1. Outcomes.
CLT maintained tight glucose control without
increasing the incidence of hypoglycemia and improved pre-lunch blood sugars,
leading the investigators to conclude that it has the potential to improve
diabetes care for very young children.
Type 1 diabetes mellitus (T1DM) is an
autoimmune disease that is driven by activated T-lymphocytes. To be fully
active, immune T-cells need a costimulatory signal in addition to the main
antigen-driven signal. A previous study showed that abatacept, a costimulation
modulator that prevents full T-cell activation, slowed reduction in b-cell
function over 2 years in individuals with recent-onset T1DM [Orban T et al. Lancet2011]. Tihamer Orban, MD, Joslin Diabetes Center, Boston, Massachusetts, USA,
presented 1-year follow-up data from the previous 2-year study [NCT00505375].
The primary study was a multicenter,
double-blind, randomized, controlled trial in which subjects (n=112) aged 6 to
45 years (mean 14 years) who were recently diagnosed with T1DM were randomly
assigned (2:1) to receive abatacept (10 mg/kg, maximum 1000 mg per dose) or
placebo infusions intravenously on Days 1, 14, and 28 and monthly thereafter
for a total of 27 infusions over 2 years. Dr. Orban reported on the effects of
discontinuing costimulation modulation with abatacept on preservation of β-cell
function in patients from this study who were followed for 1 year after
infusions were stopped.
The follow-up analysis included 93 subjects
(64 from the abatacept group and 29 from the placebo group). C-peptide 2-hour
AUC means, adjusted for age and baseline C-peptide, at 36 months were 0.215
(95% CI, 0.168 to 0.265) and 0.135 (95% CI, 0.0692 to 0.205) nmol/L for the
abatacept and the placebo groups, respectively (p=0.033). This difference was
similar to the difference observed during the treatment phase of the trial. The
C-peptide decline from baseline remained parallel with an estimated 9.5-month
delay with abatacept. HbA1C was lower in abatacept-treated patients
(p<0.001), with no difference in insulin use. A treatment effect was
observed only for race and CDR3 status.
Data from this follow-up study indicate that
costimulation modulation with abatacept slows the decline in β-cell function in
recent-onset T1DM beyond drug administration and leads to lower HbA1C levels.
These results suggest that abatacept may be useful in prevention studies in
individuals who are at high risk of T1DM and/or as a component in studies that
use a combination of different treatment strategies. Further trials are needed
to test whether or not a shorter course of abatacept treatment would be
sufficient to achieve similar beneficial effects.
Ten years of follow-up observations from the
United Kingdom Prospective Diabetes Study (UKPDS) demonstrated virtually
identical HbA1C levels in subjects who were randomly assigned to 2 different
glucose control strategies (intensive or conventional). However, subjects who
received intensive glucose control remained at a significantly lower risk of
diabetic complications. This continuing benefit of earlier improved glucose
control has been termed the type 2 diabetes legacy effect [Chalmers J, Cooper
ME. N Engl J Med 2008], an influence that is similar to the metabolic
memory that has been described for type 1 diabetes [Stumvoll M et al. N
Engl J Med 1995]. Marcus Lind, MD, University of Gothenburg, Gothenburg,
Sweden, presented data that examined the degree to which historical HbA1C
values contribute to later reductions in the risks of myocardial infarction
(MI) and all-cause mortality. An additional aim was to elucidate the
time-dependent impact of earlier HbA1C values on a year-by-year basis.
Continuous hazard functions for death and MI
from diagnosis of type 2 diabetes in relation to age, sex, HbA1C, and original
treatment assignment (intensive/conventional) were estimated in 3849
individuals from UKPDS. These data were then evaluated for different HbA1C
levels during a preceding time interval to determine the degree to which they
might explain the death and MI legacy effects.
Older age, male sex, and HbA1C, but not
treatment group, were all found to be significantly (all p<0.001) related to
MI and death. The model was used to estimate the impact of a 1% reduction in
HbA1C from each of 2 time periods (at diagnosis and 10 years after diagnosis)
on the risk of death and MI. For all-cause mortality, the results indicate the
reduction in risk from the legacy effect is almost 3 times stronger when the HbA1C
reduction is achieved early (at diagnosis) compared with later (after 10
years), and this effect is mostly because of the lower HbA1C levels at the
earlier time points. The pattern is similar, but the effects of early reduction
are somewhat less potent for MI.
The model was used to predict the relative
reduction in the probability of death for a 50-year-old man with newly
diagnosed type 2 diabetes and an HbA1C of 8% in 2 different scenarios:
immediate (at diagnosis) reduction of HbA1C by 1% and waiting 10 years for the
same HbA1C reduction. Reducing the HbA1C by 1% (to 7%) at diagnosis will result
in an 18.6% risk reduction for death compared with only a 6.6% risk reduction
if the HbA1C reduction is delayed for 10 years. Similar relationships in risk reduction
and timing of the HbA1C reduction were seen when the model was applied to MI
and to women.
Statistical modeling of UKPDS data confirmed
that earlier HbA1C levels continue to contribute to the risk of diabetic
complications, as seen in the Diabetes Control and Complications Trial [The
Diabetes Control and Complications Trial Research Group. N Engl J Med 1993]. The long-term
impact of achieved HbA1C levels explains to a large extent the sustained
reductions in the risk of death and MI that were seen in the UKPDS post-trial
monitoring period. Thus, early intensive, optimal, glycemic control is
essential to minimize the long-term risk of diabetic complications.
Twenty-three years of follow-up data from the
China Da Qing Diabetes Prevention Study (CDQPDS) show that lifestyle
intervention to prevent diabetes can reduce all-cause and cardiovascular (CV)
mortality among women with impaired glucose tolerance (IGT) but not among men.
Findings from the study were reported by Guangwei Li, MD, Department of
Endocrinology, China-Japan Friendship Hospital, Beijing, China.
In 1986, 577 adults with IGT from 33 clinics
in Da Qing, China, were randomly assigned to a control group or 1 of 3
lifestyle intervention groups (diet, exercise, or diet plus exercise). Active
intervention was carried out from 1986 to 1992. Participants who were assigned
to the exercise group or diet-plus-exercise group were encouraged to increase
the amount of their physical activity by at least 1 unit per day (as defined in
Table 1) and by 2 units per day, if possible, for participants aged <50
years with no evidence of CV disease (Table 1) [Pan XR et al. Diabetes Care1997].
Table 1. Activities Required for Increasing
Activity by One Unit of Exercise.
A 20-year follow-up study showed that
group-based combined lifestyle interventions over 6 years in people with IGT
can prevent or delay diabetes for up to 14 years after the active intervention
[Li G et al. Lancet 2008]. Lifestyle intervention for 6 years in IGT
was also associated with a 47% decline in the incidence of severe,
vision-threatening retinopathy over 20 years [Gong Q et al. Diabetologia2011].
The aim of the current trial was to examine
all-cause and CV mortality among those who participated in the 6-year lifestyle
intervention that was implemented in the Da Qing Diabetes Prevention Study. In
2009, 23 years after randomization, participants were traced to determine the
long-term impact of the interventions on mortality; 47 women and 127 men had
Mortality rates were compared between the control groups and the combined
intervention groups (diet, exercise, and diet plus exercise). All-cause
mortality was defined as death from any cause. CV mortality was defined as
death from coronary heart disease, stroke, and sudden death.
In women, combined lifestyle intervention
(diet, exercise, and diet plus exercise) reduced all-cause mortality by 53%
(hazard rate ratio [HRR], 0.47; 95% CI, 0.25 to 0.86), with cumulative
all-cause mortality of 16.2% (95% CI, 11.2 to 21.2) in the intervention group
versus 29.3% (95% CI, 17.5 to 48.0) in the control group (p=0.02). Among men,
there was no significant difference in cumulative all-cause mortality (p=0.41)
between the combined intervention and control groups (41.1% versus 46.7%).
The reduction in all-cause mortality in women
was mainly because of differences in CV mortality (heart disease and stroke;
HRR, 0.30; 95% CI, 0.12 to 0.68), with 23-year cumulative mortality of 6.8% in
the intervention group (95% CI, 3.4 to 10.2) versus 18.8% (95% CI, 8.8 to 28.8)
in the control group (p=0.006). In men, there was also no significant
difference in cumulative CV mortality (p=0.47) in the combined intervention and
control groups (26.4%; 95% CI, 21.1 to 31.6 versus 27.4; 95% CI, 18.6 to 32.2).
Data from the intervention groups (diet,
exercise, and diet plus exercise) suggest that combined lifestyle intervention
significantly lowers all-cause and CV mortality among women with IGT but not
among men. Reasons may include a large difference in baseline smoking rates
between men and women.
Apart from diabetes, measures of risk factors
for death (and CV disease) at baseline and during the trial were limited. In
turn, the investigators were unable to identify or exclude possible confounding
factors for the differences in outcomes between women and men. The reasons
the intervention group were, on average, 2 years younger than those in the control
group, but there were no differences in baseline body mass index (BMI) in
controls, 26.2±0.2 kg/m2 versus BMI in the combined intervention
group, 25.7±0.2 kg/m2. The changes in body weight during the
active-intervention period (1986 to 1992) and the entire follow-up period (1986
to 2006) did not differ significantly by group [Guangwei L et al. Lancet2008].
Glycemic management in type 2 diabetes
mellitus (T2DM) has become increasingly complex and, to some extent,
controversial. A widening array of pharmacological agents [Nyenwe EA et al. Metabolism 2011; Blonde L. Am J Med 2010; Bergenstal RM et al. Am J Med 2010] has raised concerns about their potential adverse effects, as well as new
uncertainties about the effects of intensive glycemic control on macrovascular
complications [Yudkin JS et al. Lancet 2011]. Many clinicians are,
therefore, perplexed as to the optimal treatment strategies for their patients
[Inzucchi SE et al. Diabetes Care 2012; Inzucchi SE et al. Diabetologia 2012].
Silvio E. Inzucchi, MD, Yale University
School of Medicine, New Haven, Connecticut, USA, reviewed key points from the
new Position Statement from the American Diabetes Association (ADA) and the European
Association for the Study of Diabetes (EASD) [Inzucchi SE et al. Diabetes
Care 2012; Inzucchi SE et al. Diabetologia 2012].
The statement covers the growing variety and
number of antihyperglycemic agents, new data on the benefits versus risks of
tight glycemic control, increasing concerns about drug safety, and growing
discourse about personalized medicine and patient-centered care. Dr. Inzucchi
pointed out that prior guidelines were consensus documents that did not undergo
formal Association review to become official position statements.
Main Pathological Defects in T2DM
Any rise in glycemia is the net result of
glucose influx exceeding glucose outflow from the plasma compartment [Inzucchi
SE et al. Diabetes Care 2012; Inzucchi SE et al. Diabetologia2012]. In the fasting state, hyperglycemia is directly related to increased
hepatic glucose production. In the postprandial state, further glucose
excursions result from the combination of insufficient suppression of this
glucose output and defective insulin stimulation of glucose disposal in target
tissues, mainly skeletal muscle.
Abnormal islet cell function that progresses
over time is a key and requisite feature of T2DM and the main quantitative
determinant of hyperglycemia [Ferrannini E et al. J Clin Endocrinol Metab2005] (Figure 1). However, islet dysfunction is not necessarily irreversible.
It responds to increased insulin action that relieves b-cell secretory burden
and any intervention that improves glycemia, from energy restriction to
bariatric surgery [Ferrannini E. Cell Metab 2010]. More recently, abnormalities
in the incretin system have also been identified [Nauck MA. Am J Med 2009].
Figure 1. Main Pathophysiological Defects in
Reproduced with permission from SE Inzucchi, MD.
Antihyperglycemic agents are directed at one
or more of the pathophysiological defects of T2DM, or they modify physiological
processes related to appetite or to nutrient absorption or excretion.
Ultimately, T2DM is a disease that is heterogeneous in both its pathogenesis
and clinical manifestation. This point must be considered when determining the
optimal therapeutic strategy for individual patients [Inzucchi SE et al.
Diabetes Care 2012; Inzucchi SE et al. Diabetologia 2012].
According to Dr. Inzucchi, patient-centered
care is defined as an approach to providing treatment that is respectful of and
responsive to an individual patient’s preferences, needs, and values, and it
ensures that a patient’s values guide all clinical decisions [Committee on
Quality of Health Care in America: Institute of Medicine. The National
Academies Press 2001]. He noted that this should be the organizing
principle underlying health care for individuals with any chronic disease, but
it is especially pertinent in T2DM, with the uncertainties of choice as well as
the sequence of therapy [Inzucchi et al. Diabetes Care 2012; Inzucchi
SE et al. Diabetologia 2012].
In a shared decision-making approach, the
clinician and the patient act as partners, mutually exchanging information and
deliberating on options to reach a consensus on the therapeutic course of
action [Tsapas A, Matthews DR. Diabetologia 2008]. Ultimately, the
patient makes the final decisions regarding lifestyle choices and, to some degree,
the pharmaceutical interventions used [Inzucchi SE et al. Diabetes Care 2012; Inzucchi SE et al. Diabetologia 2012].
A patient’s involvement in medical
decision-making constitutes one of the core principles of evidence-based
medicine, which mandates the synthesis of best available evidence from the
literature with the clinician’s expertise and the patient’s inclination [Guyatt
GH et al. JAMA 2000]. The implementation of the plan occurs in the
context of a patient’s real life and his consumption of public and private
resources [Inzucchi SE et al. Diabetes Care 2012; Inzucchi SE et al. Diabetologia 2012].
For many people with complex, chronic
comorbidities, the burden of treatment reduces their capacity to collaborate in
their care. Therefore, clinicians must establish the weight of burden,
encourage coordination in clinical practice, acknowledge comorbidity in
clinical evidence, and prioritize from the patient’s perspective [May C et al. BMJ 2009].
The document refers to glycemic control
pursued within a multifactorial risk-reduction framework. Such a framework is
necessary because patients with T2DM are at increased risk of cardiovascular
(CV) morbidity and mortality. Aggressive management of CV risk factors (blood
pressure and lipid therapy, antiplatelet treatment, and smoking cessation) is
likely to have even greater benefits among these patients [Inzucchi SE et al. Diabetes
Care 2012; Inzucchi SE et al. Diabetologia 2012].
The key points of the ADA/EASD Position
Statement: Management of Hyperglycemia in Type 2 Diabetes are: 1) glycemic
target blood-glucose lowering therapies must be individualized; 2) diet,
exercise, and education are the foundation of any T2DM therapy program; 3)
unless contraindicated, metformin is the optimal first-line drug; 4) after
metformin, data are limited; combination therapy with one or two other
oral/injectable agents that minimize side effects is reasonable; 5) ultimately,
many patients will require insulin therapy alone or in combination with other
agents to maintain blood glucose control; 6) all treatment decisions should be
made in conjunction with the patient (focus on preferences, needs, and values);
and 7) comprehensive CV risk reduction is a major focus of therapy [Inzucchi SE
et al. Diabetes Care 2012; Inzucchi SE et al. Diabetologia 2012].
Compared with the 2008 ADA/EASD Treatment
Algorithm, the 2012 statement is not as prescriptive/algorithmic. It calibrates
treatment targets to patients’ needs and acknowledges the role of lifestyle
change prior to metformin in selected patients. It individualizes treatment
options and harmonizes 5 dual-therapy options after metformin. It recognizes
the role of initial combination therapy (HbA1C >9%), and endorses triple
therapy, when required. It also includes insulin options beyond basal and
basal-bolus (Figure 2).
Figure 2. The ADA/EASD Position Statement on
Management of Hyperglycemia in T2DM.
Reproduced with permission from SE Inzucchi, MD.
The position statement clearly argues for
less stringent HbA1C goals in patients who are predisposed to hyperglycemia and
have limited life expectancy, advanced complications, extensive comorbidities,
or a glycemic target that is difficult to control despite intensive education,
counseling, and effective doses of glucose-lowering agents.
The statement was developed over a period of
approximately 2 years by an international writing group, chaired by Dr. Inzucchi
and Professor David Matthews from Oxford University and underwent dozens of
revisions with additional input from 25 experts around the world. It highlights
a proposed patient-centered approach that provides not only the most
comprehensive management strategy to date, but also the most vetted and
thoroughly reviewed statement ever published [Cefalu CT. Diabetes Care 2012].
It is an expansive approach that suggests
recommendations considered within the context of the needs, preferences, and
tolerances of each patient. At the same time, the recommendations clearly state
that the informed judgment and expertise of experienced clinicians will always
be necessary [Cefalu CT. Diabetes Care 2012].
This new ADA/EASD Position Statement will
generate a wide range of opinions and emotions. However, no one will disagree
with the fact that the initiative was conducted with due diligence deserving of
a document that will likely have major impact for millions of patients
throughout the world [Cefalu CT. Diabetes Care 2012].
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