Basal insulin therapy
Specification
The present invention relates to the use of a long-acting insulin, in particular
insulin glargine, in a method of reducing the risk of progression to type 2
diabetes in a patient, a method of reducing the risk of a new angina in a
patient and a method of reducing the risk of a microvascular event in a patient
comprising administering to said patient in need thereof a therapeutically
effective dosage of a long acting insulin, wherein said therapeutically effective
dosage of said long acting insulin reduces said risks.
Basal pancreatic insulin secretion is responsible for maintaining fasting
plasma glucose (FPG) levels below 5.6 mmo/l ( 100 mg/dl) in normal
individuals, and an elevated FPG level signifies that there is insufficient
endogenous fasting insulin secretion to overcome underlying insulin
resistance. This metabolic abnormality progresses with time and is reflected in
progressively higher glucose and HbA1 c levels. It and its progression are also
risk factors for cardiovascular outcomes regardless of the presence or
absence of diabetes [ 1 , 2, 3, 4, 5, 6, 7]. They are also risk factors for incident
diabetes in people with impaired fasting glucose or impaired glucose
tolerance.
Despite the link between elevated glucose levels and cardiovascular
outcomes, large outcomes trials of more versus less intense glucose lowering
with insulin plus other glucose lowering drugs have not observed a clear
cardiovascular benefit [8] and one of these trials noted increased mortality [9].
Moreover, basal insulin was used in both treatment arms in these trials so no
conclusions regarding its isolated cardiovascular effects could be drawn. Of
note, the trial with the biggest contrast in insulin use was conducted in people
with newly diagnosed diabetes and reported a 15 and 13% reduction in
myocardial infarction and death [10] respectively during an extended followup.
However this trial was not restricted to people at high risk for
cardiovascular outcomes and normal fasting glucose levels were not achieved
and maintained during the trial in the treatment group.
These results evidence that insulin itself may have cardioprotective effects
[ 1 1, 12, 13], the availability of a long-acting insulin preparation with a
predictable duration of action and low risk of hypoglycemia, and evidence that
exogenous insulin therapy may slow the decline in pancreatic dysfunction with
time [14, 15, 16]. The Outcome Reduction with an Initial Glargine Intervention
(ORIGIN) trial was a large international multicentre randomized controlled trial
designed to explicitly test this possibility in people with IFG, IGT or early
diabetes and additional cardiovascular risk factors [ 1 7].
DIABETES MELLITUS AND CARDIOVASCULAR DISEASE
People with type 2 diabetes mellitus (DM) have an increased risk of
atherosclerotic disease, including coronary heart disease, strokes, and
peripheral vascular disease. Diabetes itself, and not just the associated risk
factors of dyslipidemia, hypertension, and obesity contributes a major portion
of this risk [18]. In particular, the level of hyperglycemia may play a key role.
While the relationship of increased blood glucose to microvascular
complications is well recognized, its relation to atherogenesis was, until
recently, less well documented [ 19, 20, 2 1, 22]. A prospective, populationbased
study in middle-aged and elderly people in Finland with type 2 DM has
shown a progressive relation between baseline fasting blood glucose (FBG)
or HbA1 c , and coronary heart disease mortality [23]. In the WESDR
database, people diagnosed with diabetes at age 30 years or older had a
statistically significant increase in mortality from vascular causes for every 1%
increase in glycosylated hemoglobin [24]. The Islington Diabetes Survey
found a progressive relationship between 2-hour postprandial glucose or
HbAi c and coronary heart disease, with the stronger association with the 2-
hour glucose test [25]. In the San Antonio Heart Study, the level of
hyperglycemia was a strong, independent predictor of all-cause and
cardiovascular mortality [26].
IMPAIRED GLUCOSE TOLERANCE, IMPAIRED FASTING GLUCOSE AND
CARDIOVASCULAR RISK
A growing body of evidence indicates that the increased risk for
macrovascular complications associated with type 2 DM also extends to
individuals with glucose abnormalities that do not meet the criteria for frank
diabetes. The American Diabetes Association (ADA) defines IGT as a 2-hour
glucose level (PPG) of 7.8 - 11.1 mM (140-1 99 mg/dL) after a 75 gram oral
glucose load, with FPG levels below 7.0 mM ( 126 mg/dL) . The ADA has
recently recognized a new category of IFG, defined as a fasting plasma
glucose of 6.1 - 6.9 mM ( 110-1 25 mg/dL) [27]. Cardiovascular disease is the
leading cause of death in the U.S. population and is especially prevalent and
predictive of mortality within the diabetic, IGT, and IFG populations [ 1 8]. An
excess risk of cardiovascular events characterizes IGT and IFG as well as
type 2 diabetes, and there is a continuum of risk beginning with the mildest
degrees of abnormality of blood glucose and extending into the diabetic range
[28, 29, 30]. This "dysglycemia" and its relation to cardiovascular disease is
now the focus of much research interest [31].
The American Diabetes Association about 15 years ago lowered the fasting
plasma glucose level at which diabetes is diagnosed from 140 to 126 mg/dL
(7.8 to 7.0 mM). This was done because of the recognition that a fasting level
of 126 mg/dL (7.0 mM) was more closely correlated to a 2 hour post-load level
of 200 mg/dL ( 1 1.1 mmol) - the level above which the risk for microvascular
disease begins to rise - than 140 mg/dL (7.8 mM) [27]. This new threshold
was not, however, chosen because of any special significance with respect to
macrovascular disease, which remains a leading cause of morbidity and
mortality in people with IGT, IFG and diabetes.
The Hoorn study found an increased risk of all-cause and cardiovascular
mortality with higher 2-hour post-load glucose values and increasing HbAi c in
a general population of men and women that included people with blood
glucose levels extending from normal to the diabetic range [32]. In the EPIC
Norfolk study, an increase of 1% in HbAi cwas associated with a 28%
increase risk of death, and an increase of approximately 40% in
cardiovascular or coronary heart disease mortality, in a cohort of 4662 men
[33]. Although diabetic individuals were included in this trial, and diabetes was
found to be an independent predictor of cardiovascular risk when evaluated
separately from HbAi c (another independent predictor), only HbAl c and not
diabetes predicted CV death when both were included in the same analysis.
This further illustrates the link between glucose elevations and CV risk, versus
the presence or absence of diabetes. Similarly, a study in non-diabetic elderly
women found that all-cause mortality and coronary heart disease were
significantly related to fasting plasma glucose [34].
In a study from Oslo, non-diabetic men aged 40-59 years had a significantly
higher cardiovascular mortality rate if their FPG was > 85 mg/dL (4.7 mM)
[35]. Long-term follow-up of several prospective European cohort studies has
confirmed a higher risk of cardiovascular-related mortality in non-diabetic men
with the highest 2.5% of values of FPG and 2-hour postprandial glucose [35].
A meta-regression analysis of data from 20 cohort studies found a
progressive relationship between glucose levels and cardiovascular risk even
below the cutoff points for diagnosis of DM [29]. Likewise, in the 23-year Paris
Prospective Study of 701 8 middle-aged nondiabetic men, increased fasting or
2-hour postprandial blood glucose was associated with increased total and
coronary mortality in a graded, non-threshold relationship [36].
RATIONALE FOR STUDY OF OMEGA-3 FATTY ACIDS
Over the past 30 years, there has been a rapid expansion of knowledge on
the effects of omega-3 polyunsaturated fatty acids (omega-3 PUFA, or n-3
PUFA) in coronary heart disease (CHD) [37]. Omega-3 PUFA include linolenic
acid as well as eicosapentaenoic acid (EPA) and docosahexaenoic acid
(DHA). Linolenic acid is an essential fatty acid provided by dietary sources
including soybean and canola oils. EPA and DHA are also provided by dietary
sources (eg, fish oils), but can also be derived by chain elongation and
desaturation of linolenic acid.
Omega-3 PUFAs inhibit platelet aggregation and are anti-inflammatory [37].
Potential cardioprotective effects of n-3 PUFA which have been studied
include decreasing circulating proatherogenic and prothrombotic factors such
as arachidonic acid, thromboxane A2, fibrinogen, platelet-derived growth
factor, and platelet activating factor, as well as circulating triglycerides,
chylomicrons, and Lp(a). Conversely, n-3 PUFA administration has been
shown to increase the circulation of cardioprotective factors such as
prostacyclin, tissue plasminogen activator, endothelium-derived relaxation
factor, and HDL cholesterol [37].
Data from epidemiological studies [37] are mixed, but on the whole, suggest
an association between n-3 PUFA intake and decreased risk of adverse CV
events, particularly sudden death or death due to CHD. Rates of other CV
events, such as Ml, have been less closely linked to low blood levels or intake
of n-3 PUFA.
A few important secondary intervention studies have been done, all in Ml
survivors, examining the impact of n-3 PUFA intake on reduction of CV risk. In
the Diet and Reinfarction Trial (DART), a 29% decrease in all-cause mortality
over 2 years was seen in men given a diet increased in fish, vs no diet advice
[38]. In the Lyon Diet Heart Study, an n-3 PUFA-enriched diet conferred a
73% reduction in risk for CV death or nonfatal Ml over a mean follow-up of 27
months [39]. Finally, the open-label GISSI-Prevenzione Trial [40]
demonstrated a 15% relative risk reduction in a combined outcome of CV
death, nonfatal Ml, and nonfatal stroke in a population of 11,324 Ml survivors
who consumed 850-882 mg of n-3 PUFA per day, on average.
The overall benefits of n-3 PUFA treatment in GISSI were attributable to
decreases in the risk of all-cause cardiovascular death, and of sudden death,
with little impact on the incidence of Ml or stroke.
Few adverse effects of n-3 PUFA have been demonstrated. Increases in
blood glucose in diabetic participants, mild tendencies to bleeding, increased
LDL concentrations, and increased PA1- 1 levels have been noted in some
trials. These effects have not been borne out in larger trials, and the LDL
effects seem to be transient in longer studies (possibly related to the
triglyceride-lowering effects of n-3 PUFA). A recent article [41] described n-3
PUFA as safe and effective in hypertriglyceridemic states, both primary and
secondary (such as dysglycemia). A recent NIH workshop on the efficacy and
safety of n-3 PUFA in people with diabetes concluded that further intervention
studies of n-3 PUFA in the diabetic population are needed to clarify these
issues.
Because of the aggregate evidence suggesting that increased n-3 PUFA
intake can protect patients at risk for CV morbidity and mortality from future
events, particularly CV death, this agent has been chosen as a separate
treatment for the dysglycemic participants of the ORIGIN Study. Omega-3
PUFA may have a more profound effect in the setting of dysglycemia, in view
of the lipid abnormalities and prothrombotic tendencies of the population, both
of which may be favorably affected by n-3 PUFA augmentation.
RATIONALE FOR THE STUDY OF INSULIN GLARGINE
The ORIGIN study is a large-scale intervention trial of the use of insulin to
decrease the risk of cardiovascular mortality and morbidity in a population of
participants with impaired glucose tolerance (IGT), impaired fasting glucose
(IFG), or early type 2 diabetes. This study has the acronym ORIGIN (Outcome
Reduction with an initial Glargine intervention).
Although there is enhanced awareness of cardiovascular risk factors in the
American population (e.g. regular surveillance and intervention for blood
pressure and lipid abnormalities), until recently, the excess risk of
cardiovascular disease associated with dysglycemia has received little
recognition. Consequently, people with IFG or IGT are rarely treated with
interventions aimed at reducing blood glucose levels. This is in part because
mild hyperglycemia is often asymptomatic (as is the case for hypertension
and hyperlipidemia), and because of the perceived risk of existing
antihyperglycemic therapies for associated morbidity (e.g. the tendency of
some agents to promote hypoglycemia). Additionally, there are no data to
evaluate whether lowering blood glucose in those with IFG or IGT will
decrease microvascular disease.
Evidence has provided support for a beneficial effect of insulin treatment
started at the time of a myocardial infarction. In the DIGAMI study [42],
diabetic patients hospitalized with acute Ml were allocated to receive an IV
insulin-glucose infusion in-hospital followed by intensive chronic outpatient
treatment with insulin. Compared to standard treatment, the insulin-treated
participants had a significant 28% reduction of all-cause mortality. Most of
these deaths were cardiovascular in etiology. The most striking reductions in
mortality were seen in the subset of patients without prior insulin treatment,
with low cardiovascular risk pre-MI. In those individuals significant survival
differences were even seen pre-discharge (while still in hospital post-MI), and
enhanced survival in the same cohort was also observed during long-term
follow-up.
Part of the benefit of insulin treatment was likely due to improved long-term
glycemia post-MI, but the rapid benefits in-hospital suggest that other, more
acute, effects of insulin besides long-term glycemic control may have played a
role. These may include improved platelet function, decreased PAI-1 levels,
and insulin-mediated reductions in circulating free fatty acid levels with
consequent improved dyslipidemia and decreased myocardial oxygen
requirement. Chronic insulin therapy may thus provide a level of protection
against the cumulative deleterious effect of even subacute episodes of
ischemia, and on the progression of atherosclerosis.
A recent study from Belgium [43] reinforces the beneficial role of insulin
treatment in critically ill subjects. In this trial, critical-care post-surgical patients
with random blood glucose values greater than 110 mg/dL (6.1 mM) were
treated while in the ICU either with an insulin infusion to lower blood glucose
to the 80-1 10 mg/dL (4.4-6.1 mM) range; or to receive insulin infusions only if
blood glucose exceeded 2 15 mg/dL ( 1 1.9 mM), to reduce the blood glucose to
between 180 and 200 mg/dL ( 10-1 1.1 mM). Twelve-months follow-up showed
a significant reduction in overall mortality in the intervention group (8.0%,
versus 4.6% in the control group); most of the benefit was attributable to the
cohort of subjects who were in the ICU for 5 days or more. In-hospital
mortality, septicemia, acute renal failure and hemodialysis incidence, and
transfusion requirements were also significantly reduced in the intervention
group versus the control group.
The use of exogenous insulin in an IGT, IFG, or diabetic population might
confer several potential metabolic and cardiovascular benefits [44, 45, 46, 47,
48]:
1. The fact that it is finely titratable and durable (compared to oral antidiabetic
agents) may translate into a powerful effect to delay the exposure of target
tissues to toxic levels of glycemia.
2 . Insulin-mediated suppression of circulating free fatty acids (FFA) will:
- reduce VLDL synthesis and improve lipoprotein patterns (i.e. lower
triglycerides, and increase HDL-C);
- reduce lipotoxicity at the level of the beta cell and at insulin's target
tissues;
- reduce obligatory oxidative metabolism in ischemic myocardium.
3 . Exogenous insulin will prevent metabolic decompensation due to stress,
that is either mild and frequent (i.e. daily stresses and minor illness or
injury), or severe and less common (i.e. major injury, illness, surgery,
vascular events). These stress events would normally suppress
endogenous insulin responses even when a pharmacologic secretagogue
or sensitizer is present; exogenous, injected insulin cannot be suppressed
in such a way.
4 . Nitric oxide-mediated vasodilation and endothelial function are abnormal in
those with IFG, IGT, or diabetes. Additionally, markers of endothelial
inflammation are increased. These abnormalities are all improved by
insulin treatment [49, 50, 5 1, 52].
Insulin glargine ((Gly A21 ) Arg (B31 ) Arg (B32) human insulin) is an approved
insulin analog characterized by a smooth, 24-hr glucose lowering effect
without a definite peak. As a basal insulin supplement, insulin glargine is
capable of being finely titrated, and has no dose ceiling other than that
dictated by its glucose-lowering action. A double-blind study (HOE901/1 021 )
was conducted to explore the safety and feasibility of insulin glargine
administration to people with IGT, IFG, or early diabetes. Participants were
confined to a treatment center for two weeks, during which time they received
a calorie-restricted diet appropriate for their degree of obesity, and insulin
glargine or placebo was titrated to effect (FPG of 80 - 95 mg/dL, 4.4 - 5.3
mM). Moderate exercise challenges were performed at the beginning and end
of the study. Thirteen participants with either IGT, IFG, or early diabetes
received insulin glargine and 4 were given placebo insulin. Two of these 13
insulin glargine subjects experienced hypoglycemia, versus none of the
placebo-treated subjects. All the episodes were mild, generally occurred prior
to lunch or supper (but not in response to exercise), and resolved rapidly on
snacking or eating. Based on this pilot study, insulin glargine presents a low
risk for hypoglycemia in this population even when diet prescriptions for
calorie restriction are implemented. The pilot study opened the way for the
full-scale investigation in ORIGIN of the safety and efficacy of insulin glargine
in the chronic intensive treatment of hyperglycemia across the whole
dysglycemic population.
RATIONALE FOR EXTENDING THE ORIGIN TRIAL
By the spring of 2008, several studies had reported new data pertaining to the
effect of glucose-lowering interventions in people with type 2 diabetes. These
studies include: a) the passive follow-up of the United Kingdom Prospective
Diabetes Study (UKPDS) of people with newly diagnosed diabetes [53], b) the
ACCORD study of 10251 people with established diabetes (mean duration 10
years) and high CV risk [54], c) the ADVANCE study of 11140 people with
established diabetes (mean duration 8 years) [55] and high CV risk; d) the VA
diabetes trial (VADT) of 1791 people (mainly men) with established diabetes
and high CV risk (not yet published); and d) the PROACTIVE study [56] which
tested the effect of pioglitazone versus placebo in 5238 people with
established diabetes (mean duration 8 years) and high CV risk. All of these
findings were reported after ORIGIN recruitment had been completed, and
with the exception of the PROACTIVE study reported the effect of more
versus less intensive glucose lowering on CV outcomes.
These studies' data are generally consistent with the hypothesis that a glucometabolic
intervention may reduce CV outcomes in people with type 2
diabetes. Specifically, the significant 15% lower rate of myocardial infarction
and 13% lower risk of death after 17 years of follow-up of the UKPDS
participants (and 8.5 years after the active treatment phase ended) [53], a
significant 24% reduced risk of myocardial infarction and a trend suggesting a
reduced composite CV outcome during 3.5 years of follow-up in the ACCORD
trial [54], a significant 17% reduced risk of myocardial infarction, a trend
suggesting a reduced composite CV outcome in the VADT [57], and a 16%
reduction in myocardial infarction, stroke or CV death together with a trend
suggesting a reduced primary composite CV outcome in PROACTIVE during
2.9 years of follow-up [55], all support this possibility. Unfortunately, the
truncated follow-up of the ACCORD study (due to the increased mortality in
the treatment group) precluded the ability to determine if there is a long-term
benefit. Moreover, the fact that it took approximately 3 of the 5 years of followup
to achieve a stable (but modest) HbA1 c between-group contrast in
ADVANCE, the small sample size and low power of the VADT, and the short
follow-up of the PROACTIVE trial reduced the power of these studies to
clearly detect a benefit,
Indeed, inspection of the event curves for these trials as well as the long-term
follow-up of the DCCT in people with type 1 diabetes study [58] suggest that
any CV benefit of a glucose-lowering intervention requires at least 3 years
after a stable glycemic or therapeutic contrast has been achieved to begin to
become apparent, and more than 5 years to be clearly detectable. For
example, in the UKPDS obesity study, the effect of metformin on the risk of
myocardial infarction and death became apparent only after 4-5 years [59].
These trials also indicated that a gluco-metabolic intervention may be more
effective in people with earlier or less advanced diabetes. Thus the UKPDS
identified a long-term CV benefit in people with newly diagnosed diabetes
[53], and the ACCORD trial reported a clear reduction in the CV composite
outcome exceeding 20% in the prospectively identified subgroup of
participants whose baseline HbA1 c level was less than 8% [54]. Finally, data
presented by the VADT investigators [57] suggested that participants with a
shorter duration of diabetes may realize a greater CV benefit from a glucometabolic
intervention.
The ORIGIN trial had a mean follow-up of 3.5 years as of July 2008 and was
originally scheduled to end after a median follow-up of approximately 4.5
years. It has several unique features that address many of the questions
raised by the aforementioned trials [60]:
a) participants at high CV risk but at a much earlier stage of dysglycemia are
being studied;
b) participants had lower baseline HbA1 c levels with either "prediabetes",
newly diagnosed diabetes, or a relatively short 5 year mean duration of
diabetes;
c) it is designed to test the effect of insulin-replacement therapy (i.e. insulinmediated
normoglycemia as measured by the fasting plasma glucose)
versus usual care, and not to test the effect of a lower versus higher
HbA1c level;
d) insulin replacement therapy also lowers free fatty acid levels, which are
themselves significant risk factors for CV outcomes.
e) it continues to be monitored by an experienced IDMC which has not raised
any safety concerns to date.
In summary, the following considerations all supported a 24 month extension
of ORIGIN:
a) Recent studies suggest that if there is a CV benefit to a gluco-metabolic
intervention it will take up to 5 years after a stable contrast has emerged to
be detectable.
b) The extension will test more than 5 years of a stable contrast.
c) The extension will allow further accrual of events and will increase power.
d) ORIGIN is the only trial of an insulin-mediated intervention in people with
early dysglycemia, who represent a large number of people at high risk for
CV outcomes.
e) The study hypotheses remain unchanged.
f) The plan to extend the study is only based on the above considerations
and not on any analyses of interim outcome data, which have only been
seen by the IDMC.
STUDY OBJECTIVES
PRIMARY OBJECTIVES
To determine whether insulin glargine-mediated normoglycemia can reduce
CV morbidity and/or mortality in people at high risk for vascular disease with
either IFG, IGT, or early type 2 diabetes;
To determine whether omega-3 polyunsaturated fatty acids (n-3 PUFA) can
reduce cardiovascular mortality in people with IFG, IGT, or early type 2
diabetes.
SECONDARY OBJECTIVES
The secondary objectives of the insulin glargine study are to determine if
insulin glargine-mediated normoglycemia can reduce:
• total mortality (all causes);
• the risk of diabetic microvascular outcomes (composite outcome:
kidney or eye events);
• the rate of progression of IGT or IFG to type 2 diabetes.
The secondary objectives of the omega-3 PUFA study are to determine if n-3
PUFA reduce:
· major vascular events (a composite of: cardiovascular death; myocardial
infarction; or stroke)
• all-cause mortality
• A composite of sudden unexpected death, non-sudden arrhythmic death,
unwitnessed death, or resuscitated cardiac arrest
In the following there are definitions provided regarding cardiovascular
efficacy outcomes.
Cardiovascular Death is defined as any of the following:
Sudden Unexpected Death: defined as death that occurred suddenly and
unexpectedly in which the death is witnessed and the time of death is known:
witnessed death due to:
• An identified arrhythmia (ECG or at least monitor recording, or monitorwitnessed
arrhythmia either by a medic or a paramedic)
• Cardiac arrest or cardiovascular collapse in absence of premonitory heart
failure or myocardial infarction or other modes of death.
• Patients resuscitated from a sudden cardiac arrest who later die of the
sequelae of the event, or patients who die during an attempted
resuscitation.
Non-sudden Arrythmic Death: defined as death due to documented
arrhythmia when death is not sudden and not unexpected and is not
associated with evidence of myocardial ischemia (e.g., patient with recurrent
tachyarrhythmia or bradyarrhythmia who died 6 hours after admission to the
hospital).
Unwitnessed Death: Death that occurred in which the time of death is
unknown. In this case, the interval between the time the patient was last seen
and the time the death became known will be recorded. In some
circumstances, can be considered to be unexpected.
Fatal Myocardial Infarction (Ml): Fatal myocardial infarction may be
adjudicated in any one of the following three scenarios:
· Death occurring after a documented myocardial infarction in which there is
not conclusive evidence of another cause of death. Patients who are being
treated for myocardial infarction and who have a sudden death as the
terminal event related to the Ml will be classified as having a myocardial
infarction-related death.
· Autopsy evidence of a recent infarct with no other conclusive evidence of
another cause of death.
• A fatal myocardial infarction may be adjudicated for an abrupt death that
has suggestive criteria for an infarct but does not meet the strict definition
of a myocardial infarction. The suggestive criteria are presentation of chest
pain and one of the following:
· ECG changes indicative of a myocardial injury or
• Abnormal cardiac markers without evolutional changes (i.e., patient died
before a subsequent draw) or
• Other evidence of new wall motion abnormality
Heart Failure Death: death due to heart failure, with clinical, radiological, or
postmortem evidence of heart failure but without evidence of other cause
such as ischemia, infection, dysrhythmia. Cardiogenic shock to be included.
Death after Invasive Cardiovascular Intervention: includes death occurring
within 30 days of cardiovascular surgery, or within 7 days of cardiac
catheterization, arrhythmia ablation, angioplasty, atherectomy, stent
placement, or other invasive coronary or peripheral vascular intervention
Death Due to Stroke: Death due to stroke and occurring within 30 days of
signs/symptoms of stroke
Other Cardiovascular Causes of Death: other vascular events, including
pulmonary emboli and ruptured abdominal aortic aneurysm
Presumed Cardiovascular Death: death suspicious of cardiovascular death
with supporting clinical evidence that may not fulfill other criteria (e.g., patient
with chest pain typical for Ml, but without ECG or enzyme documentation that
fulfills Ml criteria)
Death from Unknown Cause: qualifies as a cardiovascular event unless clear
evidence of extraneous disease exists
Non-cardiovascular Death is defined as any death for which clear evidence of
a non-cardiovascular cause exists. Categories of non-cardiovascular death
include:
Malignancy
• Gastrointestinal malignancy
• Lung Malignancy
• Breast Malignancy
• Prostate Malignancy
· Brain Malignancy
• Skin Malignancy
• Multi-site malignancy
• Genito-urinary malignancy
• Other malignancy (specify)
Other Non-cardiovascular Death Not Due to Malignancy
Non-fatal Myocardial Infarction is defined as any of the following:
Non-Procedural Ml:
EITHER
Ischemic Symptoms: (pain, dyspnea, pressure) at rest or accelerated
ischemic symptoms, either of which lasts > 10 minutes that the investigator
determines is secondary to ischemia
OR
ECG changes consistent with infarction:
• New significant Q waves (or R waves in V 1-V2) in two contiguous leads in
the absence of previous LVH or conduction abnormalities
· Evolving ST-segment to T-wave changes in two or more contiguous leads
• Development of new left bundle branch block
• ST segment elevation requiring thrombolytics or PCI
AND
Cardiac Markers:
If troponin is drawn:
• Any combination of markers where troponin result is in necrosis range.
• If troponin is not in the necrosis range, at least one other marker must be >
2 x ULN.
• If troponin given in ranges, the diagnostic lower limit for Ml will be
considered the lowest value in the range indicative of necrosis.
If troponin is not drawn:
• If both CK and CKMB are drawn, both values must be > ULN.
• If both CK and CKMB are drawn and CK value is < ULN, CKMB must be >
1.5 x ULN.
· If only CKMB is drawn, must be > 1.5 x ULN.
• If only CK is drawn, must show serial changes of > 2 x ULN
Other cardiac markers: These markers would include SGOT, LDH, or
myoglobin and could be used if they are drawn to rule out myocardial injury. In
this case, they must demonstrate serial changes (> 2x ULN) and should only
be used when cardiac-specific markers are unavailable.
Procedural Ml:
• Post-PCI Ml
EITHER
New pathologic Q waves (may also have other clearly documented wall
motion abnormalities other than septal)
OR
Cardiac Markers (within 24 hours of procedure): Marker > 3 x ULN and > 50%
above last measurement if last measure was > ULN
· Post-CABG Ml
EITHER
New pathologic Q waves (may also have other clearly documented wall
motion abnormalities other than septal)
OR
CKMB (within 24 hrs of procedure): CKMB > 5 x ULN and > 50% above last
measurement if last measure was > ULN
Silent Ml:
It is acknowledged that there are instances where myocardium necrosis
attributed to myocardial infarction occurs which is clinically unrecognized. If
the investigator (based on review of the clinical status and ECGs) feels that
this occurred, he/she should submit information supporting the diagnosis of a
clinically unrecognized myocardial infarct. Support would require at least
paired ECGs showing new and significant Q-waves not attributed to
intraventricular conduction defect, left ventricular hypertrophy, pre-excitation
syndrome, or electronic pacer. In addition, confirmation may be achieved by
echocardiographic or other evidence of new regional wall motion
abnormalities. The Event Adjudication Committee (EAC) will evaluate
clinically reported events in a blinded fashion and ascertain whether they have
sufficient information to concur that a significant event, which was clinically
unrecognized, has occurred. The timing of that event would be the earliest
ECG showing new Q-waves.
Non-fatal Stroke
Stroke is defined as the presence of acute focal neurological deficit (except
for subarachnoid hemorrhage which may not be focal) thought to be of
vascular origin with signs or symptoms lasting greater than 24 hours. On the
basis of clinical symptoms, autopsy and/or CT/MRI/other imaging modality,
strokes will be classified as:
Definite or Probable Ischemic Stroke
Stroke with CT/MRI/other imaging modality performed within 3 weeks that is
either normal or shows infarct in the clinically expected area. Subgroups of
ischemic stroke include:
• Lacunar infarct - cerebral infarction with:
- Consciousness and higher mental functions maintained
- One of the typical lacunar syndromes such as pure motor stroke, pure
sensory stroke, sensori-motor stroke, or ataxic hemiparesis.
- CT/MRI/other imaging modality performed within 3 weeks that is either
normal or shows a small infarct in the basal ganglia, internal capsule,
medulla, or pons.
• Cardioembolic infarct - Cerebral infarction with:
- Absence of lacunar characteristics
- No definite evidence of large artery disease in the neck
- Major cardioembolic source present (e.g., atrial fibrillation, myocardial
infarction in the last 6 weeks, cardiomyopathy, endocarditis, or
prosthetic heart valve)
• Large artery infarct
- Absence of lacunar characteristics
- No major cardioembolic source present
- Evidence of large artery disease in the neck (eg. a bruit, or duplex scan
evidence of a stenosis of more than 50%)
• Unclassified infarct: Cerebral infarction that is not lacunar, cardioembolic
or large artery in origin (including a stroke with more than one potential
cause)
Definite Hemorrhagic Stroke:
Definite stroke with cerebral hemorrhage confirmed by CT/MRI/other imaging
modality or autopsy. Does not include hemorrhage secondary to cerebral
infarct, trauma, hemorrhage into a tumor, or vascular malformation.
Definite Stroke, Type Uncertain:
Definite stroke that does not meet the above criteria for ischemic stroke or
hemorrhage.
Subarachnoid Hemorrhage:
Typical clinical syndrome of sudden onset headache, with or without focal
signs, and CT/MRI/other imaging modality or cerebrospinal fluid evidence of
bleeding primarily in the subarachnoid space.
Revascularization Procedures include any of the following:
PTCA (balloon)
PTCA with stent
Other PCI
CABG
Carotid Angioplasty with Stent
Carotid Endarterectomy
Peripheral Angioplasty with or without Stent
Peripheral Vascular Surgery (including abdominal aortic aneurysm repair)
Limb Amputation (including partial or digit amputation) due to vascular
disease
Resuscitated Cardiac Arrest
Resuscitated cardiac arrest is defined as sudden cardiac arrest, with or
without premonitory heart failure or myocardial infarction, following which the
patient is resuscitated by cardioversion, defibrillation or cardiopulmonary
resuscitation. This definition excludes known transient losses of
consciousness such as seizure or vasovagal episodes that do not reflect
significant cardiac dysfunction. In order to meet the criteria for this event the
patient should also gain a reasonable amount of consciousness after the
resuscitation without the aid of artificial life support.
Hospitalization for Cardiovascular Causes
All hospitalizations will be encoded by the Data Center using the MedDRA
dictionary. Cardiovascular hospitalizations will be defined as any
hospitalization that is encoded by the Data Center to a term in the MedDRA
dictionary that maps to the cardiovascular body system.
Hospitalization for Heart Failure
Hospitalization for heart failure is defined as a hospitalization for congestive
heart failure or attendance in an acute care setting (Emergency Room) for
administration of intravenous diuretic, escalation of diuretic doses and/or
inotropes, and confirmed by chest x-ray.
New Angina
New onset of typical angina with documented ischemia by stress testing
(ECG, ECHO, or nuclear)
Worsening Angina
Known angina increasing in frequency, duration, and/or severity, and requiring
hospitalization and/or increased anti-anginal medication
Unstable Angina
Unstable angina is defined as ischemic symptoms: (pain, dyspnea, pressure)
at rest or accelerated ischemic symptoms, either of which lasts > 10 minutes,
that the investigator determines is secondary to ischemia
AND
Ischemic ECG changes as compared to most recent ECG or during the
previous stable phase:
• > 0.5 mm transient ST segment depression in two contiguous limb or
precordial leads
• > 1 mm transient ST elevation of two contiguous leads (or ST depression
in V 1 o V2)
• > 2 mm transient T wave change in two or more contiguous leads
OR
Cardiac Markers:
• Cardiac marker suggestive of myocardial injury, >ULN but not sufficient for
Ml criteria. If troponin is used, must be in the "suggestive" (middle) range
for necrosis.
Vascular Amputation
Amputation of a limb or part of a limb secondary to vascular insufficiency
Cognitive Function
Defined by serial cognitive testing (e.g., mini-mental status examination
[MMSE]).
In the following there are definitions provided regarding microvascular
outcome variables.
The composite microvascular outcome will be met by the development of any
of the following:
• Doubling of serum creatinine from study baseline (screening value)
· Albuminuria progression, defined as a change from normoalbuminuria to
either microalbuminuria or clinical proteinuria, or from microalbuminuria to
clinical proteinuria using the definitions in the attached table.
Definitions of Normoalbuminuria, Microalbuminuria, and Clinical Proteinuria
Method Normoalbuminuria Microalbuminuria Clinical
Proteinuria
< 30 mg/ 24 hrs or or
> 30 mg/ 24 hrs > 300
< 300 mg/ 24 hrs mg/24 hrs
Tinned Urine Collection N/A N/A > 500
for Total Protein mg/24 hrs
Excretion
• Requirement for renal replacement therapy (eg, dialysis, renal transplant),
or death due to renal failure
• Use of retinal photocoagulation or vitrectomy for diabetic retinopathy,
including macular edema
Diabetes mellitus is associated with an increased incidence of bone fractures,
and vertebral fractures result in a decrease in height.
The waist-hip ratio (WHR) has been used as an indicator or measure of the
health of a person, and the risk of developing serious health conditions.
By the Origin study it has been surprisingly found that although there was no
statistically significant difference in mortality or microvascular outcomes, there
is a trend that treatment with insulin glargine is beneficial with regard to
microvascular outcomes. Moreover, participants without diabetes at
randomization who were allocated to insulin glargine were significantly less
likely to develop protocol-defined diabetes than standard care participants.
Also, under an early intervention with insulin glargine a highly significant effect
on the development of new angina was detected.
The results of the ORIGIN study were obtained with the long-lasting insulin
glargine. Respective studies with other long-acting insulins like insulin detemir
(Levemir®) and insulin degludec (Tresiba®) lead to comparable results.
Therefore, an embodiment of the invention is a method of reducing the risk of
progression to type 2 diabetes in a patient diagnosed with a disease or
condition selected from the group consisting of impaired fasting glucose (IFG)
and impaired glucose tolerance (IGT), comprising administering to said
patient a therapeutically effective dosage of a long acting insulin, wherein said
therapeutically effective dosage of said long acting insulin reduces the risk of
progression to type 2 diabetes in said patient.
A further embodiment of the invention is a method of reducing the risk of a
new angina in a patient diagnosed with a disease or condition selected from
the group consisting of impaired fasting glucose (IFG), impaired glucose
tolerance (IGT), and type 2 diabetes, wherein the patient diagnosed with type
2 diabetes is either drug na' ve or receive an oral antidiabetic agent,
comprising administering to said patient a therapeutically effective dosage of
a long acting insulin, wherein said therapeutically effective dosage of said
long acting insulin reduces the risk of a new angina.
A further embodiment of the invention is a method of reducing the risk of a
microvascular event in a patient diagnosed with a disease or condition
selected from the group consisting of impaired fasting glucose (IFG), impaired
glucose tolerance (IGT), and type 2 diabetes, wherein the patient diagnosed
with type 2 diabetes is either drug na'fve or receive an oral antidiabetic agent,
comprising administering to said patient a therapeutically effective dosage of
a long acting insulin, wherein said therapeutically effective dosage of said
long acting insulin reduces the risk of a microvascular event.
A further embodiment of the invention is a method for preventing the
progression to type 2 diabetes in a patient diagnosed with a disease or
condition selected from the group consisting of impaired fasting glucose (IFG)
and impaired glucose tolerance (IGT), comprising administering to said
patient a therapeutically effective dosage of a long acting insulin, wherein said
therapeutically effective dosage of said long acting insulin reduces the risk of
progression to type 2 diabetes in said patient.
A further embodiment of the invention is a method for preventing a new
angina in a patient diagnosed with a disease or condition selected from the
group consisting of impaired fasting glucose (IFG), impaired glucose tolerance
(IGT), and type 2 diabetes, wherein the patient diagnosed with type 2
diabetes is either drug na' ve or receive an oral antidiabetic agent, comprising
administering to said patient a therapeutically effective dosage of a long
acting insulin, wherein said therapeutically effective dosage of said long acting
insulin reduces the risk of a new angina.
A further embodiment of the invention is a method for preventing a
microvascular event in a patient diagnosed with a disease or condition
selected from the group consisting of impaired fasting glucose (IFG), impaired
glucose tolerance (IGT), and type 2 diabetes, wherein the patient diagnosed
with type 2 diabetes is either drug na'fve or receive an oral antidiabetic agent,
comprising administering to said patient a therapeutically effective dosage of
a long acting insulin, wherein said therapeutically effective dosage of said
long acting insulin reduces the risk of a microvascular event.
A further embodiment of the invention is a method delaying the progression to
type 2 diabetes in a patient diagnosed with a disease or condition selected
from the group consisting of impaired fasting glucose (IFG) and impaired
glucose tolerance (IGT), comprising administering to said patient a
therapeutically effective dosage of a long acting insulin, wherein said
therapeutically effective dosage of said long acting insulin delays the
progression to type 2 diabetes in said patient.
A further embodiment of the invention is as described above, wherein the
microvascular event is a clinical microvascular event, in particular wherein the
microvascular event is selected from a group comprising neuropathy,
retinopathy and nephropathy, preferably wherein the nephropathy is
characterized by renal failure, end-stage renal disease, or renal death.
A further embodiment of the invention is a method for reducing the risk for
requiring treatment by laser surgery or vitrectomy in a patient diagnosed with
a disease or condition selected from the group consisting of impaired fasting
glucose (IFG), impaired glucose tolerance (IGT), and type 2 diabetes, wherein
the patient diagnosed with type 2 diabetes is either drug na' ve or receives an
oral antidiabetic agent, comprising administering to said patient a
therapeutically effective dosage of a long acting insulin, wherein said
therapeutically effective dosage of said long acting reduces the risk for
requiring treatment by laser surgery or vitrectomy in said patient.
A further embodiment of the invention is a method for reducing doubling of
baseline serum creatinine in a patient diagnosed with a disease or condition
selected from the group consisting of impaired fasting glucose (IFG), impaired
glucose tolerance (IGT), and type 2 diabetes, wherein the patient diagnosed
with type 2 diabetes is either drug na'fve or receives an oral antidiabetic agent,
comprising administering to said patient a therapeutically effective dosage of
a long acting insulin, wherein said therapeutically effective dosage of said
long acting insulin reduces doubling of baseline serum creatinine in said
patient.
A further embodiment of the invention is a method for reducing the risk of
cognitive impairment in a patient diagnosed with a disease or condition
selected from the group consisting of impaired fasting glucose (IFG), impaired
glucose tolerance (IGT), and type 2 diabetes, wherein the patient diagnosed
with type 2 diabetes is either drug na'fve or receives an oral antidiabetic agent,
comprising administering to said patient a therapeutically effective dosage of
a long acting insulin, wherein said therapeutically effective dosage of said
long acting insulin reduces the risk of cognitive impairment in said patient, in
particular wherein the patient scores 24 or less in the Mini-Mental Status
Exam (MMSE).
A further embodiment of the invention is a method for lowering the triglyceride
concentration in the blood in a patient diagnosed with a disease or condition
selected from the group consisting of impaired fasting glucose (IFG), impaired
glucose tolerance (IGT), and type 2 diabetes, wherein the patient diagnosed
with type 2 diabetes is either drug na' ve or receives an oral antidiabetic agent,
comprising administering to said patient a therapeutically effective dosage of
a long acting insulin, wherein said therapeutically effective dosage of said
long acting insulin lowers the triglyceride concentration in the blood in said
patient.
A further embodiment of the invention is a method for lowering the cholesterol
concentration in the blood in a patient diagnosed with a disease or condition
selected from the group consisting of impaired fasting glucose (IFG), impaired
glucose tolerance (IGT), and type 2 diabetes, wherein the patient diagnosed
with type 2 diabetes is either drug na'fve or receives an oral antidiabetic agent,
comprising administering to said patient a therapeutically effective dosage of
a long acting insulin, wherein said therapeutically effective dosage of said
long acting insulin lowers the cholesterol concentration in the blood in said
patient.
A further embodiment of the invention is a method of reducing the risk of a
microvascular event or a method for preventing a microvascular event as both
described above, wherein the patient has a HbA1 c > 6.4 prior to administering
the long-acting insulin.
A further embodiment of the invention is a method of reducing the risk of a
microvascular event or a method for preventing a microvascular event as both
described above, wherein the patient had a history of atrial fibrillation prior to
administering the long-acting insulin, in particular wherein the microvascular
outcome is a clinical microvascular outcome or a laboratory-based
microvascular outcome, preferably wherein the microvascular outcome is a
composite of: laser surgery or vitrectomy or blindness for diabetic
retinopathy; development of renal death or the need for renal replacement
treatment (dialysis or transplantation); doubling of serum creatinine; or
progression from lesser to greater severity of microalbuminuria.
A further embodiment of the invention is a method as described above,
wherein the long-acting insulin is selected from a group comprising insulin
glargine, insulin detemir and insulin degludec; preferably selected from a
group comprising insulin glargine.
A further embodiment of the invention is an article of manufacture comprising
- a packaging material;
- a long-acting insulin; and
- a label or package insert contained within the packaging material indicating
that patients receiving the treatment with the long-acting insulin can be treated
by a method as described above.
A further embodiment of the invention is an article of manufacture comprising
- a packaging material;
- insulin glargine; and
- a label or package insert contained within the packaging material indicating
that patients receiving the treatment with the long-acting insulin can be treated
by a method as specified above, wherein in such treatment the risk for
cardiovascular outcomes, all-cause mortality or cancer is not altered when
compared to standard glucose lowering therapy, in particular wherein the risk
for cancer is not altered when compared to standard glucose lowering therapy
with regard to any organ-specific type of cancer, in particular wherein the
long-acting insulin is selected from a group comprising insulin glargine, insulin
detemir and insulin degludec; preferably selected from a group comprising
insulin glargine.
.BRIEF DESCRIPTION OF THE DRAWINGS
Flow of study participants from screening to analysis
Forest plot of hazard ratios of the primary, secondary, and other
ORIGIN outcomes
Proportion of participants who experienced the co-primary
composite outcome of myocardial infarction, stroke, or
cardiovascular death (Panel A), these outcomes plus
revasculatization or heart failure hospitalization (Panel B), or
mortality (Panel C)
Forest plot of odds of newly diagnosed diabetes. Row 1
illustrates the odds of new diabetes as defined in the protocol;
row 2 illustrates the odds of diabetes after a s second glucose
tolerance test (done only on those without diabetes after the 1st
test) and row 3 illustrates both confirmed diabetes and
diagnoses of diabetes that were suspected but not confirmed.
Fasting plasma glucose and A1C responses by treatment
assignment. Open circles and broken lines denote standard
therapy; solid circles and lines denote treatment with insulin
glargine. The subgroups by glycemic status at entry are shown
separately: dysglycemia without diabetes in A and C, diabetes in
B and D. Medians are shown. Numbers of measurements at
each time-point for standard therapy and glargine appear at the
bottom of each panel. Std=Standard; Gla=Glargine; End=end of
treatment.
Percentages of participants with A 1C <7.0% or 6.5% by
treatment assignment over time. Open circles and broken lines
denote standard therapy; solid circles and lines denote
treatment with insulin glargine. The subgroups by glycemic
status at entry are shown separately: dysglycemia without
diabetes in A and C, diabetes in B and D.
Forest plot of Odds Ratios (OR) for maintaining mean A 1C
<6.5% over 5 years with glargine versus standard therapy, by
subgroups independently associated (p<0.05) with this outcome
in the logistic regression model shown in Table 9 . P values for
interaction between the effect of treatment assignment and each
subgroup are shown.
The invention is described in the following by examples.
EXAMPLE 1: Investigational plan
The ORIGIN study was an international, multicenter, randomized, open-label
(for insulin glargine versus standard care), double-blind (for omega-3 PUFA
versus placebo), 2x2 factorial design study to evaluate whether patients with
IGT, IFG, or early T2DM, who were at high risk for macrovascular events,
could be safely treated with insulin glargine and omega-3 PUFA, and if either
insulin glargine-mediated normoglycemia and/or omega-3 PUFA reduce or
prevent CV morbidity and/or mortality. Patients were randomized to either
receive insulin glargine treatment as a titrated regimen which targeted fasting
plasma glucose (FPG) of <95 mg/dL or standard care according to current
guidelines for dysglycemia accompanied by appropriate lifestyle
modifications. Patients were also independently randomized to receive either
ethyl esters of omega-3 PUFA or matching placebo.
The study consisted of a 2-year recruitment period, and was originally
planned to also include an average of 4 years of treatment and follow-up.
After the study was extended by 24 months, it was estimated that the mean
duration of treatment and follow-up would increase to approximately 6.5 years
and the total duration of the study to approximately 7.5 years (2 years
recruitment period and at least 5.5 years follow-up after the last patient
randomization).
However, the study was event-driven, and its actual duration was to be based
on the number of observed events. The study ended when a prespecified total
number of primary outcomes (2 200 patients having experienced at least one
component of the primary outcome) needed for a sufficient statistical power to
test the insulin glargine group against the standard care group was achieved.
If this event total had not been achieved after 7.5 years, the IDMC could have
recommended to the Steering Committee that the follow-up of patients be
extended until the prespecified number has been reached.
Approximately twelve thousand five hundred ( 12 500) dysglycemic patients
with evidence of CV disease who were at high risk for future CV events were
enrolled. The study population comprised the following three groups:
• Patients with IFG and/or IGT (ie, prediabetic patients);
• Patients with new or previously diagnosed T2DM who had been taking
no pharmacotherapy for hyperglycemia for at least the preceding 10
weeks;
• Patients with established T2DM who had been taking one oral
antidiabetic drug (OAD) at stable dose for at least the preceding 10
weeks. Patients taking combination products containing two or more
OADs were not eligible.
Patients were to be randomly assigned to receive either insulin glargine
treatment or standard care for their dysglycemia. Patients randomized to the
insulin glargine group received Lantus® (insulin glargine 100 U/mL solution)
once daily (QD) by subcutaneous (SC) injection in a titrated regimen targeting
an FPG of <95 mg/dL (5.3 mmol/L). Nondiabetic patients randomized to
standard care were followed for the development of diabetes, and were
encouraged to continue to modify diet and physical activity levels. Blood
glucose management of diabetic patients (or nondiabetic patients who
developed diabetes during the study) randomized to standard care was to be
performed according to current (at that time) guidelines. All patients were to
be encouraged to appropriately modify their lifestyle.
Patients were also to be independently randomly assigned to receive either
Omacor® (ethyl esters of omega-3 PUFA), or matching placebo.
Randomization to insulin glargine versus standard care and omega-3 PUFA
versus matching placebo could occur at separate visits for some patients, as
omega-3 PUFA and matching placebo were not available at the same time as
insulin glargine at some sites. Thus some patients were randomized to insulin
glargine versus standard care, and begin receiving their assigned treatment
from among these two, before being randomized to receive omega-3 PUFA
versus matching placebo. In the opinion of the Steering Committee, the delay
in this omega-3 randomization was not to affect patient safety or well-being,
and was to only marginally affect the power of the study to answer the omega-
3-related study questions.
In this event-driven study, patients were enrolled for approximately 7 years,
including:
• Screening: up to more than 10 weeks (a qualifying oral glucose
tolerance test [OGTT] could have been obtained up to 4 weeks prior to
signing informed consent at the screening visit ; taking OAD for at least
10 weeks at the time of screening or for 10 weeks prior to
hospitalization if identified while hospitalized for a CV event);
• Run-in: 4 to 10 days (for a successful completion of home glucose
monitoring [HGM] and self-injection of the insulin glargine placebo
[insulin pen cartridges containing physiologic saline]);
• Treatment and follow-up: a mean of 6.5 years (ranging from 5.5 to
7.5 years) from randomization till the end-of-usual follow-up [EUF];
• Post-EUF OGTT: 3 to 14 weeks (for OGTT in selected patients who
were not classified as having had diabetes by the EUF).
Routine visits were to occur at 2, 4, 8, and 16 weeks following randomization,
then every four months for the rest of the study, for all patients.
EXAMPLE 2 : Selection of study population - inclusion criteria
1. Individuals with either IFG and/or IGT, or early diabetes, as defined below.
A Impaired glucose tolerance (IGT), defined as a PPG value >140 and
<200 mg/dL (ie, >7.8 and < 11.1 mmol/L), with a FPG <126 mg/dL (7.0
mmol/L).
OR
B Impaired fasting glucose (IFG), defined as an FPG > 110 and
< 126 mg/dL (>6.1 and <7 mmol/L), without diabetes mellitus (PPG
must be <200 mg/dL [ 1 1.1 mmol/L]).
OR
C Early type 2 diabetes, defined as a FPG > 126 mg/dL (7.0 mmol/L) or a
PPG of >200 mg/dL ( 11.1 mmol/L), or a previous diagnosis of diabetes,
and either:
• on no pharmacological treatment (while ambulatory for at least 10
weeks prior to screening, with screening glycated hemoglobin
< 150% of the upper limit of normal (ULN) for the laboratory (eg,
<9% if the ULN is 6%)
OR
• taking one OAD from among sulfonylureas (SU), biguanides,
thiazolidinediones (TZDs), alpha-glucosidase inhibitors (AGIs), and
meglitinides (MGTs) at a stable dose while ambulatory for at least
10 weeks at the time of screening (or for the 10 weeks prior to
hospitalization if identified while hospitalized for a CV event), with
screening glycated hemoglobin < 33% of the ULN for the laboratory
(eg, <8% if the ULN is 6%) if taking this medication at halfmaximum
dose or greater, and glycated hemoglobin <142% of the
ULN for the laboratory (eg, <8.5% if the ULN is 6%) if taking this
medication at less than half-maximum dose. Individuals taking
combination products containing two or more OADs were not
eligible.
Men or women aged 50 years and older.
Participants must be at risk for cardiovascular disease, based on
satisfying one or more of the following criteria [MT: Was the
replacement in the amended protocol of the original protocol text
documented?]
At least one of the following CV risk factors:
a) previous Ml (>5 days prior to randomization);
b) previous stroke (>5 days prior to randomization);
c) previous coronary, carotid or peripheral arterial revascularization;
d) angina with documented ischemic changes (at least 2 mm ST segment
depression on ECG during a Graded Exercise Test [GXT]; or with a
cardiac imaging study positive for ischemia); or unstable angina with
documented ischemic changes (either ST segment depression of at
least 1 mm or an increase in troponin above the normal range but
below the range diagnostic for acute Ml);
e) microalbuminuria or clinical proteinuria (an albumin:creatinine ratio >30
g/mg in at least one first morning urine sample or timed collection of
urine with albumin excretion >20 g/min or >30 mg/24 hours or total
protein excretion >500 mg/24 hours);
f) left ventricular hypertrophy by electrocardiogram or echocardiogram;
g) significant stenosis on angiography of coronary, carotid, or lower
extremity arteries (ie, 50% or more stenosis);
h) ankle-brachial index (ABI) <0.9.
4 . Provision of signed and dated informed consent prior to any study
procedures.
5 . Ability and willingness to complete study diaries and questionnaires.
6 . Demonstrated ability to use the self-glucose-monitoring device, and to
self-inject insulin prior to randomization.
7 . A negative pregnancy test for all women of childbearing potential (ie,
ovulating, pre- menopausal, and not surgically sterile) and the
agreement of these women to use a reliable method of birth
control to prevent pregnancy during the duration of the study.
8 . Willingness to discontinue prior omega-3 PUFA supplements for the
duration of the study.
EXAMPLE 3 : Selection of study population - exclusion criteria
People with any of the following characteristics will be excluded from the
study:
1. Type 1 diabetes.
2 . Requiring ambulatory insulin treatment or uncontrolled or symptomatic
hyperglycemia that is likely to require the addition of ambulatory insulin
therapy or a new antidiabetic agent either before or within 2 weeks after
randomization.
3 . Known anti-glutamic acid decarboxylase antibody (anti-GAD Ab)
positivity in the past.
4 . Screening glycated hemoglobin > 150% of the ULN for the laboratory
(eg, >9% if the ULN is 6%).
5 . Unwillingness to inject insulin or perform self-monitoring of BG.
6 . Nonadherence to the run-in requirement to inject placebo insulin and
do capillary glucose monitoring for at least 4 days prior to
randomization.
7 . Currently planned coronary artery bypass grafting (CABG) or CABG
within the 4 years prior to screening - however, patients with angina,
Ml, or stroke since a previous CABG will be eligible for randomization,
even if the last CABG was within 4 years.
8 . Serum creatinine >2.0 mg/dL ( 176 mhhoI/L) at screening.
9 . Active liver disease, or alanine aminotransferase (ALT) or aspartate
aminotransferase (AST) >2.5 times ULN at screening.
10 . Chronic or recurrent treatment with systemic corticosteroids, or niacin
treatment for hyperlipidemia.
11. Heart failure of NYHA Functional Class III or IV.
12 . Expected survival of <3 years for non-CV causes such as cancer.
13 . Any other factor likely to limit protocol compliance or reporting of
adverse events (AEs).
14. Unwilling or unable to discontinue TZDs.
15 . Simultaneous participation in any other clinical trial of an active
pharmacologic agent.
16 . Unwillingness to permit sites to contact their primary physicians to
communicate information about the study and the participant's data and
treatment assignment.
17 . History of hypersensitivity to the investigational products.
18 . Previous randomization in this study.
19 . A prior heart transplant, or awaiting a heart transplant.
20. Known infection with human immunodeficiency virus (HIV)
EXAMPLE 4 : Study treatments
Investigational medicinal products
Insulin glargine
Patients randomized to insulin glargine received injections of insulin glargine
100 U/mL solution (Lantus®) with a pen device (Optipen®) QD SC in a titrated
regimen targeting an FPG level of <95 mg/dL (5.3 mmol/L) according to
suggested algorithms. Treatment continued until a prespecified number of
patients had experienced at least one component of the primary outcome (2
200 first coprimary outcomes);
Ethyl esters of omega-3 PUFA
Patients randomized to omega-3 PUFA were to receive one gelatin capsule of
ethylesters of omega-3 PUFA (icosapent ethyl esters 465 mg and doconexent
ethyl esters 375 mg; Omacor®) QD per os (PO). As with insulin glargine
therapy, treatment was to continue until a prespecified number of patients had
experienced at least one component of the primary outcome.
Reference therapy
Standard care
Standard care was the reference therapy for insulin glargine.
Diabetic patients (and patients who developed diabetes after randomization)
who were randomized to receive standard care were treated according to
current (at that time) guidelines and the best judgment of the treating
physician. Standard care did not include glucose-lowering drugs for
nondiabetic patients. Insulin was not to be used in the standard care group
until a patient had been taking maximal doses of treatments from at least 2 of
the following different classes of oral glucose-lowering agents:
. SU or MGT;
· metformin (MET) or another biguanide;
. TZD.
For patients taking less than maximal doses of at least 2 of these classes of
OAD, the Investigator was to consider increasing both oral agents to maximal
dose, or adding an oral agent from a third class, before beginning insulin. If
the Investigator chose to add insulin before this, he or she was required to
complete a report justifying the use of insulin. Whenever insulin was added,
the Investigator or physician could reduce or stop some or all of the OADs at
his/her discretion.
Placebo
Placebo was the reference therapy for omega-3 PUFA.
Patients randomized to the omega-3 PUFA placebo received one matching
gelatin capsule containing olive oil QD PO.
DOSAGE SCHEDULE
Insulin glargine doses were adjusted according to both laboratory and
capillary plasma glucose results.
TREATMENT ASSIGNMENTS
Randomization was stratified by investigational site.
Participants were randomized using a centralized telephone randomization
system. Each randomized participant was assigned a unique number, which
was used throughout the study.
BLINDING, PACKAGING, AND LABELING
The investigational products (insulin glargine, placebo saline for run-in
injection) has been packaged by Sanofi. Ancillary medication (metformin, SU)
has been obtained through local pharmacies.
The comparison of insulin glargine to standard dysglycemia treatment has
been carried out in open-label fashion.
EXAMPLE 5 : Summary of performance of the Origin study
Methods
ORIGIN was an international randomized factorial trial of the effect of titrated
basal insulin therapy versus standard care and of omega 3 fasty acid
supplements versus placebo on incident CV outcomes. Results of the omega
3 fatty acid arm are reported separately (REF). Participants age 50 or older
with a prior CV event (myocardial infarction, stroke, or revascularization
procedure); angina with documented ischaemia; albuminuria; left ventricular
hypertrophy; angiographic evidence of > 50% stenosis of a coronary, carotid,
or lower extremity artery; or an ankle/brachial index < 0.9 were recruited if
they also had a history of type 2 diabetes that was stable on 0 or 1 oral agent;
or IFG, IGT or newly detected diabetes based on either a FPG > 6.1 mmol/L
[ 1 10 mg/dL] or a 2 hour plasma glucose > 7.8 mmol/L [ 140 mg/dL] after a 75 g
oral glucose load. The HbA1 c level of people with prior diabetes had to be low
enough to minimize the likelihood that insulin would be needed to maintain
glycemic control during follow-up if allocated to standard care. Key exclusion
criteria included unwillingess or an inability to inject insulin or do capillary
glucose testing, a clear indication for, or intolerance to insulin or omega 3 fatty
acids, unwillingness to stop thiazolidinediones if allocated to glargine, heart
failure, or coronary artery bypass surgery within the prior 4 years with no
intervening CV event. The study was approved by each site's ethics
committee and all participants provided written informed consent.
Interventions and Follow-up schedule
Participants were asked to self-administer daily subcutaneous saline
injections and to check their capillary glucose levels during a 10 day run-in
period. Adherent participants were then provided with lifestyle advice and
randomly allocated to either insulin glargine (Lantus™) or standard
approaches to glycaemic control. Participants allocated to insulin glargine who
were also taking a thiazolidinedione stopped that medication at the time of
randomization; otherwise the insulin glargine was added to their glycemic
regimen. These participants were instructed to inject insulin glargine in the
evening, starting at 2, 4 or 6 units (depending on their initial FPG) and to
increase the dose at least once per week targeting a self-measured FPG level
< 5.3 mmol/l (95 mg/dl) and > 4 mmol/l (72 mg/dl). If target FPG levels could
not be achieved without symptomatic hypoglycemia, investigators were
permitted to replace glyburide used at baseline with a comparable dose of
glimepiride; to reduce or stop all other glucose-lowering drugs; and/or to add
metformin. If participants developed uncontrolled hyperglycemia, investigators
were permitted to add rapid-acting insulin. No other glucose-lowering
medication could be added or increased. FPG levels were measured in the
local laboratory at every visit and the results were regularly reviewed along
with the dose of insulin to ensure that insulin was being effectively trirated.
People not diagnosed with diabetes by the time of the penultimate study visit
down-titrated insulin glargine by 10 units per day and stopped any metformin
that was prescribed. If glucose levels remained in the nondiabetic range, they
were scheduled for a 75 g oral glucose tolerance test 3-4 weeks later; if this
test did not diagnose diabetes, it was repeated 10-1 2 weeks later.
Participants allocated to standard care continued the glucose-lowering
therapy that they were taking before randomization. Anyone who had diabetes
at baseline or who developed it during the trial was instructed to self-monitor
glucose levels. Investigators were advised to manage glycemia using
standard approaches according to their best judgment based on the clinical
status and clinical practice guidelines, and were permitted to add, increase,
reduce or stop any glucose-lowering drug except insulin glargine. Only
metformin and sulfonylureas were provided by the study if required. FPG
levels were measured in the local laboratory annually for people without
diabetes and at 2 years and study end for people with diabetes. People
without a diagnosis of diabetes by the last study visit were scheduled for a 75
g oral glucose tolerance test 3-4 weeks later; if this test did not diagnose
diabetes, it was repeated 10-14 weeks later.
Outcomes and other data were collected at scheduled study visits at 0.5, 1, 2,
and 4 months after randomization and every 4 months thereafter. Weight,
waist and hip circumference were measured annually. HbA1c levels were
assayed in local laboratories at every visit for the first year and then annually
in people without diabetes and every 4 months for people with diabetes. A first
morning urine collection was sent centrally and assayed for creatinine and
albumin at baseline, 2 yrs and study end.
Outcomes
There were 2 co-primary composite CV outcomes. The first was CV death,
non-fatal Ml or non-fatal stroke, and the second was a composite of any of
these events or a revascularization procedure or hospitalization for heart
failure. Secondary outcomes included a composite microvascular outcome
comprising a doubling of serum creatinine from baseline, progression of
albuminuria category from normoalbuminuria or microalbuminuria to
microalbuminuria or overt nephropathy, renal replacement therapy, renal
death, retinal photocoagulation or vitrectomy for retinopathy. They also
included new type 2 diabetes developing by the time of the 1st post-trial oral
glucose tolerance test in participants without baseline diabetes, and all-cause
mortality. Other outcomes included incident cancers, CV hospitalizations, and
angina. Cardiovascular and cancer outcomes were reviewed by adjudicators
masked to treatment allocation. Episodes of hypoglycaemia since the prior
visit were recorded at each visit. Symptomatic hypoglycemia was classified as
confirmed if a concomitant recorded capillary glucose level was < 3 mmol/L
(54 mg/dL). Severe hypoglycemia was defined as hypoglycemia that required
assistance plus either prompt recovery with glucose or glucagon or a
documented capillary glucose < 2.0 (36 mg/dL). New diabetes was diagnosed
if 2 consecutive FPG levels within a 4-month period were > 7 mM ( 126 mg/dL)
during the trial; a diagnosis of diabetes was made by a physician and a
pharmacologic antidiabetic agent was being taken and there was evidence of
either a FPG > 7 mM (126 mg/dL) or any glucose value > 11.1 mM (200
mg/dL); either 1 or more capillary glucose levels were > 11.1 mM (200mg/dl)
and a lab-measured FPG was > 7 mmol/l ( 126 mg/dl) or a lab measured
random glucose level was > 11.1 mM (200mg/dl) during down-titration of
glargine insulin; or any FPG was > 7 mM ( 126 mg/dl) or 2 hour plasma
glucose was > 11.1 mM (200 mg/dl) during the first oral glucose tolerance
test.
Trial Conduct
A mean follow-up period of approximately 4 years was originally planned. This
was extended by 10 months before recruitment had been completed after it
became clear that it took approximately 8 months of insulin glargine selftitration
to achieve a median FPG < 5.3 mmol/l. Subsequently, in light of
clinical trials published in 2008 suggesting that a longer duration of follow-up
may be required to detect any effect of a gluco-metabolic intervention, and
without any knowledge of treatment effects, the Steering Committee extended
the trial for 2 more years.
Insulin glargine (Lantus®) was provided by Sanofi and omega-3-acid ethyl
esters 90 (Omacor®) and placebo were provided by Pronova Biocare AS.
Study data were collected and independently analyzed by the ORIGIN Project
Office based at the Population Health Research Institute (PHRI) in Hamilton,
Ontario, Canada.
Statistical Analyses and Power
Data were analyzed using SAS (version 9.1 for Solarus) according to an
intention-to-treat approach described in the protocol and a predefined
statistical analysis plan. Participants who were lost to follow-up, formally
withdrew or did not consent to either of the protocol extensions were censored
at the time of their last contact. Baseline characteristics were summarized
using means and standard deviatons, medians and interquartile ranges, or
counts and percentages as appropriate. Time-to-event curves were
constructed using product limit estimation and compared using stratified logrank
tests. Hazard ratios for each outcome were calculated using Cox
regression models adjusted for the factorial allocation, baseline diabetes
status and a history of a prior CV event before randomization as described in
the protocol. The proportional hazards assumption was assessed by testing
for the interaction of time with treatment group. The incidence of new diabetes
in each allocated group between randomization and the first post-study oral
glucose tolerance test was compared using a Cochran-Mantel-Haenzel test
stratified by factorial allocation and a prior CV event, and an odds ratio was
calculated; durability of this effect was assessed by repeating the analysis
after the 2nd post-study oral glucose tolerance test.
This overall type I error of 5% for the two co-primary outcomes was
partitioned such that the first co-primary outcome was tested at P=0.044 and
the second co-primary outcome was tested at P=0.01 ; the non-additivity of
these error rates reflects the correlation between these co-primary outcomes.
The nominal level of significance for all other analyses was P = 0.05.
Predefined subgroups were sex, age (< 65 or > 65), geographical region;
ethnicity, baseline diabetes status; body mass index £ 30 or > 30 kg/m2) , prior
CV event, and factorial allocation.
Based on an annual incidence of the first coprimary outcome of 2.8%, a mean
follow-up of 6.5 years, a type 1 error rate of 0.044, noncompliance with insulin
of 20% in the glargine group and use of insulin in the control group of 5%, and
a 12 month delay before an effect of the intervention emerges, it was
estimated that 12,500 participants would yield 2200 first coprimary outcomes
and 3900 second coprimary outcomes and provide 90% power to detect
relative risk reductions of 18% and 16% respectively.
EXAMPLE 6 : Results
12,537 participants (mean age 63.5 yrs; 35% female) were enrolled from 573
clinical sites in 40 countries. Participants were randomized to either insulin
glargine or standard care between September 2003 and December 2005 and
followed for a median (IQR) period of 6.2 (5.8, 6.6) years. At study end the
primary outcome status was known for 12443 (99.3%) participants (Figure 1) .
Approximately 82% of participants had a prior history of diabetes of mean
(SD) duration 5.4 (6.0) years, 6% had newly detected diabetes and 12% had
IFG and/or IGT. The median (IQR) FPG at baseline was 6.9 (6.1 , 8.2) mmol/l.
5052 (40%) participants were not taking diabetes drugs, 3435 (27%) were on
metformin and 371 1 (30%) were on a sulfonylurea. These and other key
baseline characteristics of the 2 treatment groups are shown in Table 1. Of
note, data from an additional 75 individuals in 3 sites located were excluded
(before the trial was closed or unblinded) at the request of their respective
national regulatory agencies following site audits.
50% of participants allocated to the addition of insulin glargine to their
regimen achieved a FPG level < 5.2 mmol/l by 1 year that was maintained
throughout the trial (Table 2). The median insulin dose taken to maintain this
degree of glycemic control rose from 0.28 U/kg at year 1, to 0.40 U/kg by year
6 . At the time of the penultimate visit (i.e. before insulin glargine was tapered
and discontinued in people with no diagnosis of diabetes) insulin glargine had
been permanently discontinued by 17% of insulin glargine group participants
(Table 5). By this time, 35% were on no oral agents, 47% were taking
metformin, and 14% were taking > 2 oral agents (Table 3).
Few standard care group participants used insulin during the trial (Table 2).
Thus at 2 years only 208 (3.5%) standard care participants were using any
insulin and at the 5 year visit only 494 (9.0%) were using any insulin. By study
end, 19% were on no oral agents, 60% were taking metformin, and 42% were
taking > 2 oral agents (Table 3). In addition to the large contrast in insulin use,
the 2 different therapeutic approaches achieved a 1.6 mmol/l (29 mg/dl)
difference in FPG by 2 years and approximately a 0.3% difference in A 1C
levels during the trial (Table 2).
The incidence of the first episode of severe hypoglycemia was 1.00 per 100
person-years in the insulin glargine group and 0.31 per 100 person-years in
the standard care group (P<0.001 ) . The incidence of the first episode of
nonsevere symptomatic hypoglycemia that was confirmed by a self-measured
glucose level < 3 mmol/l (54 mg/dl) was 9.81 and 2.68 per 100 person-years
in the insulin glargine and standard care groups (P<0.001 ) respectively, and
the incidence of the first episode of any (i.e. confirmed or unconfirmed)
hypoglycemia was 16.73 and 5.1 6 per 100 person-years in the 2 groups
respectively. A total of 2691 (43%) insulin glargine participants and 4694
(75%) standard care participants did not experience any episode of
symptomatic hypoglycemia during the entire trial (Table 4). Insulin glargine
group participants gained a mean of 1.6 kg whereas standard care
participants lost a mean of 0.7 kg.
There was no statistical evidence for an interaction between the effects of
insulin glargine and the omega 3 fatty acid trial for any of the outcomes (P >
0.1 5 for all outcomes). The incidence of both co-primary outcomes did not
differ between treatment groups (Figures 2 and 3). Specifically the incidence
of the composite outcome of nonfatal Ml, nonfatal stroke or CV death (i.e. the
first co-primary outcome) was 2.94/1 00 person-years and 2.85/100 personyears
for the insulin glargine and standard care group respectively (adjusted
HR 0.99: 95%CI 0.88, 1.1 2; P=0.9). For the second co-primary outcome the
incidence was 5.53/1 00 person-years and 5.28/100 person-years for each
group respectively (adjusted HR 1.00: 95%CI 0.91 , 1.1 0; P=0.99). The effect
of the intervention on the 2 co-primary outcomes was similar across key
subgroups (Supplementary Figure 1) . Of note was statistical evidence of
variation by geographic region for the 1st co-primary outcome (interaction
P=0.005) that was not evident for the larger 2nd co-primary outcomes
(interaction P=0.09) or for ethnicity with either outcome.
There was also no statistically significant difference in mortality or
microvascular outcomes, although there is a trend that treatment with insulin
glargine is beneficial with regard to microvascular outcomes. Surprisingly,
participants without diabetes at randomization who were allocated to insulin
glargine were 27% less likely (Figure 4) to develop protocol-defined diabetes
than standard care participants (i.e. 25% versus 3 1%: OR 0.73, 95%CI 0.58,
0.92; P=0.007). When individuals without diabetes based on the the 1st oral
glucose tolerance test had it repeated a median of 100 (94-1 12) days after
insulin was stopped, additional cases of diabetes were detected in both
groups so that the total the rates were 30 and 35% respectively (OR 0.80,
95%CI 0.64, 1.00; P=0.052). Under an early intervention with insulin glargine
a highly significant effect on the development of new angina was detected. In
the glargine group 100 patients developed a new angina ( 1 .6%) whereas in
the standard care group 137 (2.2%) developed a new angina. This significant
difference (p = 0.02) was observed after the 6-7 years exposure to the
different regimens.
Finally when cases of diabetes that were suspected of having developed
during the trial (but that did not meet all of the predefined criteria) were also
included the incidence of new diabetes was reduced by 30% (i.e. 35% versus
43%: OR0.70, 95% CI0.56, 0.86; P=0.001 ) . There was no difference in the
incidence of any cancer or cancer death (Figure 2).
EXAMPLE 7 : Microvascular outcomes
There was a significant reduction in clinical microvascular events. This
includes clinical events like laser surgery, renal failure, blindness, end-stage
renal disease, or renal death. Supporting this last, there was a significant
reduction in laser surgery or vitrectomy for diabetic retinopathy. There was
also a strong trend to reducing doubling of baseline serum creatinine. The
results are summarized in Table 6 .
Furthermore, the data obtained support an effect on microvascular disease
progression in the subgroups of patients having a higher baseline A 1c, and
atrial fibrillation.
Patients with baseline A 1c < 6.4% had a risk reduction (RR) (glargine:
subcutaneous) of 1.08 (not significant), patients with A 1c > 6.4%, RR = 0.88
(0.79 - 0.98), thus statistically significant because the confidence intervall
excluded 1.
Patients with a history of atrial fibrillation at baseline had a RR of 0.74 (0.55 -
0.98), and a RR for Clinical Microvascular outcomes (non-laboratory-based)
of 0.42 (0.1 9 - 0.91 ) .
The microvascular outcome was a composite of: laser surgery or vitrectomy
or blindness for diabetic retinopathy; development of renal death or the need
for renal replacement treatment (dialysis or transplantation); doubling of
serum creatinine; or progression from lesser to greater severity of
microalbuminuria. The last 2 components are laboratory-based - the others
are "clinical" microvascular outcomes.
EXAMPLE 8 : Cognition outcomes
Overall, there was a strong trend (p=0.075) for glargine treatment to be
associated with fewer impaired patients. The data, as summarized in Table 7,
reflect the Mini-Mental Status Exam (MMSE) [61] data for the number of
participants scoring 24 or less at various timepoints (mild impairment). These
patients were examined because they represent those at greater risk of
further deterioration during the study, and still with enough patients to confer
adequate power to make statistical comparisons. There was a significant
reduction of cases of mild impairment from baseline at about 4 years.
EXAMPLE 9 : Glargine leads to a significant lowering of triglyceride
concentration in the blood
By the ORIGIN study it has been shown that the triglyceride concentration in
the blood decreased in a statistically significant manner for patients treated
with glargine vs. standard care: -0.21 (0.03) [glargine] vs. -0.1 5 (0.03)
[standard care] (P < 0.001 ) .
EXAMPLE 10 : Glargine leads to a significant lowering of cholesterol
concentration in the blood
By the ORIGIN study it has been shown that the triglyceride concentration in
the blood decreased in a statistically significant manner for patients treated
with glargine vs. standard care:
Total cholesterol change from baseline to end-of-study (in mmol/L):
Glargine Standard Care _p_
-0.41 - 0.37 0.044
EXAMPLE 11: Attainment and maintenance of A 1C <6.5 or <7.0% with
titrated Basal Insulin or Standard Oral Therapy in the ORIGIN Trial - detailed
results
OBJECTIVE—To assess the success and baseline predictors of maintaining
glycemic control for up to 5 years of therapy using basal insulin glargine
versus standard glycemic care in people with dysglycemia treated with 0 or 1
oral glucose-lowering agents.
RESEARCH DESIGN AND METHODS— Data from 12, 537 participants in the
ORIGIN trial were examined by baseline glycemic status (with or without type
2 diabetes) and by therapeutic approach (titrated insulin glargine or standard
therapy) using an intention-to-treat analysis. Median values for FPG and A 1C
during randomized treatment and percentages attaining and maintaining
<6.5% or <7.0% A 1C were calculated. Factors independently associated with
success in reaching these levels of control were analyzed with linear
regression models.
RESULTS—Both treatment strategies kept median FPG and A 1C at or below
baseline values, which were 6.9 mmol/l ( 125 mg/dl) and 6.4% respectively.
Absence of diabetes and lower baseline A1C, independent of each other,
were associated with greater likelihood of maintaining 5-year mean A 1C
<6.5%. Allocation to basal insulin glargine was also a strong predictor of
maintaining A 1C <6.5% (OR 2.98, 95% CI 2.67, 3.31 ; p<0.001 ) after
adjustment for other independent predictors. This effect was noted overall
and within all of the analyzed subgroups.
CONCLUSIONS —Intervention early in the natural history of dysglycemia can
prevent worsening of control for at least 5 years. Maintaining A 1C <6.5% is
especially likely when A 1C is lower at baseline and when basal insulin is
used.
There is a strong relationship between hyperglycemia and micro- and
macrovascular complications of type 2 diabetes ( 1-4), and treatment studies
have verified that improved glycemic control can limit some of these
complications (5-8). However, diabetes is a progressive disorder and
treatment often does not prevent a gradual increase of hyperglycemia over
time (9-1 1) . The Outcome Reduction with an Initial Glargine Intervention
(ORIGIN) trial compared the medical outcomes of two treatment methods
designed to maintain nearly normal glycemic control early in the natural
history of dysglycemia, including both individuals with elevated glucose levels
not meeting the criteria for diabetes and people with diabetes with limited prior
therapy ( 12). The 12,537 participants were randomized to treatment with
either basal insulin glargine, which was systematically titrated to maintain
fasting plasma glucose <5.3 mmol/l (95 mg/dl), or to standard therapy. The
cardiovascular and other medical outcomes of ORIGIN have been reported
previously ( 13,14). Here we report the ability of each regimen to keep HbAl c
(A1 C) below guideline-recommended target levels for up to 5 years of followup,
as well as the baseline characteristics of participants associated with
achieving this goal.
RESEARCH DESIGN AND METHODS
Participants
The rationale and design of the ORIGIN trial were reported previously (9). In
brief, it was a multinational randomized trial with a 2x2 factorial design which
tested two pairs of interventions. Titrated basal insulin glargine was
compared with standard stepwise oral therapy, and an omega-3 fatty acid
supplement with placebo. Participants were required to have a prior
cardiovascular event or other evidence of high cardiovascular risk together
with documented dysglycemia, defined as either impaired fasting glucose,
impaired glucose tolerance (or the two together), or newly detected or
previously diagnosed type 2 diabetes. Participants with diabetes could be
treated with lifestyle alone or accompanied by no more than a single oral
glucose lowering agent. The present analysis concerns the glycemic
intervention, with use of omega-3 fatty acids included only as a covariate.
Data from a population of 12,537 individuals in 40 countries were assessed.
Interventions
Participants assigned to standard therapy continued their prior oral therapies
and were managed according to the investigators' judgement and local
guidelines for glycemic control and therapeutic approaches. Investigators
were advised not to prescribe insulin for standard participants unless they
were on full doses of 2 or more oral agents. If insulin was added glargine was
not to be used. Participants assigned to basal insulin glargine who were
taking a thiazolidinedione prior to randomization stopped this medication but
continued to take other glucose-lowering agents. Insulin glargine (Lantus®,
Sanofi) was added to their regimen starting at 2 to 6 units daily, based on
fasting glucose levels. Participants were advised to inject the insulin in the
evening and to self-titrate the dosage using a simple algorithm supported by
the site investigators. Self-measured, plasma-referenced fasting capillary
blood glucose tests were done at least twice-weekly to guide titration, with the
goal of achieving and maintaining fasting glucose <5.3 mmol/l (<95 mg/dl).
Other oral agents could be continued, reduced, or discontinued as judged
appropriate during treatment with insulin glargine. The only oral agent that
could be added (if not previously used) was metformin, which the site
investigator initiated for individual participants at doses of 500 - 1000mg/day
if judged necessary to limit the risk of hypoglycemia. The importance of
lifestyle management was continuously reinforced in both treatment groups.
Measurements
In addition to self-measured glucose tests, venous blood for measurement of
fasting plasma glucose (FPG) and A 1C at local laboratories was collected at
intervals during treatment. In the case of A 1C, measurements were done at
baseline, yearly thereafter, and at the end of treatment for all participants.
Measurements of FPG were done annually and at the end of treatment for all
participants in the glargine treatment group, and at baseline, after 2 years,
and at the end of treatment for those using standard therapy.
Statistical analysis
Summary statistics were computed for baseline characteristics of the whole
population and for subgroups by glycemic treatment allocation and by
glycemic status at enrollment (dysglycemia without diabetes, or diabetes).
Median FPG and A 1C with inter-quartile ranges were computed for each
subgroup for all time points. Percentages of participants in each subgroup
having A 1C <6.5% and <7.0% (two levels commonly identified as targets for
glycemic control [ 1 5,1 6]) at each time-point were calculated. To determine
associations of baseline characteristics, glycemic status, and treatment
allocation with glycemic outcomes, findings for all randomized participants up
to 5 years of treatment were analyzed using statistical models. Data after 5
years of treatment were not included because many participants did not have
follow-up beyond that interval due to the timing of randomization. Attainment
of A 1C <6.5% or <7.0% was defined as having values below those levels at 1
year; maintenance of A 1C during treatment was defined as having the mean
of all values from 1 year to the last available measurement up to 5 years at
those levels. All analysis of the relationships between baseline
characteristics and glycemic control levels were performed using linear
regression models. Characteristics with a univariable p<0.1 in univariate
analyses were entered into multivariable models. The independent effect of
allocation to basal insulin glargine versus standard treatment was assessed
by adding allocation to a final multivariable model which included all variables
statistically significant at p<0.05 in these multivariable models. The
unadjusted effect of allocation to insulin glargine was estimated using logistic
regression and statistical tests for interactions between allocation and these
subgroups were calculated and displayed as a forest plot.
RESULTS
Baseline characteristics
The characteristics of the ORIGIN population at enrollment, divided by
treatment assignment and glycemic status, are shown in Table 8 . Of 12,537
randomized, 6,264 were assigned to treatment with insulin glargine and 6,273
to standard care. The two randomized treatment groups were alike in
baseline characteristics. Eighty-eight percent of participants had either a prior
diagnosis of diabetes (of mean duration 5.4 years) or newly detected
diabetes. The 12% without diabetes clearly differed from those with diabetes
in FPG and A 1C levels and also in other ways, including more frequent prior
CV events, use of alcohol, depression, and use of statins and beta blockers.
For the whole population, the mean age was 63.5 years, median FPG 6.9
mmol/l, and median A 1C 6.4%.
Glycemic responses during randomized treatment
Median FPG
The median period of follow-up on randomized treatment was 6.2 years. The
effect of treatment allocation on the responses of FPG and A 1C during
treatment is shown in Figure 5 . For participants without diabetes the median
FPG (inter-quartile range) was 6.1 (5.5-6.4) mmol/l prior to randomized
treatment (Figure 5A). Standard care led to little change of FPG in this
subgroup, but insulin glargine caused a sustained decrease to median values
of 5.0 (4.5-5.5), 4.9 (4.5-5.5), 5.0 (4.5-5.7), and 5.1 (4.5-5.8) mmol/l at 1, 2, 5,
and 7 years. For participants with diabetes the median baseline FPG was 7.2
(6.2-8.4) mmol/l. With standard care the values at 2 years and the end of
treatment were 6.8 (5.9-8.1 ) and 7.0 mmol/l (5.9-8.4) mmol/l (Figure 5B).
Treatment with glargine reduced median FPG to 5.2 (4.6-5.9), 5.0 (4.4-5.8),
5.1 (4.5-6.1 ) , and 5.3 (4.5-6.4) mmol/l after 1, 2, 5, and 7 years.
Median A1C
For participants without diabetes A 1C changed little from baseline with either
regimen (Figure 5C). With standard therapy the median A 1C was 5.7 (5.4-6.1 )
% at baseline, 5.7 (5.4-6.1 ) at 1 year, and 6.0 (5.6-6.4) after 5 years. For
glargine-treated participants without diabetes median A 1C was 5.7 (5.4-6.0)
% at baseline, 5.6% (5.3-5.9) at 1 year, and 5.8 % (5.4-6.1 ) at 5 years. For
participants with diabetes the median A 1C at baseline was 6.5 (6.0-7.3)
(Figure 5D). During standard care the median A1C values at 1, 2, 5 and 7
years were 6.3 (5.8-6.9), 6.4 (5.9-7.0), 6.6 (6.1 -7.2), and 6.6 (6.1 -7.3) %.
Corresponding values during treatment with glargine declined to 6.0 (5.5-6.5),
6.0 (5.6-6.6), and 6.3 (5.8-6.9), and 6.3 (5.8-6.9) %.
Percentages below 7.0% and 6.5% A1C
Of participants without diabetes at entry, more than 90% achieved A1C levels
<7.0% and more than 75% achieved an A 1C <6.5% throughout randomized
treatment with both regimens (Figure 6A and 6C). Of participants with
diabetes, 66% had an A 1C <7.0% and 47% had A 1C <6.5% before starting
treatment (Figure 6B and 6D). During glargine treatment the percentages in
the diabetic subgroup achieving an A 1C <7.0% were 88% at 1 year and 77%
at 5 years, and the percentages achieving an A 1C <6.5% were 74% at 1 year
and 60% after 5 years.
Multivariable models showing associations of selected baseline
characteristics with attaining an A 1C <6.5% or <7.0% at 1 year, and with
maintaining a mean level of <6.5% or <7.0% for up to 5 years are shown in
Appendix Table 1. The leading independent predictors of success based on
pre-randomization characteristics were lower A 1C, lack of diabetes at
baseline, and reported use of alcohol. The effect of adding allocation to
insulin glargine or standard care to the models is shown in Table 9. The
adjusted odds ratio for success in attaining and maintaining each A 1C target
when using glargine compared with standard care ranged from 2.4 to 2.9 (all
p<0.001 ) . Other significant predictors of success were lower A 1C, lack of
diabetes, and alcohol use, whereas predictors that were significant in some
but not all models included greater age, lack of a prior CV event, greater grip
strength, and lower rates of albumin excretion.
Effect of treatment allocation on achieving a mean A 1C <6.5% over 5 years in
different subgroups
Figure 7 shows unadjusted odds ratios for success in maintaining A 1C <6.5%
with glargine compared with standard therapy in baseline subgroups selected
for having a significant association (p<0.05) with treatment success in the
multivariable models. The insulin glargine regimen was more effective in all
subgroups, with no overlap of 95% confidence intervals with unity. Two
subgroups showed nominally significant interaction with treatment
assignment: glargine may have been relatively more effective in participants
with higher waist-hip ratios (p=0.01 1) and those with greater grip-strength
(p<0.001 ) .
Glucose-lowering therapies
The usage of oral glucose-lowering agents prior to randomization is listed in
Appendix Table 2 . Less than 2% of participants with dysglycemia not meeting
criteria of diabetes had used such agents prior to entry, and none at the time
of oral glucose tolerance testing during screening. Of the participants with
diabetes at enrollment, 32% were taking no oral therapy, 3 1% metformin, and
33% a sulfonylurea. Appendix Table 3 displays usage of oral agents and
insulin at the end of treatment. Of the participants without diabetes at entry,
69% of those assigned to glargine and two (0.3%) of those assigned to
standard care were taking insulin at the end of the study. At the end of followup,
2 1% of those randomized to glargine and 3 1% of those randomized to
standard care were taking one or more oral agents, most often metformin
(17%, 24%; p<0.003). Of the participants with diabetes at entry, insulin was
used at the end by 82% of those who were assigned to glargine treatment and
by 12% of those assigned to standard care (p<0.001 ) . Oral therapies were
used by 7 1% of participants with diabetes assigned to glargine and 88% of
those assigned to standard care (p<0.001 ) . Metformin was taken by 50%
and 65% of in the glargine and standard groups, respectively, and
sulfonylureas were used by 28% and 52% (each <0.001 ) . Two or more oral
agents were taken by 14% of the glargine-treated group and 42% of the
standard care group.
Hypoglycemia
The percentage of people with diabetes at enrollment having 1 or more
nonsevere hypoglycemic episodes confirmed by a glucose test <3mmol/l (<54
mg/dl ) was 10.5 per 100 person-years with glargine and 3.0 per 100 personyears
with standard treatment. Corresponding frequencies for those without
diabetes at enrollment were 5.7 and 0.3 per 100 person-years.
CONCLUSIONS
The methods of therapy used in ORIGIN attained and maintained excellent
glycemic control of both FPG and A 1C for at least 5 years of follow-up in
participants with dysglycemia. With both insulin glargine and standard care
the A 1C levels at the end of treatment were no higher than at baseline. This
pattern of glycemic control differs from that observed in some other long-term
studies in which glycemic control steadily worsened over the course of 5 to 10
years (9-1 1) . Sustained glycemic control in ORIGIN presumably resulted from
the 'treat-to-target' schemes used in each treatment arm. The dosage of
glargine was systematically adjusted seeking FPG levels <5.3 mmol/l, and
metformin could be added to mitigate the risk of hypoglycemia. Similarly,
during standard therapy oral medications were added and their dosage
increased with the aim of keeping A 1C below either 6.5% or 7.0%, depending
on locally accepted guidelines. At the end of treatment 42 % of those using
the standard regimen were taking two or more oral agents, and 14 % of
participants assigned to glargine therapy were doing so. In contrast,
treatment in the Belfast (9), UKPDS ( 10), and ADOPT ( 1 1) studies was based
on assignment to monotherapy regimens, including diet alone, metformin,
sulfonylurea, thiazolidinedione, or basal insulin, with escalation of therapy only
under certain conditions.
The results in ORIGIN also differ from those in ADVANCE ( 17), ACCORD
(18), and VADT ( 19), trials in which glucose-lowering therapies in the
intensive treatment groups were systematically adjusted seeking near-normal
glycemic control. In these studies the participants enrolled had longer
duration of diabetes and in most cases established therapy with multiple
glucose lowering agents. The A 1C levels attained in ADVANCE (6.5%) and
ACCORD (6.4%) were close to those at baseline in ORIGIN (6.5%), whereas
those in VADT were slightly higher (6.9%). However, these values were
achieved by strenuous efforts to improve control from higher levels at
baseline. Hence, maintenance of A1C at or below near-normal entry levels in
ORIGIN contrasts with the other trials' efforts to restore previously inadequate
glycemic control. Keeping glycemic control below a level associated with
increasing risk by advancing therapy as needed may be a more desirable
approach than the historically common practice of allowing marked
hyperglycemia to occur and then attempting to reduce levels to a lower target
(20-22). This concept is in keeping with the recent adoption of A 1C 6.5% as
one option for timely diagnosis of diabetes to allow intervention to minimize
the risk of complications (23,24).
Not surprisingly, allocation to basal insulin glargine with titration of dosage
seeking normal FPG levels led to a 2-3 fold increase in the likelihood of
maintaining mean A1C below 6.5% for 5 years. Moreover, this effect was
observed in all of the subgroups that were examined. Other independent
predictors of maintaining this level of glycemic control were the absence of
diabetes, lower baseline A 1C, and self-reported alcohol use. The significance
of the association of more frequent use of alcohol with better glycemic
responses is unclear. In contrast greater success of therapy associated with
less severe hyperglycemia at baseline is consistent with other reports.
Use of systematically titrated glargine was, as previously reported ( 13),
associated with 1.6 kg gain of weight and increased of risk of hypoglycemia.
However, these unwanted effects of seeking nearly normal glycemic control
were less prominent in ORIGIN than in the trials in which participants had
longer duration of diabetes and more elevated A 1C levels at baseline ( 18,1 9).
For example, the mean gain of weight with the intensive treatment regimen in
the VADT was 8.2 kg (19). Also, the annual incidence of severe
hypoglycemia with intensive treatment in ACCORD was 3.14% (25), whereas
it was 1.00% with basal insulin and 0.31 % with standard therapy in ORIGIN
( 13).
Limitations of the present analysis include the lack of additional information
regarding the effects of the treatments used and glycemic levels attained on
medical outcomes, both desirable and unwanted. Although maintenance of
nearly normal glycemic control for 5 years may be predicted to delay
development of complications of diabetes, the balance of risks to potential
benefits remains to be determined by further analyses and additional followup
of the participants.
In summary, intervention with basal insulin glargine or with standard care at
an early stage of the natural history of dysglycemia maintained median A 1C at
or below the starting level for at least 5 years. Maintaining the mean of yearly
A 1C measurements below 6.5% was more often accomplished when the
initial A 1C was lower and with titrated basal insulin than with standard care.
Legends to Tables of Example 11:
Table 8 : Logistic regression model showing independent (fully adjusted)
associations between selected baseline characteristics, including treatment
assignment, and attainment or maintenance of A1C < 6.5% or <7.0%.
Characteristics were selected by having unadjusted association with p<0.1 .
Attainment refers to the value at 1 year; maintenance refers to having a mean
of yearly measurements including years 1 up to 5 . OR=Odds Ratio;
CI=Confidence Interval.
Appendix Table 1: Clinical characteristics of participants at enrollment, by
randomized treatment groups (insulin glargine or standard therapy) and by
subgroups according to glycemic status (diabetes or not diabetes). Values
are given as percentage, mean (standard deviation), or median (inter-quartile
range) as appropriate.
Appendix Table 2 : Logistic regression model showing unadjusted associations
between baseline characteristics and attainment or maintenance of A1C
<6.5% or 7.0%. Attainment refers to the value at 1 year; maintenance refers
to the mean of yearly measurements including years 1 up to 5 . OR=Odds
Ratio; CI=Confidence Interval.
Appendix Table 3 : Glucose-lowering therapies used before randomized
treatment (A) and at the end of treatment (B) by glycemic status at baseline
and by treatment assignment.
Table 9 : Logistic regression model showing independent (fully adjusted)
associations between selected baseline characteristics, including treatment
assignment, and attainment or maintenance of A1C < 6.5% or <7.0%.
Characteristics were selected by having unadjusted association with p<0.1 .
Attainment refers to the value at 1 year; maintenance refers to having a mean
of yearly measurements including years 1 up to 5 . OR=Odds Ratio;
CI=Confidence Interval.
EXAMPLE 12 : Conclusions
Whether insulin therapy is beneficial, harmful or neutral with respect to
cardiovascular outcomes has been debated for years. The ORIGIN trial was
the first outcomes trial to explicitly test the cardiovascular effect of insulin. It
showed that targeting and achieving normal or near-normal fasting glucose
levels with basal insulin for a period of 5-7 years neither reduces nor
increases serious cardiovascular outcomes compared to achieving guidelinesuggested
glucose levels without insulin. Thus, this intervention either has no
cardiovascular effects or a longer period of observation is required to detect
any effect. This latter possibility is supported by 2 different trials in patients
with type 2 diabetes 10, 1 and 1 trial in patients with type 1 diabetes 19 in which
a cardiovascular benefit that was not apparent at the end of the active
treatment period of 6-1 0 years emerged after an additional 8-1 0 years of
passive follow-up.
ORIGIN also showed that near-normal FPG and A 1C levels can be achieved
and maintained for more than 6 years by adding 1 injection of basal insulin to
0 or 1 oral agents when self-monitored fasting glucose levels are used by
high-risk patients to self-titrate insulin glargine.
It is notable that the intervention reduced the incidence of new diabetes both
using the protocol's definition of diabetes (i.e. based on new cases up to and
including the results of the first oral glucose tolerance test done 1 month after
insulin was stopped), and after all possible cases of diabetes were included in
a sensitivity analysis. This may be due to some preservation of beta cell
function in response to several years of a reduced need to secrete all of the
required insulin, or a direct effect of insulin on the beta cell, and is unlikely to
be due to any masking of hyperglycemia by exogenous glargine insulin as its
mean duration of action is approximately 20 hours 2 .
Participants allocated to insulin glargine experienced more hypoglycemia than
standard care participants; however the absolute risk of severe and
nonsevere hypoglycemia in this population was low (i.e. approximately 0.7
more severe episodes and 11 more suspected or confirmed episodes per 100
person-years). This and the observation that 43% of insulin glargine
participants did not experience even 1 episode over a median of 6.2 years of
followup may have been due to the inclusion of people with relatively recent
dysglycemia; the use of insulin glargine with its long duration of action; the
fact that basal and not prandial insulin was used; and the concomitant use of
metformin in 47% of participants. Nevertheless the risk of hypoglycemia was
approximately 3-fold higher than in standard care participants and insuln
glargine participants experienced a 1.6 kg weight gain. The fact that no
differences in cardiovascular outcomes were noted suggests that these
adverse effects do not increase serious outcomes.
ORIGIN had several strengths. A clear and consistent difference in therapy
was achieved and maintained between treatment groups. Thus, more than
50% of people allocated to insulin glargine titrated the dose sufficiently to
achieve FPG levels below 5.3 mmol/l (95 mg/dl) and 75% of them achieved
FPG levels < 6.0 mmol/l ( 108 mg/dl) for most of the trial. This was in contrast
to standard care participants who used oral agents to manage glycemia and
achieved a final median FPG level of 6.8 mmol/l and A 1C levels consistent
with those recommended in clinical practice guidelines, and who used very
little insulin throughout the trial. The trial duration of more than 6 years, the
high follow-up rates in both groups, the large number of cardiovascular
outcomes (2.9 and 5.4 per 100 person-years for the primary composite and
co-primary expanded composite outcome respectively), and prospective
collection and adjudication of these outcomes ensured that the study had
sufficient power to detect a clinically important short or medium-term
cardiovascular effect of the intervention. Finally, the prospective collection of
data pertaining to nonsevere and severe hypoglycemia, weight gain and
cancers ensured that harms were detected and quantified.
ORIGIN'S findings should reassure clinicians and patients of the overall
cardiovascular safety of basal insulin in general and insulin glargine in
particular in people at high risk for cardiovascular outcomes with early
dysglycemia. Specifically, it does not increase cardiovascular or other serious
long-term health outcomes compared to non-insulin based approaches to
glucose lowering despite more hypoglycemia. The fact that exogenous insulin
did not increase cardiovascular outcomes in this population also alleviates
concerns regarding the cardiovascular effect of providing insulin to individuals
who are likely to be insulin resistant (such as those who participated in
ORIGIN).
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
ABI Ankle-Brachial Index
AE adverse event
AGI alpha glucosidase inhibitor
ALT alanine aminotransferase
anti-GAD Ab anti-glutamic acid decarboxylase antibody
AST aspartate aminotransferase
BG blood glucose
BID twice a day (bis in die)
BMI Body Mass Index
BP blood pressure
CABG coronary artery bypass grafting
CI confidence interval
CV cardiovascular
EAC Event Adjudication Committee
ED erectile dysfunction
EOS end-of-study
EUF end-of-usual-follow-up
FPG fasting plasma glucose
HbA1 c glycosylated hemoglobin A 1c
HDL high-density lipoprotein
HGM home glucose monitoring
HIV human immunodeficiency virus
ICU Intensive Care Unit
IEC Independent Ethics Committee
IFG impaired fasting glucose
IGT impaired glucose tolerance
ITT intention-to-treat
IV intravenous
LDL low-density lipoprotein
LVH left ventricular hypertrophy
MedDRA Medical Dictionary for Regulatory Affairs
MET metformin
MGT meglitinide
Ml myocardial infarction
MSE Mental Status Exam
NGT normal glucose tolerance
n-lgl normalized insulinogenic index
NYHA New York Heart Association
OAD oral antidiabetic drug
OGTT oral glucose tolerance test
omega-3 omega-3 polyunsaturated fatty acids
PUFA
PCI percutaneous intervention
PO per os (orally)
PPG postprandial plasma glucose
PTCA percutaneous transluminal coronary angioplasty
QD once a day (quaque die)
SC subcutaneous
SD standard deviation
SU sulfonylurea
T 1DM type 1 diabetes mellitus
T2DM type 2 diabetes mellitus
TZD Thiazolidinedione
VLDL Very low density lipoprotein
vs versus
UKPDS United Kingdom Prospective Diabetes Study
ULN upper limit of normal
WESDR Wisconsin Epidemiologic Survey of Diabetic Rethinopathy
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diagnosis of diabetes mellitus: abbreviated report of a WHO consultation.
(http://www.who.int/diabetes/publications/diaqnosis diabetes201 1/en/index.ht
)
25. Miller ME, Bonds DE, Gerstein HC, Seaquist ER, Bergenstal RM, Calles-
Escandon J, Childress RD, Craven TE, Cuddihy RM, Gailey G, Feinglos MN,
Ismail-Beigi F, Largay JF, O'Connor PJ, Paul T, Savage PJ, Schubart UK,
Sood A, Genuth S, for the ACCORD investigators. BMJ 201 0:340:b5444
Table 1: Baseline Characteristics
Insulin Glargine Standard
(N=6264) (N=6273)
Mean (SD) Age (yrs) 63.6 (7.8) 63.5 (7.9)
N Females (%) 2082 (33.2) 2304 (36.7)
N Prior CV Event (%) 3711 (59.3) 3666 (58.4)
N Hypertension (%) 4973 (79.5) 4989 (79.5)
N Current Smoking (%) 781 (12.5) 771 (12.3)
N Any Albuminuria (%)* 939 (15.0) 985 (15.7)
N ABI < 0.9 (%) 470 (7.8) 501 (8.3)
Glycemic Characteristics
N Prior DM on oral agent (%) 3748 (59.8) 3692 (58.9)
N Prior DM drug naive (%) 1414 (22.6) 1467 (23.4)
N New DM (%) 365 (5.8) 395 (6.3)
N IGT/I FG (%) 735 (11.7) 717 (11.4)
Mean (SD) Years of Diabetes 5.5 (6. 1) 5.3 (5.9)
Median FPG (IQ ) 6.9 (6.1, 8.2) 6.9 (6.0, 8.2)
Median Ale (IQR) 6.4 (5.8, 7.2) 6.4 (5.8, 7.2)
Glycemic Drugs
N Metformin (%) 1694 (27.0) 1741 (27.8)
N Sulfonylurea (%) 1901 (30.3) 1810 (28.9)
N Other (%) 173 (2.7) 178 (2.8)
N No Drugs (%) 2501 (39.9) 2551 (40.7)
er CV ?/'s Factors
Mean (SD) Systolic BP (mm) 146 (22) 146 (22)
Mean (SD) Diastolic BP (mm) 84 (12) 84 (12)
Mean Weight (SD) 83.3 (16.8) 83. 1 (17.3)
Mean(SD) Body Mass Index 29.8 (5.2) 29.9 (5.3)
Mean (SD) Waist/Hip Men 0.99 (0.09) 0.98 (0.09)
Mean (SD) Waist/Hip Women 0.90 (0.09) 0.90 (0.09)
Mean (SD) Cholesterol 4.9 (1.2) 4.9 (1.2)
Mean (SD) LDL Cholesterol 2.9 (1.0) 2.9 (1.0)
Mean (SD) HDL Cholesterol 1.2 (0.3) 1.2 (0.3)
Median (IQR) Triglyceride 1.6 (1.1, 2.2) 1.6 (1.1, 2.2)
Mean (SD) Creatinine 89.2 (22.0) 88.8 (22. 1)
Mean eGFR 77.5 (20.8) 77. 1 (21.8)
Median (IQR) Urine ACR* 0.57 (0.27, 1.96) 0.57 (0.27, 1.96)
Other Drugs
N Statin (%) 3373 (53.9) 3367 (53.7)
N ACE-I or ARB (%) 4330 (69.2) 4351 (69.4)
N Other BP Drug (%) 4478 (71.5) 4518 (72.0)
N Antiplatelet (%) 4296 (68.6) 4370 (69.7)
Table 2: Insulin Use and Dose and Glycemic Indices during the Trial
Insulin Glargine Group Standard Care Group FPG (mM) Ale (%)
N On Gla rgine Glargine Dose N On Insulin Insulin Dose Insulin Standard Insulin Standard
N (%) (U/kg) N (%) (U/kg) Gla rgine Care Glargine Ca re
Baseline 6264 6264 0 6273 0 0 6.9 (6.1, 8.2) 6.9 (6.0, 8.2) 6.4 (5.8, 7.2) 6.4 (5.8, 7.
Year l 6107 5625 (92.1) 0.28 (0.17, 0.42) 6136 110 (1.8) 0.20 (0.12, 0.35) 5.2 (4.6, 5.9) N/A 5.9 (5.5, 6.4) 6.2 (5.7, 6.
Year 2 5986 5392 (90.1) 0.36 (0.23, 0.52) 6003 208 (3.5) 0.23 (0.14, 0.39) 5.0 (4.4, 5.8) 6.6 (5.7, 7.9) 6.0 (5.5, 6.5) 6.3 (5.8, 6.
Year 3 5818 5186 (89.1) 0.38 (0.25, 0.55) 5855 304 (5.2) 0.23 (0.14, 0.40) 5.0 (4.4, 5.7) N/A 6.0 (5.6, 6.6) 6.4 (5.8, 7.
Year 4 5653 4949 (87.6) 0.39 (0.26, 0.55) 5689 399 (7.0) 0.25 (0.14, 0.40) 5.1 (4.5, 5.8) N/A 6.1 (5.7, 6.7) 6.4 (5.9, 7.
Year 5 5493 4718 (85.9) 0.39 (0.26, 0.57) 5507 494 (9.0) 0.26 (0.15, 0.43) 5.1 (4.5, 6.0) N/A 6.2 (5.7, 6.8) 6.5 (6.0, 7.
Year 6 3927 3281 (83.6) 0.40 (0.27, 0.57) 3924 392 (10.0) 0.26 (0.15, 0.46) 5.2 (4.6, 6.1) N/A 6.3 (5.8, 6.8) 6.5 (6.0, 7.
Year 7 85 1 713 (83.8) 0.41 (0.26, 0.59) 860 99 (11.5) 0.22 (0.14, 0.50) 5.2 (4.5, 6.3) N/A 6.2 (5.8, 7.1) 6.5 (6.0, 7.
All measured values are expressed as medians (interquartile range); weight at the time of the visit was used for calculations; not glargine insu lin
Table 3: Glycemic and Cardiovascular Drugs Used at Study End
Glargine Standard
N N (%) N (%)
Metformin 1 10529 2443 (46.5) 3154 (59.8) <0.001
Sulfonylurea 1 10529 1292 (24.6) 2454 (46.5) <0.001
No Oral Agents1 10529 1844 (35. 1) 1009 (19. 1) <0.001
1 Oral Agents1 10529 2661 (50.6) 2034 (38.6) <0.001
2 Oral Agents1 10529 603 (11.5) 1470 (27.9) <0.001
> 3 Oral Agents1 10529 146 (2.8) 762 (14.4) <0.001
Statin 10246 3180 (62.2) 3097 (60.4) 0.06
ACE-I/ARB 10270 3933 (76.7) 3926 (76.4) 0.71
Antiplatelet 10248 3645 (71.2) 3629 (70.7) 0.55
^ral agents refers t o oral antidiabetic drugs being taken at the penultimate visit (i.e. before
any insulin was changed or stopped)
Table 4 : Episode of Hypoglycemia
Insulin Glargine Standard Care
Severe Hypoglycemia
> 1 Episode (N/100py) 359 (1.00) 113 (0.31) <0.001
Total Episodes Durinng Follow-up 457 134
Confirmed Symptomatic Hypoglycemia
> 1 Confirmed Episode (N/100py) 2612 (9.81) 904 (2.68) <0.001
Mean Number of Episodes/yr 1.3 (2.3) 0.8 (1.2) <0.001
No Confirmed Episodes During follow-up 3652 (58.3) 5369 (85.6) <0.001
Any Symptomatic Hypoglycemia
> 1 Episode (N/100py) 3573 (16.73) 1579 (5. 16) <0.001
Mean Number of Episodes/yr 2.6 (4.1) 1.3 (2.3) <0.001
No Episodes During Follow-up (%) 2691 (43.0) 4694 (74.8) <0.001
py - person-years; requiring assistance that was either confirmed by a self-measured or laboratory plasma
glucose level < 2 mmol/l (36 mg/dl) or that recovered promptly after oral carbohydrate, intravenous glucose, or
glucagon administration; any symptomatic nonsevere hypoglycemic episode that was confirmed by a selfmeasured
glucose level < 3 mmol/l (54 mg/dl); any symptomatic nonsevere hypoglycemic episode for which
there was no confirmatory glucose level.
Table 5: Glargine Adherence
Ever Off Permanently Off
N Randomized 6264 6264
N stopped drug (%) 2671 (42.6) 1060 (16.9)
Reason Stopped
N Hypoglycemia (%) 218 (8.2) 42 (4.0)
NWt Gain (%) 4 (0. 15) 4 (0.4)
N Hyperglycemia (%) 4 (0. 15) 2 (0.2)
N Refusal (%) 1903 (71.3) 884 (83.4)
N Other (%) 542 (20.3) 128 (12.1)
Rows are mutually exclusive. The first time participants went off was used to count the reasons
for "ever off". The last time they were off and stayed off was used to count the reasons for
"permanently off".
Table 6: Microvascular outcomes
HR (95%CI) Glargine Standard
N (%) Rate N (%) Rate
Microvascular 0.90 (0.81, 1.01) 1280 3.7 1327 3.9
Clin Microvasc 0.74 (0.56, 0.98) 190 0.5 222 3.5
Laser/Vitrect 0.59 (0.38,0.91) 79 0.22 90 0.24
Renal Failure 1.27 (0.67, 2.39) 36 0.1 45 0.7
Double Cr 0.70 (0.46, 1.06) 94 0.25 110 0.3
Albumin Prog 0.92 (0.82, 1.04) 1154 3.3 1173 3.4
Table 7 : Cognition outcomes
Glargine Standard
N (%) N (%)
Baseline 483 (7.7) 520 (8.3) 0.232
2 years 433 (7.6) 440 (7.6) 0.823
~ 4 years 449 (9.0) 518 (10.3) 0.022
End of 464 (9.6) 492 (10.2) 0.358
study
Any 605 (10.4) 666 (11.3) 0.075
measure
Table 8
Table 9
Appendix Table 1
Appendix Table 2 : Glucose-lowering therapies at baseline
Oral glucose-lowering therapies used prior to enrollment by glycemic status and
treatment allocation. P-values for differences by treatment allocation are shown.
Appendix Table 3 : Glucose-lowering therapies at end of treatment
Glucose-lowering therapies used at the end of treatment by glycemic status and
treatment allocation. P-values for differences bytreatment allocation are shown.
Claims:
1. A method of reducing the risk of progression to type 2 diabetes in a patient
diagnosed with a disease or condition selected from the group consisting of impaired
fasting glucose (IFG) and impaired glucose tolerance (IGT), comprising
administering to said patient a therapeutically effective dosage of a long acting
insulin, wherein said therapeutically effective dosage of said long acting insulin
reduces the risk of progression to type 2 diabetes in said patient.
2 . A method of reducing the risk of a new angina in a patient diagnosed with a
disease or condition selected from the group consisting of impaired fasting glucose
(IFG), impaired glucose tolerance (IGT), and type 2 diabetes, wherein the patient
diagnosed with type 2 diabetes is either drug na' ve or receives an oral antidiabetic
agent, comprising administering to said patient a therapeutically effective dosage of
a long acting insulin, wherein said therapeutically effective dosage of said long acting
insulin reduces the risk of a new angina.
3 . A method of reducing the risk of a microvascular event in a patient diagnosed with
a disease or condition selected from the group consisting of impaired fasting glucose
(IFG), impaired glucose tolerance (IGT), and type 2 diabetes, wherein the patient
diagnosed with type 2 diabetes is either drug na'fve or receives an oral antidiabetic
agent, comprising administering to said patient a therapeutically effective dosage of
a long acting insulin, wherein said therapeutically effective dosage of said long acting
insulin reduces the risk of a microvascular event.
4 . A method for preventing the progression to type 2 diabetes in a patient diagnosed
with a disease or condition selected from the group consisting of impaired fasting
glucose (IFG) and impaired glucose tolerance (IGT), comprising administering to
said patient a therapeutically effective dosage of a long acting insulin, wherein said
therapeutically effective dosage of said long acting insulin reduces the risk of
progression to type 2 diabetes in said patient.
5 . A method for preventing a new angina in a patient diagnosed with a disease or
condition selected from the group consisting of impaired fasting glucose (IFG),
impaired glucose tolerance (IGT), and type 2 diabetes, wherein the patient
diagnosed with type 2 diabetes is either drug na' ve or receives an oral antidiabetic
agent, comprising administering to said patient a therapeutically effective dosage of
a long acting insulin, wherein said therapeutically effective dosage of said long acting
insulin reduces the risk of a new angina.
6 . A method for preventing a microvascular event in a patient diagnosed with a
disease or condition selected from the group consisting of impaired fasting glucose
(IFG), impaired glucose tolerance (IGT), and type 2 diabetes, wherein the patient
diagnosed with type 2 diabetes is either drug na'fve or receives an oral antidiabetic
agent, comprising administering to said patient a therapeutically effective dosage of
a long acting insulin, wherein said therapeutically effective dosage of said long acting
insulin prevents a microvascular event.
7 . A method delaying the progression to type 2 diabetes in a patient diagnosed with
a disease or condition selected from the group consisting of impaired fasting glucose
(IFG) and impaired glucose tolerance (IGT), comprising administering to said patient
a therapeutically effective dosage of a long acting insulin, wherein said
therapeutically effective dosage of said long acting insulin delays the progression to
type 2 diabetes in said patient.
8 . A method according to any of claims 3 and 6, wherein the microvascular event is a
clinical microvascular event.
9 . A method according to claim 8, wherein the microvascular event is selected from a
group comprising neuropathy, retinopathy and nephropathy.
10 . A method according to claim 9, wherein the nephropathy is characterized by
renal failure, end-stage renal disease, or renal death.
11. A method for reducing the risk for requiring treatment by laser surgery or
vitrectomy in a patient diagnosed with a disease or condition selected from the group
consisting of impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and
type 2 diabetes, wherein the patient diagnosed with type 2 diabetes is either drug
na'fve or receives an oral antidiabetic agent, comprising administering to said patient
a therapeutically effective dosage of a long acting insulin, wherein said
therapeutically effective dosage of said long acting reduces the risk for requiring
treatment by laser surgery or vitrectomy in said patient.
12 . A method for reducing doubling of baseline serum creatinine in a patient
diagnosed with a disease or condition selected from the group consisting of impaired
fasting glucose (IFG), impaired glucose tolerance (IGT), and type 2 diabetes,
wherein the patient diagnosed with type 2 diabetes is either drug na' ve or receives
an oral antidiabetic agent, comprising administering to said patient a therapeutically
effective dosage of a long acting insulin, wherein said therapeutically effective
dosage of said long acting insulin reduces doubling of baseline serum creatinine in
said patient.
13 . A method for reducing the risk of cognitive impairment in a patient diagnosed
with a disease or condition selected from the group consisting of impaired fasting
glucose (IFG), impaired glucose tolerance (IGT), and type 2 diabetes, wherein the
patient diagnosed with type 2 diabetes is either drug na'fve or receives an oral
antidiabetic agent, comprising administering to said patient a therapeutically effective
dosage of a long acting insulin, wherein said therapeutically effective dosage of said
long acting insulin reduces the risk of cognitive impairment in said patient.
14. A method according to claim 13, wherein the patient scores 24 or less in the
Mini-Mental Status Exam (MMSE).
15 . A method for lowering the triglyceride concentration in the blood in a patient
diagnosed with a disease or condition selected from the group consisting of impaired
fasting glucose (IFG), impaired glucose tolerance (IGT), and type 2 diabetes,
wherein the patient diagnosed with type 2 diabetes is either drug na'fve or receives
an oral antidiabetic agent, comprising administering to said patient a therapeutically
effective dosage of a long acting insulin, wherein said therapeutically effective
dosage of said long acting insulin lowers the triglyceride concentration in the blood in
said patient.
16 . A method for lowering the cholesterol concentration in the blood in a patient
diagnosed with a disease or condition selected from the group consisting of impaired
fasting glucose (IFG), impaired glucose tolerance (IGT), and type 2 diabetes,
wherein the patient diagnosed with type 2 diabetes is either drug na' ve or receives
an oral antidiabetic agent, comprising administering to said patient a therapeutically
effective dosage of a long acting insulin, wherein said therapeutically effective
dosage of said long acting insulin lowers the cholesterol concentration in the blood in
said patient.
17 . A method according to any of claims 3 and 6, wherein the patient has a HbA1 c >
6.4 prior to administering the long-acting insulin.
18 . A method according to any of claims 3 and 6, wherein the patient had a history of
atrial fibrillation prior to administering the long-acting insulin.
19 . A method according to claim 18, wherein the microvascular outcome is a clinical
microvascular outcome.
20. A method according to claim 18, wherein the microvascular outcome is a
laboratory-based microvascular outcome.
2 1. A method according to claim 18, wherein the microvascular outcome is a
composite of: laser surgery or vitrectomy or blindness for diabetic retinopathy;
development of renal death or the need for renal replacement treatment (dialysis or
transplantation); doubling of serum creatinine; or progression from lesser to greater
severity of microalbuminuria.
22. A method according to any of the foregoing claims, wherein the long-acting
insulin is selected from a group comprising insulin glargine, insulin detemir and
insulin degludec.
23. A method according to any of the foregoing claims, wherein the long-acting
insulin is insulin glargine.
24. An article of manufacture comprising
- a packaging material;
- a long-acting insulin; and
- a label or package insert contained within the packaging material indicating that
patients receiving the treatment with the long-acting insulin can be treated by a
method according to any of claims 1 - 23.
25. An article of manufacture comprising
- a packaging material;
- insulin glargine; and
- a label or package insert contained within the packaging material indicating that
patients receiving the treatment with the long-acting insulin can be treated by a
method according to any of claims 1 - 23, wherein in such treatment the risk for
cardiovascular outcomes, all-cause mortality or cancer is not altered when compared
to standard glucose lowering therapy.
26. An article of manufacture according to claim 25, wherein the risk for cancer is not
altered when compared to standard glucose lowering therapy with regard to any
organ-specific type of cancer.
27. An article of manufacture according to any of claims 24 to 26, wherein the longacting
insulin is selected from a group comprising insulin glargine, insulin detemir
and insulin degludec.
28. An article of manufacture according to any of claims 24 to 26, wherein the longacting
insulin is insulin glargine.