U.S. patent application number 13/152932 was filed with the patent office on 2011-11-17 for method for reducing cardiovascular morbidity and mortality in prediabetic patients and patients with type 2 diabetes.
This patent application is currently assigned to AVENTIS PHARMACEUTICALS INC.. Invention is credited to Hertzel Gerstein, Ralf Rosskamp.
Application Number | 20110281793 13/152932 |
Document ID | / |
Family ID | 23746761 |
Filed Date | 2011-11-17 |
United States Patent
Application |
20110281793 |
Kind Code |
A1 |
Rosskamp; Ralf ; et
al. |
November 17, 2011 |
Method For Reducing Cardiovascular Morbidity And Mortality In
Prediabetic Patients And Patients With Type 2 Diabetes
Abstract
This invention relates to a method of reducing cardiovascular
morbidity and mortality in a prediabetic or Type 2 Diabetes patient
population. The method comprises administering an effective dosage
of a long acting insulin, preferably insulin glargine, to a
prediabetic or Type 2 Diabetes patient.
Inventors: |
Rosskamp; Ralf; (Gladstone,
NJ) ; Gerstein; Hertzel; (Hamilton, CA) |
Assignee: |
AVENTIS PHARMACEUTICALS
INC.
Bridgewater
NJ
|
Family ID: |
23746761 |
Appl. No.: |
13/152932 |
Filed: |
June 3, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12140598 |
Jun 17, 2008 |
7977310 |
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13152932 |
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10757201 |
Jan 14, 2004 |
7405196 |
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12140598 |
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60439941 |
Jan 14, 2003 |
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Current U.S.
Class: |
514/5.9 |
Current CPC
Class: |
A61P 3/08 20180101; A61K
38/28 20130101; A61P 9/00 20180101; A61P 3/10 20180101; A61P 3/00
20180101; A61P 3/06 20180101; A61P 9/10 20180101 |
Class at
Publication: |
514/5.9 |
International
Class: |
A61K 38/28 20060101
A61K038/28; A61P 3/10 20060101 A61P003/10 |
Claims
1. A method of preventing an increase in carotid intimal thickness
in a patient diagnosed with a disease or condition selected from
the group of impaired fasting glucose (IFG), impaired glucose
tolerance (IGT), early Type 2 diabetes, and Type 2 diabetes,
comprising administering to said patient a therapeutically
effective dosage of a long acting insulin.
2. The method according to claim 1 wherein the long acting insulin
is insulin glargine.
3. The method according to claim 2 wherein the effective dosage is
in the range of about 2 to about 150 IU per day.
4. The method according to claim 3 wherein the effective dosage is
in the range of about 2 to about 80 IU per day.
5. The method according to claim 4 wherein the effective dosage is
in the range of about 2 to about 40 IU per day.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 12/140,598, filed Jun. 17, 2008, which is a division of U.S.
application Ser. No. 10/757,201, filed Jan. 14, 2004, now allowed,
which claims the benefit of U.S. Provisional Application No.
60/439,941, filed Jan. 14, 2003, both of which are incorporated
herein by reference in their entirety.
FIELD OF INVENTION
[0002] This invention relates to a method of reducing
cardiovascular morbidity and mortality in a prediabetic or Type 2
Diabetes patient population.
BACKGROUND OF THE INVENTION
Diabetes Mellitus and Cardiovascular Disease
[0003] Patients with type 2 diabetes mellitus (DM) have an
increased risk of atherosclerotic disease, including coronary heart
disease, cardiovascular disease, and peripheral vascular disease.
Diabetes itself.sup.1 and not just the associated risk factors of
dyslipidemia, hypertension, and obesity contributes a major portion
of this risk. In particular, the level of hyperglycemia may play a
key role. While the relationship of increased blood glucose to
microvascular complications is well-recognized.sup.7-9, its
relation to atherogenesis was, until recently, less well
documented. A prospective, population-based study in middle-aged
and elderly patients in Finland with type 2 DM has shown a linear
correlation between baseline fasting blood glucose (FBG), or
HbA.sub.1c, and coronary heart disease mortality.sup.10. In the
WESDR database, subjects 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,
with a hazard ratio of 1.10 to 1.28 for various types of
events.sup.11. The Islington Diabetes Survey found a linear
association between 2-hour postprandial glucose or HbA.sub.1c and
coronary heart disease, with the stronger association with the
2-hour glucose test.sup.12. In the San Antonio Heart Study, the
level of hyperglycemia was a strong, independent predictor of
all-cause and cardiovascular mortality.sup.13.
[0004] A growing body of evidence indicates that the increased risk
for macrovascular complications associated with type 2 DM extends
to patients with glucose abnormalities that do not meet the
criteria for frank diabetes. The Hoorn study found an increased
risk of all-cause and cardiovascular mortality with higher 2-hour
post-load glucose values and increasing HbA.sub.1c in a
non-diabetic general population of men and women.sup.15. In the
EPIC study, an increase of 1% in HbA.sub.1c was associated with a
28% increase in risk of death and an increase of approximately 40%
in cardiovascular or coronary heart disease mortality in a cohort
of 4,662 men.sup.4. Although diabetic subjects were included in
this trial, and diabetes was found to be an independent predictor
of cardiovascular risk when evaluated separately from HbA.sub.1c
(another independent predictor), only HbA.sub.1c and not diabetes
predicted CV death when both were included in the same analysis,
further strengthening 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.sup.16.
[0005] In a study from Oslo.sup.17, non-diabetic men aged 40-59
years had a significantly higher cardiovascular mortality rate if
their FPG was >85 mg/dL. 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.sup.18. 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.sup.3. Likewise, in the 23-year Paris Prospective Study.sup.19
of 7,018 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.
[0006] The American Diabetes Association (ADA) has recognized an
intermediate category of IFG, defined as a fasting plasma glucose
of 6.1-6.9 mmol/L, (110-125 mg/dL).sup.6, as well as the older
category of IGT, defined as a 2-hour glucose level of 7.8-11.1
mmol/L (140-199 mg/dL) after a 75 gram oral glucose load, with FPG
levels below 7.0 mmol/L. The European Diabetes Epidemiology Group,
based on a meta-analysis of 10 prospective European cohort studies,
found that IGT was associated with survival curves intermediate
between those of non-diabetic and diabetic subjects, while IFG
curves were similar to those of normoglycemic subjects. A direct
comparison revealed that IFG had a higher specificity (79%) for
predicting cardiovascular disease than IGT (57%), but IGT was a
more sensitive (54%) predictor than IFG (28%) in predicting
incident cardiovascular disease.sup.20.
[0007] In summary, the data cited above demonstrate that people
with IFG and IGT (collectively referred to as "prediabetes") have
an excess risk of development of overt type 2 diabetes, coronary
heart disease, cerebrovascular disease, and peripheral vascular
disease compared to a population with normal fasting and 2-hour
postprandial glucose levels. Further, a continuum of increasing
risk appears to exist, as opposed to a threshold level of
hyperglycemia below which no increased risk prevails.sup.2-4. IGT
and IFG subjects are currently unlikely to receive glucose-lowering
treatment with existing pharmacotherapies. Their under-treated
dysglycemia represents a large unmet medical need, and a large
public health issue.
[0008] A number of large intervention studies have been conducted
over the last two decades in both type 1 and type 2 diabetic
patients. The primary aim of these trials was to evaluate the
impact of improved metabolic control on microvascular endpoints and
the studies were designed and sized accordingly.
[0009] Macrovascular outcomes were included in these trials as
secondary endpoints and although the treatment differences seen
were not statistically significant, trends were evident in each
trial of an association between intensified glycemic control and
reduced cardiovascular mortality and morbidity.
[0010] The two principal intervention trials in recent years were
the Diabetes Control and Complications Trial (DCCT) in type 1
diabetic patients.sup.7 and the United Kingdom Prospective Diabetes
Study (UKPDS) in type 2 DM.sup.14. In the DCCT, cardiovascular
events decreased by 41% in the intensively-treated group, but this
difference was not statistically significant. In the UKPDS, which
compared the effects of intensive management to the effects of
standard care on micro- and macrovascular complications in 3,642
type 2 diabetic subjects followed for a median of 10.4 years, a
significant decrease in microvascular complications was observed in
the intensive treatment group, which achieved a significantly lower
median HbA.sub.1c of 7.0% compared to the standard group (median
HbA.sub.1c 7.9%). Although strongly suggestive, the intervention
data from this study failed to show a statistically significant
decrease in the endpoint of myocardial infarction, which decreased
by 16% with the 0.9% decrease in HbA.sub.1c (p=0.052). However,
epidemiologic analysis of the UKPDS database.sup.2 revealed that a
single percent point decrease in HbA.sub.1c was associated with a
25% reduction in diabetes-related death, a 7% reduction in
all-cause mortality, and an 18% reduction in fatal and nonfatal MI.
Similar reductions in the risk for stroke, amputation and
congestive heart failure were seen with decreasing HbA.sub.1c.
These associations of HbA.sub.1c with cardiovascular risk were
without threshold, i.e. they occurred across the entire study
population.
[0011] In the 8-year Kumamoto study.sup.3 of intensive
multiple-dose insulin treatment of type 2 diabetic patients, half
as many serious macrovascular events (MI, angina, stroke,
claudication, gangrene, or amputation) occurred in the intensive
treatment arm as in the conventional treatment arm. This reduction
was not statistically significant, in all likelihood because of the
small size of the trial (n=110): Several large prospective trials,
including the ACCORD trial (NHLBI) and the VA diabetes trial, are
now ongoing or planned to specifically and primarily evaluate the
hypothesis that treatment of diabetes in patients with
cardiovascular risk factors will reduce cardiovascular morbidity
and mortality.
[0012] Recent intervention studies in IGT have focused on the
reduction of rates of progression to type 2 diabetes. Lifestyle
interventions (primarily institution of diet and exercise plans)
have led to striking reductions in progression from IGT to diabetes
in both the recently-completed NIH-sponsored DPP in North America
and the Finnish DPS lifestyle study. Each trial was terminated
early after independently demonstrating a 58% reduction versus
controls in development of new cases of type 2 DM from IGT in the
lifestyle intervention arm.sup.21,33. Lifestyle changes were
pursued aggressively in both studies, and whether such
interventions can be maintained indefinitely is an open
question.
[0013] Pharmacotherapies have also been tested in delaying the
development of type 2 DM: [0014] Metformin treatment of IGT in the
DPP study was associated with a statistically significant 31%
reduction in the rate of progression to type 2 DM..sup.21 [0015]
Acarbose in the STOP-NIDDM trial reduced the progression from IGT
to type 2 DM from 41.8% in the placebo arm to 32.8% over 3.6 years'
median duration of treatment (p<0.05) as well as reducing the
risk of CV events by 49%..sup.40 [0016] Troglitazone in the halted
TRIPOD study; 12.3% of placebo-treated subjects versus 5.4% of
troglitazone-treated subjects with prior gestational diabetes
developed type 2 DM over a mean of 30 months of treatment
(p<0.05)..sup.45
[0017] With the exception of the STOP-NIDDM study, cardiovascular
risk reduction data from these recent diabetes prevention studies
are all pending publication. At present the only other data
available on CV risk reduction in the IGT/IFG population from
treatment with pharmacologic antihyperglycemic agents come from a
small Swedish study conducted in the 1960s which demonstrated a
reduction in CV events in IGT subjects with the use of
tolbutamide.sup.22,23. Clearly new therapies for glucose lowering
must be tested for their effects on serious cardiovascular outcomes
in this population.
[0018] Recent evidence has provided support for a beneficial effect
of insulin treatment in improving cardiovascular outcomes in
patients with diabetes. The DIGAMI study.sup.24, in which diabetic
patients hospitalized with acute MI were allocated to receive an IV
insulin-glucose infusion in-hospital followed by intensive chronic
outpatient treatment with insulin, versus standard treatment,
showed a significant 28% reduction of all-cause mortality in the
patients who received intensive insulin treatment. 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 subjects significant survival differences were even seen
pre-discharge, while still in hospital post-MI, and enhanced
survival in the same cohort was also seen in long-term
follow-up.
[0019] Part of the benefits of insulin treatment was likely due to
improved long-term glycemia post-MI, but the in-hospital results
suggest that other, more acute, effects of insulin besides
long-term glycemic control may have played a role, such as improved
platelet function, decreased PAI-I 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.
[0020] A recent study from Belgium.sup.25 reinforces the beneficial
role of insulin treatment of critically-ill subjects. In this
trial, critical-care post-surgical patients with random blood
glucose values greater than 110 mg/dL were treated while in ICU
either with an insulin infusion to lower blood glucose to the
80-110 mg/dL range (intervention); or to receive insulin infusions
only if blood glucose exceeded 215 mg/dL, with the aim of infusion
to reduce blood glucose to between 180 and 200 mg/dL (control).
Twelve-month follow-up showed significantly different reductions of
8.0% and 4.6% in overall mortality in the intervention and control
groups respectively, and most of the benefit was attributable to
the cohort of subjects who were in 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.
[0021] The use of exogenous insulin in a IGT, IFG, or diabetic
population should confer several potential metabolic and
cardiovascular benefits associated with insulin treatment: [0022]
1. A powerful effect to delay the exposure of target tissues to
toxic levels of glycemia that is finely titratable and durable,
compared to oral antidiabetic agents. [0023] 2. Suppression of
circulating free fatty acids (FFA) with: [0024] Reduced VLDL
synthesis and improved lipoprotein patterns (lower triglycerides,
increased HDL-C) [0025] Reduced lipotoxicity at the level of the
beta cell and on insulin's target tissues [0026] Reduced obligatory
oxidative metabolism in ischemic myocardium [0027] 3. Prevention of
metabolic decompensation (including both glucose and FFA) due to
stress, both mild and frequent (daily stresses and minor illness or
injury) and severe and less common (major injury, illness, surgery,
vascular events). These stress events will suppress endogenous
insulin responses even when a pharmacologic secretagogue or
sensitizer is present, but exogenous, injected insulin cannot be so
suppressed. [0028] 4. In addition, recent work has demonstrated
direct associations between insulin treatment and enhanced nitric
oxide-mediated vasodilatation, which is impaired in
insulin-resistant states such as IGT, IFG and diabetes.sup.26,27.
Moreover, reductions in the endothelial dysfunction.sup.28 and
inflammation.sup.29 that are characteristic of both diabetes and
atherosclerosis have been demonstrated following insulin
treatment.
[0029] Whereas insulin therapy is undoubtedly efficacious in
reducing blood glucose concentrations and, as noted above, may
hypothetically improve survival in individuals with dysglycemia,
outcome studies using insulin in this population have not been done
to date. Several reasons may account for this including a) the need
for insulin to be injected as opposed to be taken orally; b)
concerns regarding the side effect of hypoglycemia; (low blood
glucose) c) epidemiologic evidence linking high serum insulin
levels to macrovascular disease; d) the very recent recognition
that glucose is a risk factor for cardiovascular outcomes across
the range from normal through all stages of diabetes; e) lack of
predictability in the action of long-acting insulins; and f) lack
of experience in achieving near-normal glucose levels with insulin
preparations available to date.
[0030] Many of these issues are, however, not relevant today.
First, it is now widely recognized that the epidemiologic
relationship between hyperinsulinemia and macrovascular disease is
extremely unlikely to imply a cause-effect relationship. This is
based on randomized controlled trial evidence from both the DCCT
and the UKPDS trials that individuals who were given exogenous
insulin in an effort to reduce the risk of microvascular disease
had a trend towards fewer, not more, adverse cardiovascular
outcomes. This conclusion is supported by other studies discussed
above, including the DIGAMI study, the Kumamoto study, a
meta-analysis of studies of intensified insulin therapy in type 1
diabetes, and several other analyses. It therefore appears that
hyperinsulinemia as a result of exogenous administration of insulin
is not a cardiovascular risk factor. Second, the potential of
intensified insulin therapy has achieved new attention in light of
the UKPDS and the potential benefits of tight glycemic control in
people with type 2 diabetes. Third, the simplicity of glucose
monitoring devices and the decreasing costs of home glucose
monitoring, as well as the negligible discomfort associated with
today's injection devices available today, have made injections and
blood glucose monitoring more accessible and easier for patients to
accomplish. Fourth, there is growing recognition of the importance
of metabolic abnormalities as a cause of cardiovascular disease.
Finally, there are new long acting analog insulins having
properties such as a longer duration of action (up to 24 hours) and
a smoother profile, with a less defined peak of action which make
them viable treatment agents in the IGT, IFG early Type 2 diabetes
populations.
[0031] Lantus.RTM. LANTUS (insulin glargine) is a recombinant human
insulin analog that is a long-acting (up to 24-hour duration of
action), parenteral blood-glucose lowering agent..sup.39 The
post-marketing surveillance safety database experience reveals no
increased incidence of hypoglycemia or unexpected adverse reactions
compared to other marketed insulin preparations. In a multiple-dose
pharmacokinetic study, Lantus.RTM. LANTUS (insulin glargine) levels
were shown to reach steady-state after 2 doses (2 days) of
treatment (Study 1020). Treatment with Lantus.RTM. LANTUS (insulin
glargine) insulin offers the possibility of a smooth, daylong,
blood insulin profile without a definite peak that can be finely
titrated to lower subjects' FPG in a durable manner, while
minimizing the risk of hypoglycemia at other times of day.
[0032] However, a central question concerns the administration of
insulin to nondiabetic or early diabetic subjects and the
propensity for hypoglycemia this may confer. Insulin has
traditionally been reserved for treatment of more severe
hyperglycemia, in established type 1, or advanced type 2, diabetes.
In these patients the risk of hypoglycemia is greater the closer
the achieved blood glucose is to normal..sup.42
[0033] For type 2 diabetic patients, as well as individuals with
prediabetes, medical management begins with diet restriction and
exercise as tolerated.sup.30,31. Even if pharmacotherapy in the
form of oral antidiabetic drugs or insulin is needed later, diet
and exercise are always the cornerstone of disease management. No
drugs are currently approved for the treatment of prediabetes, but
most of these individuals are overweight or obese, and successful
lifestyle intervention has been shown to improve blood glucose
levels and even delay progression to diabetes.sup.32,33. Exercise
increases blood glucose uptake in muscle, and leads to a reduction
in endogenous insulin output, as little insulin is needed to
provide fuel to these tissues during exercise..sup.34 Exogenous,
pharmacologically-provided insulin present in the circulation
cannot be so modulated, and its presence can predispose to
hypoglycemia.
[0034] Exercise-induced hypoglycemia in insulin-treated diabetes
patients is well-described.sup.35,41, and is often dealt with in
practice by reducing the mealtime insulin dose, or giving oral
calories, prior to an exercise session..sup.36,37 These methods are
cumbersome, and hypoglycemia is still a risk following exercise.
The insulin dose that is most frequently modulated in response to
upcoming exercise is the short-acting insulin given before the
preceding meal, because these insulins have prominent peaks in
their actions, used to target the blood glucose rise that occurs
following a meal, but they place patients at increased risk for
hypoglycemia if there is a mismatch between insulin availability
and calories absorbed. Thus hypoglycemia is a risk for all
insulin-treated individuals, and this risk is enhanced when these
individuals exercise, and the closer to normoglycemia they are
treated.
[0035] The ideal basal insulin might be expected to be less
worrisome from this standpoint because the circulating insulin
produced would target blood glucose elevations throughout the day
rather than mealtime fluctuations. It would not demonstrate notable
peaks in plasma level, and in consequence the tendency to produce
hypoglycemia would be less than with peaked insulins. The
"Treat-to-Target" study.sup.38 in US/Canada type 2 diabetic
patients investigated whether a single bedtime dose of Lantus.RTM.
LANTUS (insulin glargine) vs. NPH insulin (a moderate- to
long-acting insulin with a pronounced peak in plasma activity for 4
to 8 hours after injection).sup.39 would achieve target metabolic
control without increasing nocturnal hypoglycemia. The trial was
successful in demonstrating both its primary objective (more
Lantus.RTM. LANTUS (insulin glargine)-treated patients than
NPH-treated patients reaching target HbA1c [<=7%] without
nocturnal hypoglycemia), but also showed significant reductions in
nocturnal hypoglycemia vs. NPH in all patients.
[0036] If peaked insulins pose a danger for hypoglycemia in
advanced type 2 diabetes, they certainly do in milder forms of
diabetes, and in prediabetes, where the blood glucose
concentrations are only modestly elevated, especially in relation
to exercise. Treatment with an insulin with notable peak effects
runs a great risk of producing low blood glucose levels that will
be bothersome and dangerous to people with these conditions. There
exists an unmet medical need to provide insulin treatment to
individuals with milder glucose intolerance who are at high risk
for CV disease. Cardiovascular disease in subjects with IGT, IFG,
and early diabetes is prevalent and life-threatening. Advances have
been made in recent years in treating the associated cardiovascular
risk factors of hypertension and hyperlipidemia. Depended upon the
results of the morbidity/mortality study association between blood
glucose elevations and cardiovascular risk in these subjects is
likewise continuous and progressive, treatment of this dysglycemia
becomes urgent.
[0037] Insulin treatment has been demonstrated to reduce CV
morbidity and mortality in a population with more advanced
diabetes, and offers this prediabetic population the possibility of
reducing cardiovascular risk through effective reductions in blood
glucose and free fatty acid levels, and in the associated tissue
damage resulting from their chronic elevations. The availability of
Lantus.RTM. insulin LANTUS (insulin glargine) creates the
possibility of treating subjects with widely-varying degrees of
dysglycemia with the effectiveness of insulin over a 24 hour period
while minimizing the risk of hypoglycemia (especially hypoglycemia
seen in association with exercise) inherent in earlier insulin
preparations with more distinct peak effects.
[0038] Diabetic dyslipidemia (DDL) in type 2 diabetes is another
condition where there exists an unmet medical need. DDL is
characterized by fasting hypertriglyceridemia, low HDL cholesterol
(HDL-C), small dense (atherogenic) LDL particles, and elevated free
fatty acid (FFA) concentrations. Whereas lipid disorders associated
with type 1 diabetes (hypertriglyceridemia with low LDL) are
simpler in etiology, and relate to insulin deficiency which, when
replaced, normalizes the plasma lipid profile, the pathophysiology
of lipid disturbances in type 2 diabetes is more complex, being
partly related to concomitant obesity and insulin resistance. Key
factors in the development of lipid abnormalities in type 2
diabetes include: [0039] Failure of suppression of
hormone-sensitive lipase in adipose tissue, which leads to
increased lipolysis and increased supply of FFA from the adipocyte
for, among other things, VLDL-triglyceride (TG) synthesis by the
liver [0040] Reduced catabolism of TG-rich particles (such as
VLDL), and reduced transfer of surface components of those
particles to HDL, partly accounting for the low HDL-C levels seen
in DDL. [0041] Accelerated transfer of cholesterol from HDL to
other lipoproteins, also contributing to low HDL-C [0042] Reduced
clearance of chylomicrons and more atherogenic chylomicron
remnants, as well as reduced clearance of other remnant particles
(intermediate-density lipoproteins or IDL) [0043] Decreased
activity of lipoprotein lipase (LPL) and hepatic TG lipase (HTGL)
which break TG down into FFA for fuel in muscle and fat cells.
[0044] Overproduction of VLDL by the liver, exacerbated by
elevations in glucose and FFA
[0045] Although the lipid abnormalities of type 2 diabetes are more
resistant to normalization with antidiabetic treatment, even when
that treatment is successful, increased insulinization has been
shown to improve most of the defects above, namely, improved lipase
activity with reduced lipolysis; increased clearance of
chylomicrons; reduced production of VLDL from the liver, both
through reduction of FFA substrate and by independent mechanisms;
and increases in HDL, generally seen in association with increased
LPL activity.
[0046] The treatment initially recommended for type 2 diabetes, and
reinforced as the cornerstone of management even after
pharmacologic treatment is initiated, is diet control and regular
exercise. When these lifestyle measures are no longer successful
alone in controlling blood glucose levels, pharmacologic treatment
is begun, traditionally using oral antidiabetic drugs alone and in
combination. Whereas there is no a priori reason why insulin cannot
be used to manage mildly diabetic patients, it is usually reserved
for late-stage diabetes management because: [0047] Insulin must be
given by injection and many patients find injections objectionable
[0048] Insulin and injections have acquired the stigma of
late-stage management--"if I'm taking insulin my diabetes must be
very severe"--and to forestall insulin is a way of saying "my
diabetes isn't so bad yet"
[0049] In fact insulin injections have become almost painless in
recent years due to improved delivery systems. The "late-stage"
stigma is based on tradition and former practice more than any real
reason why insulin should be reserved for the end game of
diabetes.
[0050] The one valid reason for not using insulin in patients as
first pharmacotherapy is a concern over the one principal side
effect of insulin--low blood glucose, or hypoglycemia. This is an
important concern in using insulin to treat early type 2 diabetes
primarily because most available insulins have a peak in their
plasma activity at a certain time following injection. It is at
these times of peak activity that the insulin-treated patient with
diabetes is most vulnerable to hypoglycemia, and diets and exercise
patterns must often be tailored around the prescribed insulin
regimen to avoid hypoglycemia. This risk is greater the closer
patients' blood glucose levels come to normal--and yet
normoglycemia is the goal of diabetes management.
[0051] There is evidence that the scientific community is taking
the abnormalities of DDL more seriously than it has in the past in
terms of the risk they pose for atherogenesis. The Adult Treatment
Panel of the NCEP on the "detection, evaluation, and treatment of
cholesterol disorders in adults" authored an update of the ATP II
summary in the Fall of 2002. The ATP III took hypertriglyceridemia
more seriously than the predecessor ATP II Committee had as a
marker for increased CV risk. The ATP III acknowledged that more
recent studies, and additional analyses of older studies, have
shown elevated TGs to be an independent risk factor for CHD,
whereas in the past the association between TG and CHD was not
independent from other confounding risk factors such as LDL and HDL
abnormalities. ATP III reduced the TG concentration threshold for
each degree of abnormality (normal, borderline, high, and very
high) from their ATP-II levels, and offered VLDL cholesterol, and
serum TG, as markers for atherogenic remnant lipoproteins, which
the committee identified as a target for intervention as well as
LDL-C. The committee formalized the concept of "non-HDL
cholesterol" (non-HDL-C) as a target for therapy in persons with
hypertriglyceridemia, perhaps more relevant than LDL-C alone in
these individuals. Non-HDL-C was seen as an acceptable surrogate
for apo-B in routine clinical practice.
[0052] ATP III pointed out that when fasting TG are less than 200
mg/dl, VLDL-C is not markedly elevated, and non-HDL-C correlates
very well with LDL-C. As TG rises above 200 mg/dL, the relation
between LDL-C and non-HDL-C is looser, and LDL-C alone
"inadequately describes the CV risk associated with atherogenic
lipoproteins." When fasting TG exceed 500 m/dL, much of the
cholesterol resides in nonatherogenic forms of TG-rich
lipoproteins, and non-HDL-C becomes "less reliable as a predictor
of CHD risk." On the other hand, the risk of markedly elevated TG
(>500 mg/dL) for pancreatitis has long been recognized, even by
FDA, and here too the ability of insulin to reduce these elevations
may exceed what other OADs can deliver. Thus there are two
categories of elevations in fasting TG that may be amenable to
insulin treatment, and for which insulin may be superior to OADs.
One is elevations in the 500-1000 mg/dL range, for which
hypertriglyceridemia alone is the target, being a surrogate for
reduction in risk for pancreatitis. The other is elevations in the
200-500 mg/dL range, for which hypertriglyceridemia is one of a
host of biomarkers associated with CHD risk; non-HDL-C, HDL-C, and
remnant lipoproteins being other, perhaps more important endpoints
in this regard.
SUMMARY OF THE INVENTION
[0053] The present invention provides a method of treating IGT in a
patient comprising administering an effective dosage of a long
acting insulin.
[0054] The present invention also provides a method of treating IFG
in a patient comprising administering an effective dosage of a long
acting insulin.
[0055] The present invention also provides a method of treating
Type 2 diabetes, particularly early Type 2 diabetes, in a patient
comprising administering an effective dosage of a long acting
insulin.
[0056] The present invention also provides a method of treating
diabetic dyslipidemia in a Type 2 diabetes patient comprising
administering an effective dosage of a long acting
[0057] The present invention also provides a method of treating
atherosclerosis in a patient with a disease or condition selected
from the group of IFG, IGT or Type 2 diabetes, particularly early
Type 2 diabetes, comprising administering an effective dosage of a
long acting insulin.
[0058] The present invention also provides a method of improving
endothelial function in a patient diagnosed with a disease or
condition selected from the group of IFG, IGT or Type 2 diabetes,
particularly early Type 2 diabetes, comprising administering an
effective dosage of a long acting insulin.
[0059] The present invention also provides a method of preventing
an increase in left ventricular mass in a patient diagnosed with a
disease or condition selected from the group of IFG, IGT or Type 2
diabetes, particularly early Type 2 diabetes, comprising
administering an effective dosage of a long acting insulin.
[0060] The present invention also provides a method of improving
left ventricular diastolic and systolic function in a patient
diagnosed with a disease or condition selected from the group of
IFG, IGT or Type 2 diabetes, particularly early Type 2 diabetes,
comprising administering an effective dosage of a long acting
insulin.
[0061] The present invention also provides a method of preventing
an increase in carotid intimal thickness in a patient diagnosed
with a disease or condition selected from the group of IFG, IGT or
Type 2 diabetes, particularly early Type 2 diabetes, comprising
administering an effective dosage of a long acting insulin.
[0062] The present invention also provides a method of reducing
blood glucose levels in a patient diagnosed with a disease or
condition selected from the group of IFG, IGT or Type 2 diabetes,
particularly early Type 2 diabetes, comprising administering an
effective dosage of a long acting insulin.
[0063] The preferred long acting insulin for each of the above
methods is insulin glargine.
DETAILED DESCRIPTION OF THE INVENTION
[0064] Study HOE901-1021 was conducted to test the safety,
efficacy, and tolerability of Lantus.RTM. LANTUS (also known as
HOE901 and insulin glargine) in treating individuals with IGT, IFG,
and mild diabetes. As stated earlier, this patient population is at
high risk for CV disease.
[0065] Study HOE901/1021 was a randomized, single-blind
(pharmacist-unblinded), inpatient, dose-titration study designed to
examine the safety and efficacy of HOE901 given once a day
subcutaneously at bedtime in a novel population: people with
impaired glucose tolerance (IGT) or impaired fasting glucose (IFG).
It was conceived as a pilot study for a large international trial
of HOE901 in a dysglycemic population of IGT, IFG, and early type 2
diabetes in order to investigate dosing in the prediabetic
(IFG/IGT) population for the first time. Of special interest was
the incidence of hypoglycemia during the study.
[0066] The study was conducted at three centers in the US. After
screening tests, including fasting plasma glucose (FPG) and post
prandial plasma glucose (PPG; two hours following a 75 g oral
glucose load) for classification as IGT, IFG, diabetic, or normal
glucose tolerance (NGT), and after satisfying other inclusion
criteria including the ability to perform moderate exercise on a
stationary bicycle, subjects were admitted to an inpatient study
center. They were confined there for the next 15 days, during which
time they were randomly assigned to receive either HOE901 once per
day subcutaneously in the evening, or matching placebo (saline)
injections in a 3:1 randomization (HOE901:placebo). Baseline
assessments included a 5-point (before each meal, bedtime, and 3
AM) and 8-point (5-point plus readings 2 hours after each meal)
blood glucose profile on separate days, and 15 minutes of exercise
on a stationary bicycle at a level of exertion of "somewhat hard"
on the Borg scale with blood glucose values monitored during and
for 3 hours following the exercise. Each subject received a 25
kCal/kg diet while confined in the study center. Capillary whole
blood glucose values were recorded on HemoCue devices. Episodes of
hypoglycemia (blood glucose.ltoreq.50 mg/dL [2.8 mM] or symptoms
with blood glucose.ltoreq.65 mg/dL [3.6 mM]) were recorded.
[0067] Once randomized, subjects' bedtime doses of study drug were
titrated to achieve a fasting blood glucose (FBG) of 80-95 mg/dL
[4.4 mM-5.3 mM]. Dose increases were based on FBG values and were
performed every 2 days. Subjects remained at the site until the end
of the confinement period, regardless of when target FBG levels
were achieved. Five-point blood glucose profiles were performed
every other day, with 8-point blood glucose profiles performed on
alternate days. At endpoint all baseline procedures, including an
8-point blood glucose profile, and an exercise assessment, were
repeated.
[0068] Subjects were treated from 18 Feb. 2002 to 17 Apr. 2002.
Data from the study are still being analyzed, but principal results
of the study are summarized below.
[0069] Twenty-one subjects were enrolled into the study. Two
discontinued before completion: 1 HOE901 subject due to
hypoglycemia, who however, never received study drug, and 1 subject
withdrew prior to randomization. Nineteen subjects completed the
study, 15 in the HOE901 group and 4 in the placebo group. The table
below summarizes the demographic and baseline characteristics of
these subjects.
TABLE-US-00001 Demography and baseline characteristics
Characteristic Placebo HOE901 All Female 4 (80.0%) 6 (37.5%) 10
(47.6%) Male 1 (20.0%) 10 (62.5%) 11 (52.4%) Mean age (yrs) 54.6
54.8 54.7 Median age (yrs) 53.0 52.0 53.0 Mean BMI (kg/m2) 31.2
30.7 30.8 Number (%) of subjects with: IGT/IFG 2 (40.0%) 7 (43.8%)
9 (42.9%) Type 2 diabetes 3 (60.0%) 7 (43.8%) 10 (47.6%) NGT 0
(0.0%) 2 (12.4%) 2 (9.5%) Mean screening values for: FPG (mg/dL)
114 110 111 PPG (mg/dL) 212 192 197
[0070] Although it was intended to enroll only IGT/IFG subjects,
difficulties in locating enough of these subjects in the timeframe
allotted for enrollment necessitated the inclusion of subjects who
were found to be diabetic at screening (none were known to be
diabetic prior to the study). Two subjects were enrolled with NGT
(FPG and PPG of 100 and 133, and 95 and 135 mg/dL,
respectively).
[0071] The starting dose following randomization for all subjects
was initially set at 6 IU. Because of the occurrence of
hypoglycemia in 2 subjects at this dose, the starting dose was
reduced to 4 IU. The mean dose at endpoint (Day 12) was 8.4 IU for
HOE901 (0.096 IU/kg), and 17.0 IU (0.195 IU/kg) for placebo.
[0072] All but 2 subjects in the HOE901 group had reached an FPG of
100 mg/dL by Day 12, and all but 4 had reached the FBG target of 95
mg/dL or less.
[0073] FIG. I displays the mean blood glucose values on the 8-point
profiles at Day -1 (baseline) and on Day 12 (endpoint). As seen,
there were small reductions from baseline to endpoint in mean blood
glucose concentrations in the HOE901 group, ranging from 2.0 to
13.3 mg/dL at different time points. Mean FBG was reduced from 98.1
to 85.6 mg/dL, and mean daylong blood glucose was reduced by 8.8
mg/dL, in the HOE901 group. In the HOE901 group the lowering of
blood glucose from Day -1 to Day 12 was not confined to the fasting
time point, but occurred daylong, at each time point.
[0074] In contrast, in the placebo group mean blood glucose values
increased at most time points, with a mean FPG increase from 103.8
to 111.3 mg/dL and a mean daylong blood glucose increase of 8.2
mg/dL. The placebo group mean response was heavily influenced by 1
of the 4 subjects who had large increases in 8-point blood glucose
over the course of the study, for unclear reasons.
[0075] It is clear from these data and the mean screening values in
the table above that there was a drop in mean fasting glucose in
the HOE901 group between screening and Day -1 (baseline).
Differences in blood glucose measurements (plasma at screening,
whole blood at Day -1) contributed to the observed drop in blood
glucose between these two time points, however, the likely reason
for most of this difference was the institution of a diet policy in
both groups (in this study a diet similar to what would be
prescribed in these subjects in practice (25 Kcal/kg) was used).
Diet compliance in subjects with dysglycemia is classically poor,
but because the subjects were confined in this study, they were
perforce adherent to the diet regimen, and it was effective in
lowering their blood glucose levels. No such decrease in mean FBG
occurred between screening and Day -1 in the 5 subjects taking
placebo. Mean body weight was reduced in both the placebo group and
HOE 901 over the course of the study, by 0.25 and 0.44 kg
respectively.
[0076] FIG. II below illustrates mean blood glucose responses
before (-0.25 hr) and for 3 hours following the 15-minute
stationary bicycle exercise period. As can be seen, mean blood
glucose was similar before and after treatment with HOE901, and did
not approach the hypoglycemic range. In the placebo group mean
blood glucose showed a notable increase from Day -1 to Day 12, due
to 2 of the 4 subjects in that group who demonstrated large
increases over baseline by Day 12, for reasons which are unclear
but are possibly related to relative physical inactivity over the 2
weeks of confinement, with resultant decreased insulin sensitivity
at the time of the assessment on Day 12. It is noteworthy that no
hypoglycemic events were reported during exercise for any
subject.
[0077] Treatment-emergent adverse events (TEAEs) occurred in 10
subjects in the HOE901 group (16 events) vs. 2 in the placebo group
(5 events). Each event occurred in only 1 individual except for
headache, which occurred in 3 HOE901 subjects. Only 2 HOE901
subjects and 1 placebo subject had events that were considered by
investigators as possibly related to study drug. The HOE901 events
were 2 episodes of headache, and one of hypoglycemia. The two
headaches occurred in subjects who had hypoglycemic events on the
same days and at approximately the same time as the headaches.
There were no serious adverse events during the study. Subject 3011
(who reported dizziness as an adverse event during screening) was
removed from the study by the sponsor prior to receiving any study
drug dose because of hypoglycemia that occurred during
screening.
[0078] HOE901 treatment plus modest calorie restriction was
effective in lowering blood glucose values in these dysglycemic
individuals to target FBG levels. Daylong (8-point) blood glucose
profiles were lowered in parallel to FPG in the HOE901 group. A
relatively low dose of HOE901 (mean of only 8.4 IU) was required to
achieve the glucose goals under these test conditions. Blood
glucose profiles in response to exercise fell only modestly over
the course of the study in the HOE901 group. Blood glucose
responses in the placebo group increased over the course of the
study in both 8-point and exercise assessments, but the small size
of this group and the atypical responses of 1 or 2 subjects makes
drawing conclusions from the placebo responses difficult.
[0079] Only mild hypoglycemia occurred in 4 out of 16 subjects
treated with HOE901 in this study. These hypoglycemic events
generally occurred before lunch or supper, and resolved promptly
with oral caloric intake. No episodes of hypoglycemia occurred in
relation to exercise. Although the calorie-restricted diet subjects
consumed during this study doubtless played a role in the
occurrence of these events, the diet was typical in size for what
is recommended to these frequently overweight individuals. Based on
this study in individuals with IGT, IFG, or mild untreated type 2
diabetes, the administration of HOE 901 seems safe and well
tolerated. Hypoglycemia can occur, but is manageable not related to
exercise, and detectable with the aid of home glucose
monitoring.
[0080] Thus in this study it was possible to use Lantus.RTM. LANTUS
(insulin glargine) to treat the mildly hyperglycemic subjects to
normoglycemic levels without hypoglycemia in relation to exercise.
These data have prompted the undertaking of a large intervention
trial, the ORIGIN study, wherein it is expected that Lantus.RTM.
LANTUS (insulin glargine) will be shown to be efficacious in
reducing CV disease, with low risk for producing hypoglycemic side
effects in relation to the exercise which forms a cornerstone of
the glucose management of these individuals. The ORIGIN study will
randomly allocate approximately 10,000 subjects with IGT, IFG, or
early type 2 diabetes at risk for cardiovascular morbidity (because
of a history of previous serious cardiovascular events, or because
of significant cardiovascular risk factors) either to treatment
with a single injection of Lantus.RTM. LANTUS (insulin glargine)
per day, titrated to produce a FPG of 95 mg/dL or less without
hypoglycemia, or to standard treatment of each condition. Examples
of serious cardiovascular events include, but are not limited to,
previous myocardial infarction, stroke, angina with documented
ischemic changes, previous coronary, carotid or peripheral arterial
revascularization, or left ventricular hypertrophy by
electrocardiogram or echocardiogram. Examples of significant
cardiovascular risk factors include, but are not limited to,
previous myocardial infarction, stroke, angina with documented
ischemic changes, previous coronary, carotid or peripheral arterial
revascularization, or left ventricular hypertrophy by
electrocardiogram or echocardiogram. This standard treatment plan
includes a stepped-care algorithm for the institution of therapy in
subjects who are either diabetic at baseline, or who become so
during the trial. Monitoring of, and treatment intervention in,
these control subjects will occur in a manner that is at least as
aggressive as that recommended by currently-accepted standards of
care (e.g. ADA guidelines). The morbidity/mortality study will be
multicenter, international, randomized, and open-label, with a mean
treatment duration of 5 years. The primary outcome variable is a
composite cardiovascular endpoint of cardiovascular deaths,
nonfatal MI and stroke, revascularization, hospitalization for
heart failure CHF, and unstable angina. Secondary variables include
all-cause mortality and rates of development or progression of
microvascular disease. A separate investigation will examine the
progression to type 2 diabetes in the IGT and IFG subjects treated
with Lantus.RTM. LANTUS (insulin glargine) versus usual care.
[0081] Despite the novelty of the treatment paradigm proposed for
the ORIGIN study, it is believed that hypoglycemia will be minimal
based on several factors: [0082] 1. The 24-hour plasma insulin
profile without a definite peak resulting from Lantus.RTM. LANTUS
(insulin glargine) administration, decreasing the vulnerability of
patients to excessive insulin concentrations which have
historically occurred at unpredictable times during the day, and to
unpredictable degrees, with other insulin preparations. [0083] 2.
The gradual dose titration scheme proposed for the study.
Lantus.RTM. LANTUS (insulin glargine) doses will start low, from
2-6 IU per day and the insulin administered will be distributed
over a 24-hour period. Dose increases will be small, and made only
after FPG levels from previous doses have reached steady-state.
[0084] 3. The goal of Lantus.RTM. LANTUS (insulin glargine)
titration is a target FPG of 95 mg/dL. This is at the upper end of
the normal range for subjects without diabetes. Many IGT subjects
in this trial will have an FPG in the target range from the start
of the study, and if assigned to receive Lantus.RTM. LANTUS
(insulin glargine) will consequently receive the starting dose
only. In any case, the risk of nocturnal hypoglycemia resulting
from Lantus.RTM. LANTUS (insulin glargine) administration which has
reduced FPG to the vicinity of 95 mg/dL should be minimal,
especially since most of these subjects will exhibit a degree of
decreased insulin sensitivity. [0085] 4. Subjects will be asked to
monitor their blood glucose at home especially during titration, to
detect any tendency to hypoglycemia in that setting (peri-exercise,
after missed meals, overnight).
[0086] The results of the 1021 Study which confirmed the safety and
tolerability of Lantus.RTM. LANTUS (insulin glargine) in drug-naive
type 2 diabetes patients as well as in prediabetic individuals,
also support Lantus' LANTUS' (insulin glargine) special usefulness
in patients with moderate to severe DDL.
[0087] Insulin has features that make it especially useful in the
patient with pronounced diabetic dyslipidemia, as compared to the
oral antidiabetic agents usually used as initial pharmacotherapy.
The "Treat-to-Target" study (HOE901/4002) of Lantus LANTUS (insulin
glargine) in a type 2 diabetic population inadequately treated with
oral drugs was notable in demonstrating the success of Lantus
LANTUS (insulin glargine) and its comparator, NPH insulin, in
reducing blood glucose levels to target levels in the majority of
randomized patients. NPH insulin despite having a prolonged
duration of action, has a pronounced peak effect from 3-6 hours
after injection, rendering it less suitable in the management of
the patient with milder diabetes due to the risk for hypoglycemia.
Indeed even in this more severely diabetic population Lantus LANTUS
(insulin glargine) demonstrated significant advantages over NPH in
hypoglycemia, especially nocturnal hypoglycemia.
[0088] As a consequence of the excellent glycemic control attained,
which set the standard for glycemic control in future trials, the
4002 study results are especially useful as an assessment of
Lantus's LANTUS (insulin glargine) effects on lipids. The effects
of Lantus LANTUS (insulin glargine) in the population of the
"treat-to-target" 4002 study on fasting TG levels increased with
the magnitude of baseline TG elevations: reductions of 24%, 34%,
and 38% were seen in fasting TG levels with, respectively, all
patients; those with fasting TG in the 300-499 mg/dL range (13% of
the 4002 population); and those with elevations of 500 mg/dL or
more (another 8% of the 4002 population). It is also notable that
highly statistically significant reductions in non-HDL-cholesterol
(see below) were seen in the two pooled treatments in the 4002
study, greater in magnitude the higher the baseline level of
TG.
[0089] There is evidence from the literature that use of
sulfonylurea (SU) as initial drug treatment of the type 2 patient
with DDL exerts a weaker effect on reduction of
hypertriglyceridemia, or on increasing HDL-C, than is seen with
insulin, and/or that the effects are less durable. In order to
compare the effects of Lantus LANTUS (insulin glargine) on fasting
TG and non-HDL-C levels with oral agents from the sulfonylurea
class, the glimepiride (Amaryl.RTM. AMARYL) database at Aventis was
examined. Both multicenter placebo-controlled studies in the
Amaryl.RTM. AMARYL (glimepiride) registration database demonstrated
a more modest effect of Amaryl.RTM. AMARYL (glimepiride) on both TG
and non-HDL-C concentrations than Lantus LANTUS (insulin glargine)
demonstrated in the 4002 study, despite a prominent effect of
Amaryl.RTM. AMARYL (glimepiride) to lower blood glucose. These
results are shown in Table 1 below for patients with various levels
of fasting hypertriglyceridemia.
TABLE-US-00002 TABLE 1 Summary of lipid data for LANTUS (from 4002
Study) and AMARYL (from two AMARYL studies with placebo control)
Change at Subgroup by TG Sample Endpoint % reduction LANTUS-
Variable baseline range size Treatment Baseline Endpoint (Mean/SD)
from baseline AMARYL Triglycerides 300-500 44 LANTUS 362 240
122.5/102 34% 16% 52.5 50 AMARYL 390 321 -70.0/111 18% 500-1000 25
LANTUS 661 409 -252.0/208 38% 5% 34.4 16 AMARYL 662 445 -217.6/188
33% 300-1000 69 LANTUS 470 301 -169.4/160 36% 13% 63.6 66 AMARYL
459 350 -105.8/147 23% 200-500 124 LANTUS 288 232 -56.3/117 25% 13%
21.7 129 AMARYL 299 265 -34.6/107 12% Non-HDL 300-500 44 LANTUS 180
152 -27.6/36 15% 12% 21.9 Cholesterol 50 AMARYL 203 198 -5.7/32 3%
Total 500-1000 25 LANTUS 186 171 -14.1/35 8% -2% -9.0 16 AMARYL 224
200 -23.1/35 10% 300-1000 69 LANTUS 181 163 -18.5/40 10% 5% 8.6 66
AMARYL 209 198 -9.9/33 5% 200-500 124 LANTUS 167 155 -12.5/33 7% 4%
5.8 129 AMARYL 197 191 -6.7/30 3% HDL 300-500 44 LANTUS 40 40 0.1/6
50 AMARYL 36 37 1.2/6 500-1000 25 LANTUS 33 36 3.1/7 16 AMARYL 37
39 1.6/6 300-1000 69 LANTUS 37 38 1.2/7 66 AMARYL 36 37 1.3/6
200-500 124 LANTUS 42 41 -0.6/8 129 AMARYL 38 39 1.2/5 LDL All 306
LANTUS 113 110 -3.3/27 272 AMARYL 142 140 -1.5/23
[0090] The lipid-lowering effects of metformin are variable
depending on the study and clinical setting, but while the
TG-lowering and HDL-increasing effects of metformin are generally
superior to SU, they do not exceed the effects of insulin quoted
above. Thiazolidinediones (TZDs) differ in their
effects--pioglitazone is associated with notable beneficial effects
on the abnormalities of DDL, whereas rosiglitazone seems to have
almost no effect on these parameters (confirmed significantly
inferior to Lantus LANTUS (insulin glargine) in Study 4014, which
compared Lantus.RTM. LANTUS (insulin glargine) and rosiglitazone in
type 2 diabetic patients already treated with other oral
antidiabetic drugs--see Table 2 below).
TABLE-US-00003 TABLE 2 Summary of lipid data for LANTUS and AVANDIA
from Study 4014 Change at Subgroup by TG Sample Endpoint %
reduction LANTUS- Variable baseline range size Treatment Baseline
Endpoint (Mean/SD) from baseline AVANDIA Triglycerides 300-500 11
LANTUS 380 277 102.8/130 27% 18% 68.5 18 AVANDIA 376 341 -34.3/159
9% 500-1000 4 LANTUS 817 494 -323.3/268 3 AVANDIA 572 649 77.0/548
200-500 37 LANTUS 285 234 -50.2/101 18% 18% 47.7 51 AVANDIA 294 291
-2.5/133 0.1% Non-HDL 300-500 11 LANTUS 156 150 -5.9/22 4%
Cholesterol 18 AVANDIA 177 207 29.8/47 -17% Total 500-1000 4 LANTUS
178 153 -25.3/25 3 AVANDIA 231 261 30.0/48 200-500 37 LANTUS 168
152 -15.5/32 51 AVANDIA 41 59 29.2/48 HDL 300-500 11 LANTUS 32 34
2.2/4 18 AVANDIA 38 41 3.8/6 500-1000 4 LANTUS 28 29 1.0/3 3
AVANDIA 39 38 -1.0/8 200-500 37 LANTUS 38 40 1.2/5 51 AVANDIA 38 40
2.6/6 LDL 200-500 34 LANTUS 115 111 -4.3/34 46 AVANDIA 99 129
29.7/36
[0091] The special advantages of insulin in the treatment of
diabetic dyslipidemia, which along with insulin's established
effectiveness in blood glucose control, suggest that it is a
preferred treatment compared to available oral antidiabetic drugs.
Until recently, the drug treatment of blood glucose elevations in
drug-naive diabetic patients has consisted of oral antidiabetic
agents because of a fear of hypoglycemia from the use of insulin in
this population. The novel development is the availability of
Lantus.RTM. LANTUS (insulin glargine), the first truly basal
insulin, which by virtue of its flat pharmacokinetic profile and
24-hour duration of action, can supply a steady insulin effect with
low risk for hypoglycemia due to the lack of a pronounced peak
effect. Because of this, insulin treatment of the diabetic patient
previously treated with lifestyle measures only, is possible, and
thus insulin treatment of patients in this category with pronounced
diabetic dyslipidemia is possible, to reduce their elevated blood
lipid values as well as their elevated blood glucose values.
[0092] In view of the data described above, treatment with long
acting insulin, particularly insulin glargine, is expected to
safely and effectively retard atherosclerosis progression in
patients with IGF, IFG or Type 2 diabetes, particularly early Type
2 diabetes by improving glycemic control and by additional
mechanisms including decreased free fatty acid production, improved
control of dyslipidemia, decreased oxidative stress and increased
endothelial nitric oxide availability.
[0093] Treatment with long acting insulin, particularly insulin
glargine, is also expected to safely and effectively improve
vascular function in patients with IGT, IFG or Type 2 diabetes,
particularly early Type 2 diabetes. Long acting insulin,
particularly insulin glargine, is expected to improve endothelial
function based on its effects on smooth muscle cells, endothelial
cells, suppression of cytokines, coagulants and increased
endothelial nitric oxide synthase. Coronary endothelial dysfunction
is defined as an impaired vasodilatory response to intracoronary
infusion of acetylcholine (Ach) and is predictive of vascular
events. Acute studies have shown that a physiological increase in
the circulating insulin concentration potentiates Ach-induced
vasodilation..sup.43 In another study, after two months of insulin
therapy, patients with type 2 diabetes saw an increase in the blood
flow response to Ach and restored the ability of insulin to acutely
potentiate Ach-induced vasodilation..sup.44
[0094] Finally, patients with diabetes have been shown to have
increased left ventricular mass and abnormalities in left
ventricular (LV) diastolic and systolic function, often referred to
as diabetic cardiomyopathy. These abnormalities may extend also to
patients with "mild" prediabetic hyperglycemic disorders. Treatment
with long acting insulin, particularly insulin glargine, is
expected to prevent an increase in LV mass and improve or prevent
an increase in both LV diastolic and systolic function in patients
with IGT, IFG or Type 2 diabetes, particularly early Type 2
diabetes.
[0095] Treatment with long acting insulin, particularly glargine,
is expected to prevent an increase in carotid intimal thickness of
the extracranial carotid artery. Measurement of carotid intimal
thickness is a highly reproducible technique, which correlates with
risk factors for atherosclerosis progression in coronary disease
and stroke (N Engl J. Med. 1999; 340:14-22). Angiotensin-converting
enzyme inhibitors and the insulin sensitizing thiazolidinediones
are all agents which have been shown to reduce carotid intimal
thickness in placebo controlled trials (Circulation. 2001;
103:919-925; J Clin Endocrinol Metab 1998; 83:1818-1820; J Clin
Endocrinol Metab 2001; 86:34552-3456).
[0096] The amount of long acting insulin necessary to achieve the
desired biological effect depends on a number of factors, for
example the specific long acting insulin chosen, the intended use,
the mode of administration and the clinical condition of the
patient. The daily dose of insulin glargine is generally in the
range from 2 to about 150 IU per day. More preferred is a daily
dose in range in the range of 2 to about 80 IU per day. Even more
preferred is a daily dose in the range of about 2 to about 40 IU
per day.
[0097] As used herein, the term "patient" means a warm blooded
animal, such as for example rat, mice, dogs, cats, guinea pigs, and
primates such as humans.
[0098] As used herein, the term "treat" or "treating" means to
alleviate symptoms, eliminate the causation of the symptoms either
on a temporary or permanent basis, or to prevent or slow the
appearance of symptoms of the named disorder or condition.
[0099] As used herein, the term "effective dosage" means a quantity
of the compound which is effective in treating the named disorder
or condition.
[0100] As used herein, the term "long acting insulin" is an insulin
analog that is a long acting (up to 24-hour duration of action)
blood glucose lowering agent. Such long acting insulins include,
but are not limited to, Lantus.RTM. LANTUS (insulin glargine), NPH,
Lente.RTM. LENTE human insulin zinc suspension (rDNA origin),
Ultralente.RTM. ULTRALENTE human insulin extended zinc suspension
(rDNA origin), and Semilente.RTM. SEMILENTE (prompt insulin zinc
suspension).
[0101] As used herein, the term "early Type 2 diabetes" is defined
as a FPG.gtoreq.126 mg/dl (7.0 mM) or a PPG.gtoreq.200 mg/dL (11.1
mM), or a previous diagnosis of diabetes, and either:
1) 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 for the laboratory (e.g.
<9% if the upper limit is 6%) or 2) taking one OAD (from among
sulfonylureas, biguanides, thiazolidinediones, alpha-glucosidase
inhibitors, and meglitinides) at a stable dose 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 <133% of the upper limit of
normal for the laboratory (e.g. <8% if the upper limit is 6%) if
taking this medication at half-maximum dose or greater, and
glycated hemoglobin <142% of the upper limit of normal for the
laboratory (e.g. <8.5% if the upper limit is 6%) if taking this
medication at less than half-maximum dose.
[0102] The citation of any reference herein should not be construed
as an admission that such reference is available as "Prior Art" to
the instant application.
[0103] Various publications are cited herein, the disclosures of
which are incorporated by reference in their entireties.
BRIEF DESCRIPTION OF THE DRAWINGS
[0104] FIG. I depicts mean blood glucose values on the 8-point
profiles at Day 1 (baseline) and Day 12 (endpoint).
[0105] FIG. II illustrates mean blood glucose responses before
(0.25 hr) and for 3 hours following the 15 minute stationary
bicycle exercise period.
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