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.

Description of the Invention

SUMMARY OF THE INVENTION

The present invention provides a method of treating IGT in a patient comprising administering an effective dosage of a long acting insulin.

The present invention also provides a method of treating IFG in a patient comprising administering an effective dosage of a long acting insulin.

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.

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 insulin.

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.

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.

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.

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.

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.

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.

The preferred long acting insulin for each of the above methods is insulin glargine.

DETAILED DESCRIPTION OF THE INVENTION

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.

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.

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.

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.

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.

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 (see Original Patent) summarizes the demographic and baseline characteristics of these subjects.

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).

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.

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.

FIG. I (see Original Patent) 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 timepoints. 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 timepoint, but occurred daylong, at each timepoint.

In contrast, in the placebo group mean blood glucose values increased at most timepoints, 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.

It is clear from these data and the mean screening values in the table above (see Original Patent) 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 timepoints, 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.

FIG. II (see Original Patent) 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.

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.

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.

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 adminstration 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.

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.

Despite the novelty of the treatment paradigm proposed for the ORIGIN study, it is believed that hypoglycemia will be minimal based on several factors: 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. 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. 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. 4. Subjects will be asked to monitor their blood glucose at home especially during titration, to detect any tendency to hypoglycemia in that setting (pen-exercise, after missed meals, overnight).

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.

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.RTM. LANTUS (insulin glargine) in a type 2 diabetic population inadequately treated with oral drugs was notable in demonstrating the success of Lantus.RTM. 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.

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.

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 (see Original Patent) for patients with various levels of fasting hypertriglyceridemia.

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 (see Original Patent)).

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.

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.

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

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.

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 atheosclerosis progression in coronary disease and stroke (N Engl J. Med. 1999; 340:14-22). Angiotensin-converting enzme 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).

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.
 

Claim 1 of 48 Claims

1. A method of treating impaired glucose tolerance (IGT) in a patient in need thereof comprising administering an effective dosage of a long acting insulin.
 

____________________________________________
If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.