Clinical Trials Web

Aliskiren Combined with Losartan in Type 2 Diabetes and Nephropathy

2008-06-06T04:34:00.000-07:00

Image via WikipediaThe pathogenesis of diabetic nephropathy is multifactorial, and the renin–angiotensin–aldosterone system plays an important role.1,2 Persistent proteinuria is the hallmark of diabetic nephropathy, a condition that is characterized by a progressive rise in blood pressure, a declining glomerular filtration rate, and a high risk of fatal or nonfatal cardiovascular events. The degree of proteinuria is closely associated with the rates of renal and cardiovascular events.3,4 Furthermore, a reduction in proteinuria is associated with a slowing of both the decline in the glomerular filtration rate5 and the progression to end-stage renal disease.6 In addition, decreasing proteinuria is associated with improved cardiovascular outcomes in patients with diabetic nephropathy7 and arterial hypertension.8 As a result, a reduction in proteinuria has been widely used as a surrogate end point for renoprotection.

During the past two decades, the outlook for patients with diabetes who have microalbuminuria or macroalbuminuria has improved, probably owing to early aggressive lowering of blood pressure and blocking of the renin–angiotensin–aldosterone system.3,4,9,10,11,12 However, there is still a large, unmet need to develop strategies for the prevention of diabetic nephropathy and its progression to end-stage renal disease. Diabetic nephropathy remains the leading cause of end-stage renal disease in the developed world.

The aim of this trial was to evaluate the potential renoprotective capacity of direct renin inhibition with aliskiren in patients with hypertension, type 2 diabetes, and proteinuria who were already receiving the maximal recommended renoprotective treatment with losartan (100 mg daily) and optimal treatment for hypertension. In addition, the safety of dual blockade of the renin–angiotensin–aldosterone system was monitored and recorded.

Characteristics of the Patients

Baseline demographic, clinical, and biochemical characteristics and the number of patients who were receiving glucose-lowering and lipid-lowering therapies and aspirin (≤325 mg daily) were balanced between the two groups, except that the patients in the placebo group were slightly older (P=0.009) (Table 1). The mean glycated hemoglobin values remained unchanged, at 8.0%, in the aliskiren group and rose to 8.1% in the placebo group, and the numbers of severe hypoglycemic episodes were zero and one, respectively. Additional blood-pressure–lowering drugs that were taken by patients in the two groups are shown in Table 2.
Discussion

The present trial shows that treatment with 300 mg of aliskiren daily reduces albuminuria in patients with hypertension, type 2 diabetes, and proteinuria who are receiving the recommended maximal renoprotective treatment with losartan and optimal antihypertensive therapy. Furthermore, a 50% reduction in albuminuria was seen twice as often in the group that received 300 mg of aliskiren daily as in the group that received placebo. The benefits of aliskiren appear to be independent of the systemic blood pressure; average trough systolic and diastolic blood pressures during the study were only marginally lower in the aliskiren group than in the placebo group, and an analysis that adjusted for these small differences confirmed the renoprotective effect of aliskiren. In addition, the decline in kidney function tended to be smaller among the patients who received aliskiren than among those who received placebo.

The benefit of blocking the renin–angiotensin–aldosterone system in patients with diabetes who are at risk for end-stage renal disease is now well established.3,4,10,11,12 However, most studies to date also show that renal disease progresses in many patients despite treatment with angiotensin-converting–enzyme (ACE) inhibitors or angiotensin II–receptor blockers.3,4,10,11,12 Consequently, alternatives that optimize the blockade of the renin–angiotensin–aldosterone system are being explored in the hope that a more complete blockade will lead to a better therapeutic outcome.17 New renoprotective strategies include dual blockade of the renin–angiotensin–aldosterone system with the use of ACE inhibitors and angiotensin II–receptor blockers, very high doses of angiotensin II–receptor blockers,18,19,20 aldosterone blockade,21,22 and, as in the present study, direct renin inhibition.

Aliskiren, the renin inhibitor used in our study, has a 40-hour half-life and reduces both blood pressure and plasma renin activity. It is well established that a dose of 300 mg of aliskiren is optimal for the reduction of blood pressure.23 Further information concerning the development of oral renin inhibitors and their pharmacokinetic and pharmacodynamic properties, with a focus on aliskiren, is available in a recent review.24

In a study reported in 2000 that involved patients with type 2 diabetes, hypertension, and microalbuminuria, Mogensen et al.25 showed that treatment with a combination of submaximal doses of candesartan and lisinopril was more effective in reducing blood pressure (reductions in systolic pressure of approximately 10 mm Hg and in diastolic pressure of approximately 6 mm Hg) than therapy with only one agent; however, the effectiveness of the combined therapy in reducing albuminuria was not firmly established. Since then, numerous small studies, often using submaximal doses of ACE inhibitors in patients with diabetic nephropathy, have shown a significant reduction in blood pressure and albuminuria with this treatment strategy.26 In contrast, a large, randomized, controlled trial involving patients with type 2 diabetes, hypertension, and albuminuria who received the maximal recommended doses of ramipril and irbesartan failed to show a significant effect of combination therapy, as compared with monotherapy, on albuminuria,27 despite a significant reduction in systemic blood pressure. However, this study may have been underpowered, owing to a more marked variability in the urinary albumin excretion rate than anticipated. Our study was larger and adequately powered, and the results clearly support a specific renoprotective effect of aliskiren — namely, a beneficial effect on kidney function beyond the effect on hypertension. However, we cannot completely rule out the possibility that changes in antihypertensive medications after randomization might have confounded the results of our study.

Glomerular proteinuria is determined by four factors: the mean transcapillary hydraulic-pressure difference, the glomerular surface area, and the size selectivity and charge selectivity of the glomerular filter. In diabetic nephropathy several of these variables are abnormal, and blockade of the renin–angiotensin–aldosterone system has been shown to normalize directly measured or estimated glomerular hydraulic pressure,28,29,30 to reduce the shunt-like defects in the membrane, at least in part,31,32 and to restore the charge-selectivity properties of the glomerular membrane.33

In our study, the estimated glomerular filtration rate was nearly identical in the two groups at baseline, whereas the decline in the glomerular filtration rate tended to be smaller among the patients who were treated with aliskiren for 6 months than among the patients who were given placebo. Long-term studies (more than 2 years' duration) must be conducted to elucidate whether the beneficial effect on the kidney that is seen in the short term is sustained.

Previous studies with antihypertensive drugs have usually shown an initial drop in the glomerular filtration rate that is steeper than the sustained decline.11,34 Recently, a study of healthy people on a low-sodium diet has shown that renal vasodilatation with aliskiren far exceeds that seen with ACE inhibitors and angiotensin II–receptor blockers.35 These results indicate that aliskiren may provide greater and thus more effective blockade of the renin system in the kidney. Since the renin system is enhanced in patients with diabetes, as compared with controls,36 a more pronounced difference in renal vasodilatation may be expected during aliskiren therapy.

During the course of the trial, the average difference in blood pressure was only 2 mm Hg systolic and 1 mm Hg diastolic in favor of the dual blockade of the renin–angiotensin–aldosterone system. Studies of the same treatment approach (300 mg of aliskiren combined with 320 mg of valsartan37 or 10 mg of ramipril38) in patients with essential hypertension have shown at least a doubling of the difference in blood pressure in the combination-therapy groups as compared with the monotherapy groups. A likely explanation for this finding is that the patients in these two trials had a much higher average baseline blood pressure than the patients in our study, whose baseline blood pressure was well controlled. Even though many of the patients in both of our study groups received three or more antihypertensive agents, our systolic blood-pressure goal of 130 mm Hg was reached in less than half the patients, whereas our diastolic blood-pressure goal of 80 mm Hg was reached in the majority of patients in both groups. Previous studies among patients with diabetic nephropathy have also shown that ideal control of systolic blood pressure is very difficult to attain in patients with diabetes, probably owing to the presence of diabetic macroangiopathy.2,3,4,11

It is possible that aliskiren also differs from ACE inhibitors or angiotensin II–receptor blockers in other ways that might explain these results. In 2002, Nguyen et al.39 discovered a (pro)renin receptor that was detected in the brain, heart, liver, and kidney. Prorenin, when bound to the (pro)renin receptor, displayed enzymatic activity and activation of intracellular signaling pathways without proteolytic removal of the prosegment. Recent studies in animals with diabetes40,41 and in in vitro conditions with high glucose42 have shown that aliskiren reduces the number of (pro)renin receptors in the kidney, mitigates profibrotic activity in the kidney, and nearly abolishes the apoptotic effects on cultured podocytes. Furthermore, data from transgenic (mRen-2)27 rats with diabetes suggest that aliskiren has a greater renoprotective capacity than ACE inhibitors.43 These findings are consistent with the observation that an elevated plasma prorenin level is associated with the development of diabetic nephropathy.1

The combination therapy consisting of the maximal recommended doses of aliskiren and losartan had similar tolerability to therapy with placebo and losartan, consistent with findings in an earlier study of the combination of aliskiren and valsartan.37 Hyperkalemia was reported in 5.0% of the patients in the aliskiren group and in 5.7% of the patients in the placebo group. The number of patients with a serum potassium level of 6.0 mmol per liter or more was higher with the combined drugs than with placebo, although the occurrence of such cases, after adjustment for the nine patients who were mistakenly enrolled in the trial, was low.

In conclusion, aliskiren appears to have a renoprotective effect that is independent of its blood-pressure–lowering effect in patients with type 2 diabetes who are receiving the maximal recommended renoprotective treatment and optimal antihypertensive therapy.

Supported by Novartis Pharma
References

Metformin versus Insulin for the Treatment of Gestational Diabetes

2008-05-07T19:42:00.000-07:00

Image via WikipediaGestational diabetes is a complication in about 5% of pregnancies, is increasing in prevalence, and is associated with complications to the pregnancy and a long-term risk of diabetes in both mother and offspring.1,2,3,4,5 Intervention to change lifestyle and, if maternal hyperglycemia persists, treatment with additional insulin have been shown to improve perinatal outcomes.6,7 Women who begin insulin therapy require education to ensure the safe administration of insulin. Use of insulin is also associated with hypoglycemia and weight gain. The use of safe and effective oral agents may offer advantages over insulin.

Oral metformin is a logical option for women with gestational diabetes mellitus. It improves insulin sensitivity, probably by activating AMP kinase, and is not associated with weight gain or hypoglycemia.8,9 Reported outcomes of its use during pregnancy have been favorable10,11,12,13,14,15,16,17,18,19 except for one small, retrospective cohort study20 that showed increased rates of perinatal loss and preeclampsia as compared with insulin treatment. Metformin crosses the placenta and could affect fetal physiology directly.21 Its use in pregnancy remains controversial; to our knowledge, only two small, randomized trials comparing metformin with insulin have been reported to date.22,23

We designed the Metformin in Gestational Diabetes Trial to rule out a 33% increase in a composite of perinatal complications in infants of women treated with metformin as compared with insulin. Our hypotheses were that perinatal outcomes would be similar for both treatments, that women would consider metformin a more acceptable treatment than insulin, and that metformin would improve markers of insulin sensitivity in the mother and baby.

Discussion

We found no significant increase in a composite measure of neonatal complications among women with gestational diabetes mellitus who were randomly assigned to metformin as compared with those who were assigned to insulin. Rates of neonatal hypoglycemia, one of the components of the composite end point, were similar in the two groups, but severe hypoglycemia (<1.6 mmol of glucose per liter [28.8 mg per deciliter]) occurred significantly less often in infants of women taking metformin. We did not see a reduction in the insulin concentration in umbilical-cord serum in the metformin group, but this finding should be interpreted with caution, since results were available for less than half of the participants.

Prematurity was included as part of the composite outcome. The rationale was that if metformin had any unanticipated adverse effect on fetal growth or well-being, there would be more iatrogenic preterm births. The frequency of preterm birth was higher in the metformin group than in the insulin group, but the difference was associated with a greater frequency of spontaneous (rather than iatrogenic) preterm births that could be due to chance or to an unrecognized effect of metformin on the labor process. The increased rate of preterm birth was not associated with higher rates of other complications, probably because the difference between the two groups in mean gestational age at delivery was clinically insignificant. In a previous cohort of women with gestational diabetes mellitus who were treated with either insulin or glyburide, the rates of preterm delivery were 13% for the insulin group and 12% for the glyburide group, but the causes of preterm birth were not documented.28

In our study, 46.3% of women taking metformin required supplemental insulin. This proportion is likely to vary in other populations, depending on patient characteristics and target levels of glucose.

How do the effects of metformin in women with gestational diabetes mellitus compare with those reported for glyburide? In a randomized trial comparing glyburide and insulin in 404 women with gestational diabetes mellitus, glycemic control and pregnancy outcomes were similar between groups (although the trial was underpowered to address neonatal complications).29 Subsequent experience with glyburide shows that approximately 20% of women change to insulin.30,31 To our knowledge, there are no published trials comparing metformin with glyburide, and comparisons among available data are limited by differences in study populations and glycemic aims.

Although our study was not designed to compare the outcome of combined treatment with that of either treatment alone, the rate of neonatal complications did not differ significantly between women who required supplemental insulin and those who received metformin alone. Moreover, women receiving combined treatment required less insulin and gained less weight than those taking insulin alone.

Strengths of this trial are that it took place within routine clinical practice and included the spectrum of women with a diagnosis of gestational diabetes mellitus. A weakness is that treatment was open-label, since blinding was not considered practical or ethical. A methodologic limitation is that we used a superiority design to assess whether insulin was superior to metformin and have accepted rather than proved the null hypothesis (that there is no difference between treatments). Nonetheless, the 95% confidence interval for the relative risk of the composite measure of neonatal complications suggests that an increase in risk of more than 10% with metformin is implausible. In addition, a post hoc analysis using a noninferiority design and a proposed margin of 1.33 (33% change in complications) supports the conclusion that metformin is not inferior to insulin (relative risk, 1.00; 97.5% CI, 0.89 to 1.12). Finally, the composite outcome included outcomes of differing clinical significance.32 However, data pertaining to the individual components of the composite measure serve to inform clinicians about several relevant effects of metformin.24

Clinicians may remain circumspect about using metformin until follow-up data for offspring are available. The offspring from this trial are being assessed at 2 years of age. Data at 18 months of age from 126 infants of women with polycystic ovarian syndrome who were treated with metformin have provided preliminary reassurance of a lack of effect on growth and on motor and social development.33

In conclusion, our findings suggest that metformin, alone or with supplemental insulin, is an effective and safe treatment option for women with gestational diabetes mellitus who meet the usual criteria for starting insulin, and that metformin is more acceptable to women with gestational diabetes mellitus than is insulin. Further follow-up data are needed to establish long-term safety.

Supported by grants from the Auckland Medical Research Foundation, the National Women's Evelyn Bond Charitable Trust, the Health Research Council of New Zealand, and the National Health and Medical Research Council of Australia.

Dr. Moore reports receiving speaking fees from Sanofi-Aventis. No other potential conflict of interest relevant to this article was reported.

We thank all the clinic teams that provided daily support to the researchers and all the women with gestational diabetes mellitus who carefully considered the study and agreed to take part.

* The investigators in the Metformin in Gestational Diabetes (MiG) Trial are listed in the Appendix.

Ranibizumab For Diabetic Eye Disease Shows Promising Results

2008-04-30T11:08:00.000-07:00

A JDRF collaboration between Johns Hopkins researchers and Genentech has shown that a drug for the treatment of diabetic eye disease has performed better in clinical trials than the current standard treatment using laser surgery.

These findings, representing the six-month end-point evaluation of the READ-2 clinical trial coordinated by The Johns Hopkins University, were presented Monday at the 2008 Annual Meeting of The Association for Research in Vision and Ophthalmology, in Fort Lauderdale, Florida.
According to Barbara Araneo, Ph.D., director of the complications program at JDRF, "These are very encouraging results, showing that drugs we have been testing in human clinical trials can be effective in slowing or stopping the effects of eye disease brought on by diabetes."

The multi-center READ-2 Study (Ranibizumab for Edema of the mAcula in Diabetes), which began in December 2006, was designed to test the long-term safety and effectiveness of injections of the drug ranibizumab in patients with diabetic macular edema, a condition characterized by swelling of the central portion of the retina, or macula, at the back of the eye. In addition, the trial sought to determine the comparative efficacy of ranibizumab versus conventional treatment - laser photocoagulation therapy - or both together.

Macular edema, one of the most common causes of blindness, occurs when fluid and protein deposits collect on or under the macula, causing it to thicken and swell.

Participating in the clinical trial were 126 diabetic patients (average age 62) with documented Diabetic Macular Edema prior to enrollment; the majority had 20/80 vision in the eye that was treated. Patients were randomly assigned to receive one of three interventions: ranibizumab, laser photocoagulation, or a combination of the two treatments. At each visit over the course of the six-month treatment period, patients were evaluated for vision, retinal thickening, and general eye health. Although the study ended at six months, patients will be monitored for two years.

Patients treated with ranibizumab experienced significantly greater improvements in visual acuity, or clarity of vision, compared with patients receiving either of the other interventions. On average, the vision of ranibizumab-treated patients improved to 20/63 at month six, compared with essentially unchanged acuity scores of about 20/80 in both the laser and the combination treatment groups.

In addition, patients treated with ranibizumab had a 56 percent reduction in excess retinal thickness, whereas only an 11 percent reduction was seen in those receiving laser treatments.

Sirtris Announces SRT501 Lowers Glucose In Twice-Daily Dosing Clinical Trial

2008-04-18T04:15:00.000-07:00

Sirtris Pharmaceuticals, Inc. (NASDAQ: SIRT), a biopharmaceutical company focused on discovering and developing small molecule drugs to treat diseases of aging such as Type 2 Diabetes, announced positive top-line data from its twice-daily dosing study of SRT501, the company's proprietary formulation of resveratrol. The Phase 1b clinical trial, which tested either 1.25 or 2.5 grams of SRT501 given twice daily to Type 2 Diabetic patients, found that the patient group receiving 2.5 grams twice a day had significantly lower blood glucose levels as determined through an oral glucose tolerance test (OGTT) at the test's two-hour time point, as compared with the placebo group.

At 2.5 grams twice daily, the study also found that SRT501 had a statistically significant lowering of both fasting blood glucose and glucose levels after meals, known as the postprandial period, an important timeframe for Type 2 Diabetics who need better control of blood sugar levels after eating. While not at the level of statistical significance, this dose level also showed a strong trend in lowering postprandial insulin levels.

At 1.25 grams given twice daily, SRT501 also showed strong trends. While not at statistical significance, SRT501 at 1.25 grams given twice per day lowered fasting and postprandial glucose, and glucose when challenged with an OGTT at the two-hour time point on day 27 of the trial as compared to the placebo group. The data suggest a dose response.

The company plans to present the full data at the American Diabetes Association annual meeting in June.

"With this study, and the Phase 1b once daily dosing study data that we announced in January of this year, we have now observed a lowering of glucose in Type 2 Diabetic patients in two clinical trials with SRT501," says Peter Elliott, Ph.D., Senior Vice President of Development at Sirtris. "The two Phase 1b clinical trials tested SRT501 at different dosage levels and dose time points. While the primary focus of each study was safety and blood levels of SRT501, by developing the studies as we did, we are also able to see signs of efficacy and dose response."

"Our clinical trial program with SRT501 further validates our approach in targeting the SIRT1 enzyme for the development of a potential new treatment for Type 2 Diabetes," says Christoph Westphal, M.D., Ph.D., CEO and Vice Chair of Sirtris. "Today's Phase 1b announcement is the second time we've seen a translation of the positive results from preclinical studies carry over to humans."

The current multi-center, blinded and randomized Phase 1b study included approximately 100 Type 2 Diabetic patients divided into three groups. The first patient group received 1.25 grams of SRT501 twice daily for a total daily-dose level of 2.5 grams. The second patient group received 2.5 grams twice daily for a total daily-dose level of 5.0 grams. The third group received placebo twice daily.

The study was designed to assess the safety, tolerability and pharmacokinetics of twice-daily, orally administered dosing of SRT501 at 2.5 and 5.0 total grams. In both patient cohorts receiving SRT501, the drug was found to be safe and well-tolerated, with no evidence of drug accumulation. The study also indicates that suitable pharmacokinetics, a measure of drug levels in the blood, was achieved.

In January of this year, Sirtris announced positive Phase 1b trial results of its once-daily dosing of SRT501 at 2.5 and 5.0 grams. In that study, SRT501 was also found to be safe and well-tolerated and to significantly lower glucose as compared to the placebo group in an OGTT at the two-hour time point as part of the 28 day trial of patients with Type 2 Diabetes.

SRT501 is currently being tested in patients with Type 2 Diabetes in a Phase 2a study in combination with metformin, the current first-line therapy for Type 2 Diabetes. Results from this trial are expected in the second-half of this year.

Sirtris has also identified new chemical entities (NCEs) that are chemically distinct from resveratrol, and in in-vitro tests are up to 1,000 times more potent. In preclinical models of Type 2 Diabetes, Sirtris' NCEs have lowered glucose and improved sensitivity.

TAXUS(R) Express(TM) Stent Shows Similarly Low Re-intervention Rates In Diabetic Patients Compared To Non Diabetics In ARRIVE 1 And 2 Registries

2008-03-30T04:25:00.000-07:00

Boston Scientific Corporation (NYSE: BSX) announced results from an analysis of 4,772 patients from its TAXUS ARRIVE 1 and 2 registries, designed to assess the performance of the TAXUS(R) Express2(TM) Paclitaxel-Eluting Coronary Stent System in real-world practice. The one-year pooled ARRIVE data confirmed the known higher mortality rate for diabetics versus non-diabetics with cardiovascular disease(1), but showed that the TAXUS Stent had similarly low rates of stent-related cardiac death, myocardial infarction (MI), stent thrombosis, and major cardiac events (MCE) across those two patient subsets. The study also showed similar rates of target vessel re-intervention (TVR) and TAXUS-related TVR in indicated patients(2) per the European Union (EU) label, whether or not they had diabetes. Analysis of the data was presented by D. Lynn Morris, M.D., at the SCAI Annual Scientific Sessions in Partnership with the ACC/i2 Summit in Chicago.

The pooled analysis included one-year data on 1,530 medication-requiring diabetic patients and 3,242 non-diabetic patients from the ARRIVE registry program. Due to significant disparity in baseline characteristics between diabetic and non-diabetic patients, propensity score analysis was used to allow for adjustment of baseline differences (other than the presence of diabetes) between the two groups.

The results showed diabetic patients had the well-known higher overall adjusted one-year mortality rate than patients without diabetes (3.7% vs. 2.3%, respectively, p=0.016), with the difference being driven by the cardiac death rate (2.3% vs. 1.2%, p=0.014), and reflecting the more advanced cardiac disease associated with diabetes. However, this difference was not related to the TAXUS Stent as the TAXUS Stent-related cardiac death rates at one-year were comparable in diabetics and non-diabetics, respectively (1.0% vs. 0.7%, p=0.29) in this patient population(2). Additionally, TAXUS Stent-related MCE rates (cardiac death, MI, and re-intervention) at one year were comparable (5.7% vs. 5.6%, p=0.80), as was the incidence of TAXUS Stent-related MI (1.6% vs. 1.2%, p=0.26), in both groups. Stent thrombosis at one year was low and showed no significant difference between diabetics and non-diabetics under Protocol definition (1.5% vs. 1.3%, p=0.59) or ARC Definite/Probable (1.7% vs. 1.2%, p=0.29). Unadjusted one-year rates of TAXUS Stent-related cardiac death, TAXUS Stent-related MCE, TAXUS Stent-related MI, and protocol-defined stent thrombosis showed no differences between the two populations (p-values of 0.30, 0.74, 0.31, and 0.65, respectively), suggesting that the safety profile is comparable for the two groups despite increased underlying risk in patients with diabetes.

Additionally, the ARRIVE analysis confirmed that the TAXUS Stent maintained comparable re-intervention rates in the diabetic and non-diabetic patient populations in ARRIVE 1 and 2. Rates of one-year TVR, whether adjusted or unadjusted, were similar between the patient groups (6.1% vs. 6.0%, p=0.80, adjusted). TAXUS Stent-related re-intervention of a target vessel (equivalent to target lesion revascularization, or TLR) was also similar between the patient groups (4.3% vs. 4.5%, p=0.70), despite the known higher risk for re-intervention in diabetic patients.

"The ARRIVE diabetic subset data demonstrated that the TAXUS Stent mitigated the adverse effect of diabetes as a risk factor for restenosis and repeat procedures in the patients studied," said Dr. Morris of the Albert Einstein Medical Center in Philadelphia, PA. "While the diabetic patients had more cardiac risk factors and co-morbidities than non-diabetics, the TAXUS- related cardiac death, MI and stent thrombosis in the ARRIVE 1 and 2 registries were similar in both groups, even without adjustment for risk factors."

"Our extensive ARRIVE registries provide valuable insights into diabetic patients who are often at higher risk for mortality and repeat stenting procedures," said Paul LaViolette, Chief Operating Officer at Boston Scientific. "The ARRIVE data demonstrated that the TAXUS Stent neutralized diabetes as a risk factor for clinical restenosis in the patients studied."

The growing diabetic subset accounts for more than one-quarter of all coronary interventional procedures in the United States. Diabetes is generally associated with an increased risk of cardiovascular events and patients with diabetes are more likely than non-diabetic patients to require repeat procedures due to a higher incidence of restenosis following angioplasty and stenting.

The safety and effectiveness of the TAXUS Express Stent has not been established in patients with diabetes in the United States.

Boston Scientific is a worldwide developer, manufacturer and marketer of medical devices whose products are used in a broad range of interventional medical specialties. For more information, please visit: http://www.bostonscientific.com.

New York-Presbyterian/Weill Cornell is First New York Medical Center to Offer Tantalus Clinical Trial to Diabetes Patients

2008-03-29T03:49:00.000-07:00

Implantable Device Designed for Type-2 Diabetes Patients Who Are Overweight and Do Not Respond to Current Oral Anti-Diabetic Treatments

Device Applies Electrical Stimulation to Stomach as Person Eats

NEW YORK, March 28 /PRNewswire/ -- New York-Presbyterian Hospital/Weill Cornell Medical Center is recruiting patients for a national clinical research study of an investigational implantable device designed to help those with type-2 diabetes who are overweight and do not respond to current oral anti- diabetic treatments.

The Tantalus(R) System is designed to sense naturally occurring electrical activity of the stomach in real time and automatically apply electrical stimulation when a person eats. The device is implanted though a minimally invasive laparoscopic procedure that can be performed in an outpatient setting.

New York-Presbyterian/Weill Cornell is the first New York metro area medical center to recruit and actively enroll patients in this study. Diabetes affects more than one million New Yorkers.

"Even with current medications and lifestyle changes, controlling type-2 diabetes in patients who are overweight can be difficult. This new treatment potentially offers new hope for patients who have been unsuccessful in managing their diabetes and weight," says Dr. Louis Aronne, clinical site principal investigator, director of the Comprehensive Weight Control Program at New York-Presbyterian/Weill Cornell and clinical professor of medicine at Weill Cornell Medical College.

An earlier, smaller study published in the Journal of Obesity Surgery found that the device reduced hunger and body weight in morbidly obese patients. Improvements in blood pressure were also seen.

"The primary objective of the current study is to evaluate the safety and efficacy of the Tantalus in treating overweight patients with type-2 diabetes. The device's impact on weight loss, blood pressure and other clinical and metabolic parameters will also be studied," says Dr. Gregory F. Dakin, the study's co-principal investigator, bariatric and laparoscopic surgeon at New York-Presbyterian/Weill Cornell and assistant professor of surgery at Weill Cornell Medical College.

To be considered for the trial, patients must meet certain inclusion criteria, including a diagnosis of type-2 diabetes (treated with oral medications, only), a body mass index (BMI) between 28 and 45 kg/m2 and an age between 18 and 70 years. BMI can be determined by using an online calculator and entering weight and height information (one example here: http://www.nhlbisupport.com/bmi/).

New York-Presbyterian/Weill Cornell is one of thirty sites in the U.S. participating in the study, which is funded by MetaCure, the manufacturer of Tantalus. The device is currently CE-marked in Europe.

The national epidemic of type-2 diabetes, most often associated with being overweight, continues to accelerate and affects more than 20 million Americans. About one million new people are diagnosed with the disease annually. The most common form of diabetes, type-2 diabetes, left untreated, may result in damage to the eyes, kidneys, nerves or heart and lead to major health complications later in life, or to death.

For more information on and to be considered for the study, please call the study coordinator at (212) 583-1000 or email smw2004@med.cornell.edu.

Source: MetaCure

CONTACT: Erich A. Sandoval for MetaCure, +1-212-867-1773,
esandoval@lazarpartners.com

Web site: http://www.nhlbisupport.com/bmi

Challenging The Norm May Lead To New Therapy For Type 2 Diabetes

2008-03-23T08:56:00.000-07:00

What happens when leading biochemists get together to challenge conventional pharmaceutical theories? Often, incredible new drug therapies are born. Recently, this same scenario began when two former major pharma scientists challenged the concept behind the leading treatments for type 2 diabetes, a disease that impacts millions of Americans

They saw the side effects caused by the current therapy like high blood pressure and weight gain, and went to work on a hypothesis that the current receptor was leading to these side effects associated with PPAR-based therapies.

As non-conventional as the theory was, it's working. Drs. Jerry Colca and Rolf Kletzien, co-founders of Kalamazoo, Michigan-based Metabolic Solutions Development Company (MSDC), have completed Phase I clinical studies and just received second phase funding from a Michigan-based science fund. They have applied for an FDA fast-track review of their work.

"We are pleased that our lead compound performed so well in Phase I studies," said Colca, MSDC's chief scientific officer. "Pre-clinical studies suggest that this compound can deliver significant pharmacological benefit without the complications inherent in current PPAR-based therapies."

Metabolic Solutions Development Company
http://www.msdrx.com

Oramed Pharmaceuticals Granted Approval To Conduct Phase 2A Trials Of Its Oral Insulin Capsule

2008-03-19T02:43:00.001-07:00

Oramed Pharmaceuticals Inc. has been granted approval by the Institutional Review Board (IRB) committee of Hadassah Medical Center in Jerusalem to conduct a Phase 2A study of its oral insulin on diabetic volunteers. This Phase 2A study is designed to evaluate the safety and efficacy of Oramed's oral insulin capsule on Type II diabetic volunteers. This study is slated to begin in the second quarter of 2008. The trials are expected to last several months.

"Oramed's oral insulin aims to revolutionize the current methods of treating diabetes," said Nadav Kidron, CEO of Oramed Pharmaceuticals. "An effective oral insulin capsule would make insulin an earlier form of treatment for diabetes patients, thereby allowing them to better control and balance their disease, leading to a healthier overall condition."

About Oramed Pharmaceuticals

Oramed Pharmaceuticals is an Israeli-based company focused on the development of oral delivery solutions based on proprietary technology. Diabetes is one of the most rapidly growing diseases in the world and is one that requires constant and often unpleasant monitoring and drug therapy regimens. Oramed is currently developing an orally ingestible insulin capsule for the treatment of diabetes. The company is also pursuing the development of oral delivery solutions for other drugs and vaccines.

Sulodexide ( Sulonex MR ) Phase 3 Clinical Trial Failed

2008-03-09T06:50:00.000-07:00

Keryx Biopharmaceuticals, Inc. (Nasdaq: KERX) announced top-line results from its SUN-MICRO Phase 3 clinical trial of Sulonex (sulodexide) for the treatment of diabetic nephropathy. The Company announced that this Phase 3 clinical trial failed to meet the primary objective of the study, which was to increase the proportion of patients that achieve therapeutic success at 6 months as compared to placebo over background therapy of maximal doses of ACE-inhibitors or ARBs. Therapeutic success was defined as (i) conversion from microalbuminuria to normoalbuminuria, as measured by albumin/creatinine ratio (ACR), with at least a 25% reduction in ACR relative to baseline ACR, or (ii) a 50% reduction in ACR relative to baseline ACR. In addition, in reviewing the mean changes in ACR over time, Sulonex and placebo appeared to be similar.

"We are all very disappointed with the outcome of this Study. While this represents the end of one chapter for Keryx, it is not the end of Keryx. Drug development is inherently risky and, accordingly, we have spent the last several years building what we believe to be a promising product portfolio in the event our lead drug failed. We plan to re-focus our primary efforts and resources on rapidly moving Zerenex forward for ESRD patients with hyperphosphotemia and Perifosine forward for cancer. Our goal is to have Perifosine in a pivotal program this year and be well into our Zerenex high-dose Phase 2 trial before the end of the year."

ABOUT KERYX BIOPHARMACEUTICALS, INC.

Keryx Biopharmaceuticals is focused on the acquisition, development and commercialization of medically important, novel pharmaceutical products for the treatment of life-threatening diseases, including renal disease and cancer. Keryx is developing Zerenex(TM) (ferric citrate), an oral, iron-based compound that has the capacity to bind to phosphate and form non-absorbable complexes. Zerenex is currently in Phase 2 clinical development for the treatment of hyperphosphatemia (elevated phosphate levels) in patients with end-stage renal disease, or ESRD. The Company is also developing KRX-0401 (perifosine), a novel, potentially first-in-class, oral anti-cancer agent that modulates Akt, a protein in the body associated with tumor survival and growth. KRX-0401 also modulates a number of other key signal transduction pathways, including the JNK and MAPK pathways, which are pathways associated with programmed cell death, cell growth, cell differentiation and cell survival. KRX-0401, which is currently in Phase 2 clinical development for multiple tumor types, is expected to move into a Phase 3 clinical program in 2008. The Company also has an active in-licensing and acquisition program designed to identify and acquire additional drug candidates.