NAVIGATOR Shows Valsartan Delayed Progression to Type 2 Diabetes in At-Risk Cardiovascular Patients With Impaired Glucose Tolerance

EAST HANOVER, N.J., March 14 /PRNewswire/ -- Results from a landmark study involving more than 9,000 people showed that the high blood pressure medicine valsartan delayed progression to type 2 diabetes in patients with cardiovascular disease or risk factors and impaired glucose tolerance (IGT), a common pre-diabetic condition.

Primary data from the NAVIGATOR (Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research) trial, initiated in 2001, were presented today at the American College of Cardiology Annual Meeting in Atlanta and simultaneously published online in the New England Journal of Medicine. The study assessed whether valsartan or the oral anti-diabetic agent nateglinide could delay progression to diabetes or reduce the incidence of cardiovascular events in people with IGT and cardiovascular disease or risk factors.

"Obesity and hypertension are global health epidemics, and many of these patients have problems with impaired glucose tolerance. From numerous studies, we know that patients with IGT have an increased risk for type 2 diabetes and cardiovascular disease," said Dr. Robert Califf, Vice Chancellor for Clinical Research at Duke University School of Medicine and Director of the Duke Translational Medicine Institute, Durham, NC, USA. "It is critical that we continue to search for pharmacologic interventions that may reduce the incidence of diabetes and cardiovascular disease while emphasizing to our patients that weight loss, as little as 5%, may improve outcomes."

Patients in the study with IGT and cardiovascular disease or other risk factors, who received valsartan for at least five years in addition to background therapy and a study-specific lifestyle-modification program, achieved a statistically significant 14% reduction in their risk of developing new-onset diabetes compared to those in the non-valsartan group.

Valsartan therapy did not show a reduction in the risk of cardiovascular events in this well-managed group of patients, while nateglinide-based therapy did not show a reduction in the incidence of new-onset diabetes or of cardiovascular events in this study population.

Trevor Mundel, M.D., Global Head of Development at Novartis Pharma AG said: "As a global leader in cardiovascular and metabolic health, Novartis is committed to advancing public health and policy pertaining to diabetes. We are very pleased with the findings of the NAVIGATOR study as they add to the large body of scientific information on valsartan."

The worldwide prevalence of diabetes is expected to increase by 50% (i.e. from 285 to 439 million patients) by 2030. IGT is a defined stage in the development of diabetes, and it has been suggested that up to 70% of people with impaired fasting glucose (IFG) and IGT are likely to develop type 2 diabetes over their lifetime. Current guidance from the American Diabetes Association, American College of Endocrinology/American Association of Clinical Endocrinologists and the World Health Organization recommends a variety of interventions for the management of pre-diabetes, based on lifestyle modification.

"Lifestyle modification remains the primary intervention for the prevention of diabetes. The NAVIGATOR study shows that valsartan, when added to a lifestyle-modification program, can delay progression to diabetes in people who are at high cardiovascular risk and have impaired glucose tolerance," said Dr Rury Holman, Professor of Diabetic Medicine at the Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, United Kingdom.

Novartis plans to discuss the results of this study with the U.S. Food and Drug Administration with a view to applying for a label change for valsartan. Valsartan is currently indicated for the treatment of high blood pressure, for the treatment of heart failure, and reducing the risk of cardiovascular mortality in patients who have suffered a heart attack (myocardial infarction). Nateglinide is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. Neither valsartan nor nateglinide is currently indicated for the treatment of patients with IGT.

About the study

NAVIGATOR was a prospective, multinational, randomized, double-blind, placebo-controlled, two-by-two factorial design trial being conducted in 39 countries at nearly 800 sites. The 9,306 patients enrolled in the trial had IGT and were either older than age 50 with diagnosed cardiovascular disease or older than age 55 with at least one risk factor for cardiovascular disease, such as high blood pressure, family history of heart disease, high cholesterol or smoking. In addition to background therapy and a study-specific lifestyle modification program, patients were randomized to receive either valsartan, nateglinide, valsartan and nateglinide together, or placebo.

NAVIGATOR had three co-primary endpoints. The first endpoint was confirmed progression to overt diabetes, defined according to standard WHO/ADA criteria. The second ('core' cardiovascular) endpoint was a composite of time to first occurrence of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke or hospitalization for heart failure. The third ('extended' cardiovascular) endpoint consisted of the core cardiovascular endpoint plus revascularization and hospitalization for unstable angina. The median follow-up time (for vital status) was 6.5 years.

The primary NAVIGATOR results for valsartan were as follows:

• Statistically significant reduction in the risk of progression to diabetes of 14% (HR 0.86, 95% CI 0.80–0.92; p<0.001) compared to non-valsartan treatment
• No statistical significant reductions of the 'core' (HR 0.99, 95% CI 0.86–1.14; p=0.42) and 'extended' (HR 0.96, 95% CI 0.86–1.07; p=0.22) CV endpoints

The primary results for nateglinide were as follows:

• No reduction compared to non-nateglinide treatment in terms of progression to diabetes (HR 1.07, 95% CI 1.00–1.15, p=0.98)
• No statistical significant reductions of the 'core' (HR 0.94, 95% CI 0.82–1.09, p=0.22) and 'extended' (HR 0.93, 95% CI 0.83–1.03, p=0.08) CV endpoints

Valsartan was dosed up to 160 mg once daily. During the course of the study, 556 participants (12%) in the valsartan group and 531 (11%) in the non-valsartan group discontinued study drug due to an adverse event. The most common adverse event seen in the valsartan group was hypotension. Nateglinide was dosed up to 60 mg three times daily. During the course of the study, 520 participants (11%) in the nateglinide group and 485 (10%) in the non-nateglinide group discontinued study drug due to an adverse event. The most common adverse events seen in the nateglinide group were hypotension-related and hypoglycemia.

Disclaimer

The foregoing release contains forward-looking statements that can be identified by terminology such as "risk," "continue to search," "may," "committed," "expected," "likely," "can," "plans," or similar expressions, or by express or implied discussions regarding potential new indications or labeling for valsartan or regarding potential future revenues from valsartan as a result. You should not place undue reliance on these statements. Such forward-looking statements reflect the current views of management regarding future events, and involve known and unknown risks, uncertainties and other factors that may cause actual results with valsartan to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantee that valsartan will be submitted or approved for any additional indications or labeling in any market. Nor can there be any guarantee that any such additional indications or labeling will result in valsartan achieving any particular levels of revenue in the future. In particular, management's expectations regarding valsartan could be affected by, among other things, unexpected regulatory actions or delays or government regulation generally; the company's ability to obtain or maintain patent or other proprietary intellectual property protection; competition in general; government, industry and general public pricing pressures; unexpected clinical trial results, including unexpected new clinical data and unexpected additional analysis of existing clinical data; the impact that the foregoing factors could have on the values attributed to the Novartis Group's assets and liabilities as recorded in the Group's consolidated balance sheet, and other risks and factors referred to in Novartis AG's current Form 20-F on file with the US Securities and Exchange Commission. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those anticipated, believed, estimated or expected. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.

About Diovan

DIOVAN (valsartan) is indicated for the treatment of hypertension.  DIOVAN may be used as monotherapy or in combination with other antihypertensive medications.

IMPORTANT SAFETY INFORMATION

WARNING: AVOID USE IN PREGNANCY

When pregnancy is detected, discontinue DIOVAN as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus.  [See WARNINGS and Precautions: Fetal/Neonatal Morbidity and Mortality (5.1) in full Prescribing Information]

Excessive hypotension was seen in patients treated with DIOVAN. Volume and/or salt depletion should be corrected in patients prior to administering DIOVAN. Caution should be observed when initiating DIOVAN in patients with heart failure or recent myocardial infarction, and in patients undergoing surgery or dialysis.

DIOVAN should be used with care in patients with mild-to-moderate hepatic impairment, including patients with biliary obstructive disorders, because of lower valsartan clearance. Monitor these patients for worsening of hepatic or renal function, including fluid status and electrolytes.

There has been no long-term use of valsartan in patients with unilateral or bilateral renal artery stenosis, but an effect similar to that seen with ACE inhibitors (increases in serum creatinine or blood urea nitrogen) should be anticipated with DIOVAN.

Care should be exercised when dosing DIOVAN in patients with renal artery stenosis or severe heart failure. As a consequence of inhibiting the renin-angiotensin system, changes in renal function may be observed. In patients with severe heart failure, decline in renal function and, rarely, acute renal failure and/or death has been associated with inhibiting the renin-angiotensin system.

Evaluation of patients with heart failure or post-myocardial infarction should always include assessment of renal function. Dosage reduction and/or discontinuation of the diuretic and/or valsartan may be required.

The most common adverse reactions that occurred more frequently with DIOVAN than placebo in hypertension patients were viral infection (3% vs 2%), fatigue (2% vs 1%), and abdominal pain (2% vs 1%).

About Starlix

STARLIX (nateglinide) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus

IMPORTANT SAFETY INFORMATION

STARLIX is contraindicated in patients with a known hypersensitivity to the drug or its inactive ingredients, in patients with type 1 diabetes, and in patients with diabetic ketoacidosis. Patients with diabetic ketoacidosis should be treated with insulin.

All oral blood glucose lowering drugs that are absorbed systemically are capable of producing hypoglycemia. Patients should be advised to take STARLIX 1 to 30 minutes prior to eating a meal and to skip the dose if the meal is missed.

STARLIX should be used with caution in patients with moderate to severe liver disease because such patients have not been studied.

STARLIX should not be used during pregnancy.

The most common adverse events which occurred more frequently in STARLIX patients than placebo patients were upper respiratory infection (10.5% vs 8.1%), back pain (4.0% vs 3.7%), flu symptoms (3.6% vs 2.6%), dizziness (3.6% vs 2.2%), arthropathy (3.3% vs 2.2%), and diarrhea (3.2% vs 3.1%

For full prescribing information log onto www.pharma.us.novaris.com or contact Christine Cascio at 1-862-778-8026 or [email protected].

About Novartis

Located in East Hanover, New Jersey, Novartis Pharmaceuticals Corporation is an affiliate of Novartis AG, which provides healthcare solutions that address the evolving needs of patients and societies. Focused solely on healthcare, the Novartis Group offers a diversified portfolio to best meet these needs: innovative medicines, preventive vaccines, diagnostic tools, cost-saving generic pharmaceuticals and consumer health products. The Novartis Group is the only company with leading positions in each of these areas. In 2008, the Group's continuing operations achieved net sales of USD 41.5 billion and net income of USD 8.2 billion. Approximately USD 7.2 billion was invested in R&D activities throughout the Group. Headquartered in Basel, Switzerland, Novartis Group companies employ approximately 99,000 full-time-equivalent associates and operate in more than 140 countries around the world. For more information, please visit http://www.us.novartis.com.

SOURCE Novartis