Diovan und Starlix: Schlechte Nachrichten aus Atlanta

The blue circle symbol used to represent diabetes.
Diabetes-Symbol: Image via Wikipedia

Großer Rückschlag für Novartis: Diovan (Valsartan) schützt Patienten mit gestörter Glukosetoleranz und kardiovaskulären Erkrankungen oder Risikofaktoren zwar signifikant vor einem Diabetes. Der Effekt ist aber nur gering. Und Starlix (Nateglinide) bringt überhaupt nichts. Diese Ergebnisse der „NAVIGATOR“-Studie von Novartis sind heute in Atlanta vorgestellt worden und zeitgleich im „New England Journal of Medicine“ veröffentlicht worden.

Weder Diovan noch Starlix haben im Vergleich zu Placebo nach den aktuellen Daten der Studie irgendeinen signifikanten Einfluss auf das kardiovaskuläre Risiko, wobei alle Studienteilnehmer während der im Mittel fünfjährigen Studiendauer an einem Lifestyle-Interventionsprogramm teilnahmen.

Die 14prozentige Reduktion der Diabetes-Inzidenz in der Diovan-Gruppe sei recht bescheiden im Vergleich zu dem, was in anderen Studien mit einer Änderung des Lebensstils erreicht worden sei, so die Autoren der Valsartan-Studie unter Leitung von  Dr. John J. McMurray von der Universität von Schottland. Der Effekt von Diovan war nach Angaben der Wissenschaftler auch geringer als der von Acarbose, Metformin oder Rosiglitazon, wobei es keine Daten aus ähnlich langen Studien zu diesen Antidiabetika in Kombination mit einer Lebensstiländerung gebe.

Besonders enttäuschend sind die Ergebnisse für Novartis zu Nateglinide: Denn in der Starlix-Gruppe gab es sogar einen Trend zu einer höheren Diabetes-Inzidenz.

„Die Ergebnisse der NAVIGATOR-Studie sind ausgesprochen negativ heißt es in einem Kommentar von Dr. David M. Nathan (Massachusetts General Hospital in Boston) im „NEJM“. Es sei aber zu berücksichtigen, dass möglicherweise die hohe Ausfallrate in der Valsartan-Gruppe und die schlechte Compliance den fehlenden Effekt von Diovan auf die kardiovaskulären Ereignisse beeinflusst hätten.

Hier sind die Ergebnisse zu Diovan:

Kombinierte primäre Endpunkte Valsartan (n=4631) in Prozent Placebo (n=4675) in Prozent HR
Diabetes mellitus 33,1 36,8 0,86
Kombinierte Endpunkte: Herzkreislauf-Tod, nicht-tödliche und tödliche Infarkte, nicht-tödlicher Schlaganfall, Klinikaufenthalt wegen instabiler AP, Herzinsuffizienz oder Revaskularisierung 14,5 14,8 0,96
Kombinierte Endpunkte: Herzkreislauf-Tod, nicht-tödlicher Herzinfarkt, nicht-tödlicher Schlaganfall, Hospitalisierung wegen Herzinsuffizienz 8,1 8,1 0,99

Nathan vermutet, dass die Diovan-Ergebnisse auf die tägliche Praxis keinen Einfluss haben. Es könne aber sein, dass die FDA die Zulassung auf die Diabetes-Prävention erweitere. Allerdings habe sich Diovan von allen Medikamenten zur Diabetes-Prävention als das schwächste Präparat erwiesen. Außerdem sei es eins der teuersten.

Hier die Ergebnisse zu Starlix:

Kombinierte primäre Endpunkte Nateglinide (n=4645) in Prozent Placebo (n=466) in Prozent HR
Diabetes mellitus 36,0 33,9 1,07
Kombinierte Endpunkte: Herzkreislauf-Tod, nicht-tödliche und tödliche Infarkte, nicht-tödlicher Schlaganfall, Klinikaufenthalt wegen instabiler AP, Herzinsuffizienz oder Revaskularisierung 14,2 15,2 0,93
Kombinierte Endpunkte: Herzkreislauf-Tod, nicht-tödlicher Herzinfarkt, nicht-tödlicher Schlaganfall, Hospitalisierung wegen Herzinsuffizienz 7,9 8,3 0,94

Laut Dr. Rury R . Holman (Churchill Hospital in Oxford, GB) hatte Starlix nicht nur keinen Einfluss auf die kardiovaskulären Ereignisse und die Diabetes-Inzidenz. Unter dem Novartis-Präparat nahm sogar der Blutzucker zwei Stunden nach Glukose-Belastung um im Mittel 4,37 mg/dl zu. Dies könnte allerdings eine Folge davon gewesen sein, dass Starlix am Morgen vor dem Glukose-Belastungstest abgesetzt worden und es dann zu einem Rebound-Effekt gekommen sei. Eine andere Möglichkeit sei, dass die Reaktionsfähigkeit der Betazellen auf Glukose langfristig geschwächt werde.

Interessant ist der Kommentar des US-Kardiologen Professor James H. Stein aus Madison in Wisconsin – insbesondere zu der angeblichen Sicherheit von Starlix:

„Studies that test the strategy of “preventing diabetes” by administering an anti-glycemic medication really represents a “sleight of hand” by the pharmaceutical sponsors, who are looking to expand their market for blood sugar-lowering medication. After all, what is the difference between a pre-diabetic patient on a diabetes drug and a diabetic patient on a diabetes drug? Nothing, except catching the disease at an earlier stage, with an intervention of unknown long-term benefit and well known short-term risks and expense. You prevent diabetes, defined by a number, by lowering the number — not a really impressive trick. Now, if treating early prevents micro- and macro-vascular complications of diabetes, there might be a benefit to starting them early. But pharmacologically preventing the “development of diabetes” is not a real goal. It is a surrogate for a surrogate of a surrogate.

To this end, I congratulate the NAVIGATOR investigators for looking at preventing CVD events, but I am not at all surprised it was a negative study in regard to nateglinide. Secretagogues like repaglinide do not reduce CVD events even in individuals with diabetes, and there are mechanistic reasons to suspect harm, related to hypoglycemia and perhaps the effect of inhibiting the K-ATP channel in the myocardium.

Also, I think the authors’ conclusion that the drug “appears to be safe” is overstated. Although well-powered for efficacy, it was not big enough or long enough to exclude safety concerns, and it certainly can’t address safety in people with established CVD, in whom hypoglycemia has been shown to be predictive of mortality and CVD events, and in whom K-ATP channel inhibition could be very harmful. It is noteworthy that nateglinide binds more avidly to the cardiac K-ATP receptor (SUR2A) than the pancreatic K-ATP (SUR 1) and does so with an affinity similar to tolbutamide, which increased CHD events back in the 1980’s University Group Diabetes Study.

Finally, to say nateglinide “did not reduce the incidence of diabetes” is completely misleading– it increased it by 7% with a p=0.05. To me that is not safe, either. The explanation of rebound is an unconvincing hypothesis; “special pleading” for a drug without a niche. I suspect long-term beta cell failure was the reason.

In the end, our focus on drugs for individuals with glucose intolerance is a big distraction from proven interventions for diabetes and CVD prevention – diet and exercise. And for those who do fail, we have two good drugs: acarbose, which in patients with pre-diabetes reduced CVD events and progression to diabetes and metformin, which modestly reduced development of diabetes, but at least seems to reduce CVD events among diabetic patients. This disease is all about lifestyle, and if they fail lifestyle, acarbose may be the best answer. It may cause gas – but I suspect most people would put up with it if they knew it reduced diabetes, HTN, and CVD by 36-49% over 3.3 years.

Regarding the valsartan arm – it was a small effect for a class of dugs that we commonly use in these sorts of patients only. It is of interest, but not a game-changer.“


Hier ist die Stellungnahme von Novartis:


NAVIGATOR shows valsartan delayed progression to type 2 diabetes in at-risk cardiovascular patients with impaired glucose tolerance

  • NAVIGATOR study involved more than 9,000 patients, making it one of the largest and longest global trials to date in pre-diabetic patients
  • Valsartan-based regimen reduced risk of developing new-onset diabetes by 14%, but did not reduce risk of cardiovascular events
  • Nateglinide-based regimen did not reduce incidence of new-onset diabetes or of cardiovascular events

Basel, March 14, 2010 – 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, USA[1] and simultaneously published online in the New England Journal of Medicine[2],[3]. 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[1],[2].

Valsartan therapy did not show a reduction in the risk of cardiovascular events in this well-managed group of patients[1],[2], while nateglinide-based therapy did not show a reduction in the incidence of new-onset diabetes or of cardiovascular events in this study population[1],[3].

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 [4]. IGT is a defined stage in the development of diabetes[5], 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[6]. 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[7],[8],[9].

„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[2],[3]

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[2].

The primary NAVIGATOR results for valsartan were as follows:[1],[2]

  • 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 statistically significant reduction 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:[1],[3]

  • 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 statistically 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 the 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 events and hypoglycemia[2],[3]

Interessanter Link: Cardiobrief

Siehe auch

„Reuters“

Gina Kolata in der „New York Times“

„Hippokranet“


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