Valsartan was associated with a significant reduction in new-onset diabetes compared to amlodipine in a further pre-specified analysis of the VALUE trial, presented by°Dr. Sverre Kjeldsen°(Oslo, Norway) at the 15th European Meeting of Hypertension, held in Milan from June 17-21, 2005.
With valsartan there were 580 new cases of diabetes (11.5%) and with amlodipine there were 718 new cases (14.5%) reported (p<0.0001). The number of patients needed to treat to prevent 1 case of new onset diabetes was only 33.
Kjeldsen stated the data presented suggest that valsartan may have a beneficial effect on glucose metabolism. VALUE is the largest trial using an ARB, and included 9995 high-risk non-diabetic patients. Kjeldsen noted that the protective effect of valsartan was most pronounced in patients with the greatest susceptibility for developing diabetes.Evaluating the patients by tertiles of risk, more than a 6-fold increase in the incidence of new diabetes was found in the highest tertile compared to the lowest tertile. A significant prevention in new diabetes was found with valsartan in the 2nd tertile (p=0.0058) and 3rd tertile of risk (p=0.0007).
New-onset diabetes was defined as the presence of 1 or more of these factors: patient included in the adverse event database for diabetes; concomitant medication database for new drug treatment for diabetes); increased fasting glucose (≥7.0 mmol/L) at study end in the patients without diabetes at baseline (n=9995).
Of the 9995 patients without diabetes at baseline, 5032 were in the valsartan arm and 4963 in the amlodipine arm. The two groups were well balanced at baseline. About 41% were women, about 67 years old, BMI of 28, and a blood pressure of 154/88 mm Hg. The groups were also well balanced for the qualifying risk factor, with about 35% having high cholesterol, 26% smokers, and 19% proteinuria. Also, in terms of antihypertensive medications at baseline, the 2 groups were well balanced, with 37% on an ACE inhibitor, 35% on a beta blocker, and 41% on a CCB; these drugs were discontinued at randomization into the trial.
During the trial, there were some differences in antihypertensive treatment between the 2 groups. More patients in the amlodipine arm remained on monotherapy throughout the trial compared to valsartan (22% vs 16%, respectively). More patients in the valsartan group had add-on therapy of a diuretic than in the amlodipine arm (26% vs 24%, respectively), and more patients in the valsartan arm received both a diuretic and beta-blocker than in the amlodipine arm (18.4% vs 18.0%), yet they still had less new onset diabetes during the course of the trial.
The mean systolic blood pressure (SBP) and mean diastolic blood pressure (DBP) were slightly higher in the valsartan group than in the amlodipine group for the first 3 months.
Significant reductions in new onset diabetes for each criterion of detection were found
|Detection criterion||Valsartan (%)||Amlodipine (%)||P value|
|Adverse event reporting||328 (6.5)||436 (8.8)||<0.0001|
|New anti-diabetic medication||254 (5)||298 (6)||<0.0365|
|Final glucose value||313 (6.2)||387 (7.8)||<0.0020|
Notably, primary events began to occur in the patients without diabetes at baseline but who developed diabetes during the trial, with a curve beginning to mirror the curve for the event rate in the patients who had diabetes at baseline. The number of events was smaller in the patients who did not have diabetes at baseline, but the length of the trial was short. However, this does show that developing diabetes does confer the risk of events.
By tertiles of cardiac risk, there was more new onset diabetes in the highest risk 3rd tertile compared to the 1st and 2nd quartiles 878 (26.4%) patients, 138 (4.1%) patients, and 282 (8.5%), respectively. The 1st tertile had 3331 patients, and the 2nd and 3rd each had 3332 patients.
The primary hypothesis of the main VALUE trial was that in hypertensive patients at high cardiovascular risk, for the same level of blood pressure control, valsartan will be more effective than amlodipine in reducing cardiac morbidity and mortality. VALUE was the first trial to compare a modern ARB (valsartan) to the most widely used third-generation CCB (amlodipine). It was designed to evaluate the effectiveness of a valsartan-based regimen versus an amlodipine-based regimen on overall cardiac outcomes. VALUE is the largest trial in hypertension using an ARB.On multivariate analysis, 6 predictors for risk of developing new-onset diabetes were found: glucose, BMI, use of diuretic plus beta blocker, White race, age, and heart rate.
The patients were treated or untreated hypertensive patients (for untreated, a SBP of 160-210, and for DBP <105), older than 50 years of age, and were at high risk for cardiac events, defined as one or more risk factors or diseases.