Ajay Gupta presented “The determinants of new onset diabetes among hypertensive patients randomized in the ASCOT-BPLA trial” at the 2006 ESC/WCC on Wednesday， September 6. 2006 in Barcelona， Spain. The objectives of this analysis were to determine the predictors of new onset diabetes (NOD) and to develop a risk score to identify those at high risk. 

Background 

The ASCOT-BPLA study was terminated early， after 5.5 years， because the results demonstrated significant CV benefits in patients receiving the amlodipine- versus the atenolol-based therapy. These benefits were particularly noticeable in CV mortality， which was 24% lower in the patients in the amlodipine arm. NOD developed in nearly 10% of the patients who were not diabetic at baseline; the rate was 31% lower in the amlodipine arm. 

Patients and methods 

The ASCOT study included 19，257 patients， of whom 5，137 (27%) had diabetes at baseline. Diabetes was defined by any of the following three criteria; 1.WHO 1999 criteria 2.Self-reported and receiving treatment for their diabetes 3.Presenting with impaired fasting glucose and glucosuria. The remaining 14，120 nondiabetic patients were equally distributed between the amlodipine and atenolol groups (7，046 and 7，074， respectively). 

Development of diabetes 

In total， 1，366 patients developed diabetes: 567 (8%) in the amlodipine arm and 799 (11.4%) in the atenolol arm. This represents a 31% reduction in the amlodipine arm (HR 0.69， 95% CI 0.62-0.77， p<0.0001). （Table:Baseline characteristics of the NOD vs the non-NOD patients） From the table it is evident that patients who developed diabetes during the study had the following characteristics: ·Younger ·Higher BMI measurements ·Higher serum triglyceride ·Higher BP levels， ·Lower HDL-cholesterol levels. 

Risk factors for the development of NOD 

A univariate analysis was performed to identify which baseline demographic and treatment characteristics were most significantly associated with the development of NOD. Since the potential risk factors uncovered by this analysis were not necessarily independent variables， a multivariate analysis was then performed to determine the contribution of each to overall risk. The following 11 risk factors were identified as the most important (positive or negative) to overall risk. （Table:Multivariable Cox proportional hazard model） This multivariate analysis demonstrated the following: ·Fasting blood sugar， BP， weight， and triglyceride levels were significant risk factors for development of NOD. It is worth noting that the WHO and NCEP definitions of metabolic syndrome include these components. ·An amlodipine-based treatment， along with HDL-C and total cholesterol， was associated with a lower incidence of NOD. There is no easy explanation for the apparent benefits of total cholesterol. ·Higher age is also associated with a lower incidence of NOD， a finding compatible with the known epidemiology of NOD， the incidence of which increases up to the age of 60 and decreases thereafter. Given that the majority of patients in ASCOT were over 60， they had passed the age were onset of New Onset Diabetes was most likely. ·It might be possible to explain the influence of non-CAD medications if the medications involved were known 

Risk score 

The 11 risk factors listed in the previous table were used to calculate the individual risk score for all patients in the study. The risk scores and associated hazard ratios were then presented in quartiles and compared with actual rates of diabetes mellitus in these groups. （Table:Hazard ratios based on risk scores in quartile） The risk score is the first to be developed for NOD and reflects the relative risk (not the absolute risk) of developing NOD between quartiles of patients in ASCOT. The first quartile consists of patients at lowest relative risk for developing NOD， while the fourth quartile consists of patients at highest relative risk for developing NOD. It is standard to assign a risk of 1 to the “reference group” or to the quartile at lowest risk. When the HR of the 1st quartile i.e. those at lowest risk in the study， is set at 1， the risk is 2.5- fold higher in the 2nd quartile， 5.04 times higher in the 3rd quartile， and more than 19-fold higher in the 4th quartile of patients at highest risk. The great difference between the risk scores for each of the quartiles demonstrates highly significant discriminatory power. Most of the risk factors comprising the score are modifiable， which may influence how aggressively to treat individual risk factors as well as the choice of antihypertensive therapy. This could also be a factor in evaluations of total risk management. Work is ongoing to develop this risk table into a simple absolute risk calculator that can be used in general practice. 

Comments 

·The risk of having or developing diabetes is at least twice as great in hypertensive vs normotensive persons ·The presence of diabetes increases the risk of CV disease by 2- to 4-fold ·In ASCOT， almost 10% of the patients developed diabetes during the 5.4-year follow-up ·NOD occurred predominantly in patients with several of the risk factors included in the definition of metabolic syndrome， particularly in patients with relatively high rates of fasting blood sugar at baseline ·Compared with the atenolol-based therapy， amlodipine-based therapy， decreased the risk of developing NOD by 31% unadjusted and 34% adjusted. This is most likely due to the well-known negative effect of b-blockers and diuretics (as also seen in ALLHAT). The use of perindopril in the amlodipine arm is expected to contribute to this benefit. Amlodipine itself is considered metabolically neutral ·A patient’s risk of developing diabetes can be calculated， which may be used to determine the best possible treatment strategy ·Although it is not yet proven that drug-related diabetes carries the same poor long-term prognosis as diabetes in general， several guidelines caution that the use of a b-blocker diuretic regimen may increase a patient’s risk of developing diabetes. As a result of the ASCOT - BPLA results， the joint NICE/BHS guideline was revised to recommend calcium channel blockers as first-line therapy and relegates b-blockers to third-line treatment because of the increased likelihood that patients will develop NOD 

Conclusions 

·Hypertensive patients are at increased risk of developing diabetes， which substantially increases their risk of developing CV complications ·Baseline fasting blood sugar， H