1. Determinants of new onset diabetes among hypertensive patients randomised in the ASCOT-BPLA Trial
Dr Ajay K Gupta
International Centre for Circulatory Health NHLI, Imperial College London
Presented on behalf of the ASCOT Investigators

2. Background
Hypertension and diabetes are common co-morbid conditions, and their relationship is complex
Hypertension is an independent risk factor for diabetes development, and increases risk by 2-3 times
Recent studies have shown that antihypertensive drugs -particularly beta-blockers and diuretics - variably potentiate this enhanced risk
Controversy still persists because of methodological criticisms of these studies, and lack of robust evidence for reduction in cardiovascular benefits as a result of new onset diabetes development
In MRFIT trial( Stamler et al Diabetes care 1993) the risk at any given level of SBP was times higher in those with type2 diabetes than in their non-diabetic counterparts for a given level of SBP.
Therei s an increasing body of data that aggressive management of blood pressure in patients with diabetes reduces the cardiovascular morbidity and mortality in addition it also reduces the renal complications. In SHEP elderly with type 2 diabetes benefited more as compared to non diabetic patients. Similarly in HOT it was shown the risk of cvd mortality in patients with the diabetes the reduction of diastolic pressures from <90 to <85 further reduced the CVD events. In systolic hypertension in Europe trial, the risk reduction in mortality for a comparable blood pressure reduction of mm of Hg, the risk reduction in non diabetic patients was 13% as compared to 76% in the patients with diabetes.
Overall the benefit confiremed per mm of Hg blood pressure reduction is more in patients with diabetes as compared to non-diabetic patients with hypertension.
OBJECTIVE--To assess predictors of CVD mortality among men with and without diabetes and to assess the independent effect of diabetes on the risk of CVD death. RESEARCH DESIGN AND METHODS--Participants in this cohort study were screened from 1973 to 1975; vital status has been ascertained over an average of 12 yr of follow-up (range yr). Participants were 347,978 men aged yr, screened in 20 centres for MRFIT. The outcome measure was CVD mortality. RESULTS--Among 5163 men who reported taking medication for diabetes, 1092 deaths (603 CVD deaths) occurred in an average of 12 yr of follow-up. Among 342,815 men not taking medication for diabetes, 20,867 deaths were identified, 8965 ascribed to CVD. Absolute risk of CVD death was much higher for diabetic than nondiabetic men of every age stratum, ethnic background, and risk factor level--overall three times higher, with adjustment for age, race, income, serum cholesterol level, sBP, and reported number of cigarettes/day (P < ). For men both with and without diabetes, serum cholesterol level, sBP, and cigarette smoking were significant predictors of CVD mortality. For diabetic men with higher values for each risk factor and their combinations, absolute risk of CVD death increased more steeply than for nondiabetic men, so that absolute excess risk for diabetic men was progressively greater than for nondiabetic men with higher risk factor levels. CONCLUSIONS--These findings emphasize the importance of rigorous sustained intervention in people with diabetes to control blood pressure, lower serum cholesterol, and abolish cigarette smoking, and the importance of considering nutritional-hygienic approaches on a mass scale to prevent diabetes.

3. ASCOT-BPLA 19,342 hypertensive patients ASCOT-BPLA
atenolol ± bendroflumethiazide
PROBE
design
amlodipine ± perindopril
placebo
atorvastatin 10 mg
Double-blind
ASCOT-LLA
10,305 patients
TC ≤ 6.5 mmol/L (250 mg/dL)
www. ascotstudy.org

4. New onset diabetes* in ASCOT-BPLA%
10.0
Atenolol  thiazide
(No. of events = 799)
8.0
31%
6.0
Cumulative Events
Amlodipine  perindopril
(No. of events = 567)
4.0
2.0
0.0
Years
0.0
1.0
2.0
3.0
4.0
5.0
* New onset diabetes was a pre-specified outcome in ASCOT

5. Objectives
To determine the predictors of new onset diabetes (NOD) among hypertensive patients in ASCOT-BPLA
To develop a risk score to identify those at high risk

6. Outcome definitions
Baseline diabetes : Presence of any 1 of 3 criteria
FPG ≥ 7 mmol/l and/or random glucose ≥11.1mmol/l
Self reported diabetes and receiving dietary or drug therapy
Presence of both IFG (≥ 6mmol/l) and glucosuria in absence of above two criteria (endpoint committee exclusion definition)
New onset diabetes : according to WHO 1999 definition

7. Methods
A multivariable Cox proportional hazard regression model was developed using forward stepwise selection (p<0.05) with age, sex and blood pressure treatment group as covariates. The model was assessed for internal validity and discriminative ability
Based on the Cox model, risk scores for individuals were estimated by summing of the product of the coefficient and the variable value
Risk scores were divided into quartiles and model calibration was evaluated by comparing the observed outcomes with the predicted outcomes

8. ASCOT-BPLA: Trial Profile
19342 randomised
85 excluded because of blood pressure measurement irregularities
19257 evaluable
5137 with “diabetes” at baseline*
14120 patient at risk of NOD
7046 in atenolol-based treatment group
7074 in amlodipine-based treatment group
Out of patients, were non diabetic ( mean age 62.8 ± 8.5yr)
Overall, 1366 (9.6%) developed diabetes , median follow-up 5.5 years (IQR yr) with incidence rate 18.6 per 1000 pyrs.
799/7046 (11.36%) developed diabetes on atenolol based treatment with incidence rate of 22.1 per 1000pyrs
567/7074 (8.02%) developed diabetes on amlodipine based treatment with incidence rate of 15.2 per 1000pyrs
799 (11.4%) developed new onset diabetes
567 (8%) developed new onset diabetes

9. Baseline characteristics
At risk population (n=14120)
Remain non-diabetic
(n=12754)
Develop diabetes
(n=1366)
Percent/mean±SD
Atenolol-based group (%)
49.0
58.5
Age (yrs)
63.0 ± 8.5
61.6 ± 8.3
Male (%)
77.8
80.7
BMI (kg/m2)
27.9 ± 4.3
30.2 ± 4.5
Current smoker (%)
69.5
72.9
TC/HDL ratio
4.8
5.1
Total cholesterol (mmol/l)
6.0 ±1.1
5.9 ±1.1
HDL (mmol/l)
1.34 ±0.4
1.23 ±0.3

10. Baseline characteristics
At risk population (n=14120)
Remain non-diabetic
(n=12754)
Develop diabetes
(n=1366)
TG (mmol/l)
1.73 ± 0.9
2.11 ± 1.1
FPG (mmol/l)
5.3 ± 0.6
5.9 ± 0.7
>4 risk factors (%)
12.3
15.5
H/O previous anti-HT drug (%)
79.4
80.1
Use of non CAD concomitant medication (%)
56.4
60.2
Previous aspirin (%)
18.9
18.4
Previous lipid lowering drugs (%)
9.0
10.1
SBP (mm Hg)
163.6 ± 17.9
165.0 ± 18.3
DBP (mm Hg)
95.3 ± 10.2
96.4 ± 10.7
HR (beats per minute)
70.8 ± 12.3
72.9 ± 12.9

11. Multivariable Cox proportional hazard model ( Primary Cox model n=12692; cases=1212)
Hazard ratio
95% confidence interval
p-value
Age>55 (per 5 year)
0.94
0.006
FBS* (per mmol/l above 5 mmol/l)
5.80
<0.001
Male sex
0.98
0.750
BMI** (per 5 units increase)
1.49
SBP (per 10 mmHg)
1.07
Amlodipine ± Perindopril
0.66
HDL Cholesterol ( per mmol/l)
0.72
0.002
Triglyceride (per mmol/l)
1.12
Total cholesterol (per mmol/l)
0.89
Use of non CAD medication (Y/N)
1.25
Alcohol intake (unit/wk)
0.99
0.017
* All those having FBS≤5 mmol/l were given baseline risk
** All those with BMI >35 kg/m2 were given similar risk, hazard ratio for every 5 unit rise from baseline

12. New onset diabetes according to risk score quartiles
0.30 4
0.20
Probability of new onset diabetes
0.10 3 2 1
0.00 1 2 3 4 5
Follow-up time (years)
Risk quartile
1st Quartile
2nd Quartile
3rd Quartile
4th Quartile
Hazard Ratio (95% CI) 1
2.5
( )
5.0
( )
19.0
( )

13. Probability of development of diabetes stratified by quartile of risk score and the treatment drug*
0.30
Atenolol-based treatment 4
0.20
Probability of new onset diabetes
Amlodipine-based treatment
0.10 3 2 1
0.00 1 2 3 4 5
Follow-up time (years)
Atenolol ± thiazide =solid; Amlodipine± perindopril=dash
*treatment adjusted for but excluded in risk score calculation

14. Observed and expected probabilities of the development of diabetes by quartile of risk score in ASCOT
Number of observed events 44
105
206
765

15. Summary & conclusions
FPG, BMI, antihypertensive therapy, HDL-c and triglyceride level are important baseline predictors for development of diabetes
Compared with use of atenolol ± thiazide, the use of amlodipine± perindopril is associated with 34% reduction in risk of NOD, and this decrease is irrespective of the baseline risk category
Risk model developed is robust, has an excellent discriminative ability, and potentially could play an important role in clinical practice