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

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 2.5-3 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 22 +-16 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 11-13 yr). Participants were 347,978 men aged 35-57 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 < 0.0001). 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.

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

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

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

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

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

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 19257 patients, 14120 were non diabetic ( mean age 62.8 ± 8.5yr) Overall, 1366 (9.6%) developed diabetes , median follow-up 5.5 years (IQR 5-6.01yr) 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

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

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

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 0.90-0.98 0.006 FBS* (per mmol/l above 5 mmol/l) 5.80 5.24-6.43 <0.001 Male sex 0.98 0.84-1.14 0.750 BMI** (per 5 units increase) 1.49 1.38-1.62 SBP (per 10 mmHg) 1.07 1.04-1.10 Amlodipine ± Perindopril 0.66 0.59-0.74 HDL Cholesterol ( per mmol/l) 0.72 0.58-0.89 0.002 Triglyceride (per mmol/l) 1.12 1.07-1.17 Total cholesterol (per mmol/l) 0.89 0.84-0.94 Use of non CAD medication (Y/N) 1.25 1.11-1.40 Alcohol intake (unit/wk) 0.99 0.99-1.00 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

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 (1.8-3.5) 5.0 (3.7-6.8) 19.0 (14.3-25.4)

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

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

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