UKPDS 39 1998.

Methods	Randomized controlled open‐label trial conducted in England, Scotland, Northern Ireland.
Participants	Newly diagnosed patients with type 2 diabetes mellitus and hypertension (SBP 160 mmHg or higher, DBP 90 mmHg or higher, or both in patients not on antihypertensive therapy and SBP 150 mmHg or higher, DBP 85 mmHg or higher, or both in patients on antihypertensive therapy), mean age 56 years (range 25 to 65 years), male (55%), white (86%), baseline SBP/DBP was 160/94 mmHg, and pulse pressure was 66 mmHg. Exclusion criteria were ketonuria > 3 mmol/L, a history of myocardial infarction in the previous year, current angina or heart failure, more than one major vascular episode, serum creatinine concentration > 175 mmol/L, retinopathy requiring laser treatment, malignant hypertension, an uncorrected endocrine abnormality, an occupation which would preclude insulin treatment (such as heavy goods vehicle driver), a severe concurrent illness likely to limit life or require extensive systemic treatment, or inadequate understanding or unwillingness to enter the study. Follow‐up: 8.4 years
Interventions	Treatment: tight BP control group (Captopril 25 mg to 50 mg twice a day or atenolol 50 mg to 100 mg/day. Supplemental drugs added frusemide 20 mg to 40 mg twice a day, slow release nifedipine 10 mg to 40 mg twice a day, methyldopa 250 mg to 500 mg twice a day, prazosin 1 mg to 5 mg three times a day given sequentially to achieve target BP) . Control: no treatment. Participants in this group were given treatment if SBP 200 mmHg or higher, DBP 105 mmHg or higher, or both (frusemide, long acting nifedipine, methyldopa, prazosin given sequentially to control BP. If possible, ACE inhibitors and beta‐blockers were avoided).
Outcomes	Mortality, stroke, CHD and CHF, systolic BP and diastolic BP
Notes	The less tight control group did not receive any treatment unless their BP rose 200/105 mmHg or higher before 1992, or 180/105 mmHg or higher after 1992. In the control group at 1 year, 50% of the patients were treated for SBP 180 mmHg or higher, DBP 105 mmHg or higher, or both, with specified drug therapy (14% were on ACE inhibitors or beta‐blockers). Patients remaining on assigned therapy at study end: beta‐blocker arm 65%, ACE inhibitor arm 78% "During the study, patients assigned captopril and atenolol took their treatment for 80% and 74%, respectively, of the total person years of follow‐up." "Increasing number of agents were required to obtain the tight blood pressure control target of < 150/85 mmHg. A similar proportion of patients were taking three or more agents in the two groups."
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Full details of this study, including the recruitment and randomisation procedure, are reported in the accompanying paper." "Randomisation stratified for those with or without previous treatment for hypertension was performed by the coordinating centre." "Randomisation produced balanced numbers of patients allocated to the various glucose and blood pressure treatment combinations for the UK prospective diabetes study and hypertension in diabetes group." Comment: stratified randomization was used for random sequence generation. The risk was judged to be low as the accompanying paper mentioned the randomization method used.
Allocation concealment (selection bias)	Low risk	Quote: "Sealed opaque envelopes were used and checked as described for the UK prospective diabetes study." "Figure 1 in the accompanying paper shows that two thirds of the patients (758) were randomly allocated tight control of blood pressure aiming for a blood pressure of < 150/85 mmHg by the co‐ordinating centre; 400 patients were randomly allocated to captopril and 358 to atenolol. The small imbalance in the numbers of patients allocated to these two treatments occurred by chance as the randomisation was not blocked. The other 390 patients were randomly allocated less tight control of blood pressure, aiming at a blood pressure of < 180/105 mmHg but avoiding treatment with angiotensin converting enzyme inhibitors or beta blockers." Comment: allocation concealment properly carried out and the two groups matched in terms of biometric and biochemical characteristics.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Quote: "open‐label study" "Captopril was usually started at a dose of 25 mg twice daily, increasing to 50 mg twice daily, and atenolol at a daily dose of 50 mg, increasing to 100 mg if required. If the blood pressure control criteria were not met in the tight control group despite maximum allocated treatment, other agents were added, the suggested sequence being frusemide 20 mg daily (maximum 40 mg twice daily), slow release nifedipine 10 mg (maximum 40 mg) twice daily, methyldopa 250 mg (maximum 500 mg) twice daily, and prazosin 1 mg (maximum 5 mg) thrice daily." Comment: participants and treating physicians were not blinded.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "All available clinical information was gathered for possible endpoints, for example copies of admission notes, operation records, death certificates and necropsy reports. Copies of these without reference to the patient's allocated or actual treatment, were formally presented to two independent physicians who allocated an appropriate code from the ninth revision of the international classification of diseases (ICD‐9) if the criteria for any particular clinical endpoint had been met. Any disagreement between the two assessors was discussed and the evidence reviewed. If agreement was not possible, the information was submitted to a panel of two further independent assessors for final arbitration." Comment: blinding was not mentioned in this paper, but the quote was taken from the accompanying article UKPDS 38. BMJ 1998; 317:703­13. The risk was judged to be low.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	There was no information for the patients lost to follow‐up, though the reasons for non‐compliance were mentioned for the two groups, which were varying. The treatment discontinuation was nearly 20% to 25%, as well as reasons varying between the two groups, and statistical analysis was carried out using intention‐to‐treat. The trial did not assess the sole action of intervention as other drugs were also allowed. Other confounding factors, such as diabetes, were not excluded and could affect the outcome.
Selective reporting (reporting bias)	Low risk	Comment: all primary and secondary outcome measures, along with microvascular and macrovascular diseases' surrogate endpoints as described in the objective were reported in the results section.
Other bias	Unclear risk	Funding: The main grants for this study were from the Medical Research Council, British Diabetic Association, the Department of Health, the National Eye Institute and the National Institute of Digestive, Diabetes and Kidney Disease in the National Institutes of Health in the United States, the British Heart Foundation, Novo­Nordisk, Bayer, Bristol Myers Squibb, Hoechst, Lilly, Lipha, and Farmitalia Carlo Erba. Other funding companies and agencies are listed in the accompanying paper. Authors stated conflict of interest: none