Ten-Year Follow-up of UKPDS Shows No Legacy Effect of In-trial Blood Pressure Control

The 10-year follow-up results of the United Kingdom Prospective Diabetes Study (UKPDS) show that the benefits seen in patients originally assigned to a strategy of tight blood pressure control were not sustained once the differences in blood pressure seen early in the trial were lost. This contrasts with the continuing benefit of earlier improved glucose control seen during the same follow-up period, with significant risk reductions for MI and all-cause mortality. This is the first time that the "legacy effect" of treatment in a blood pressure lowering trial has been reported.

UKPDS was a randomized, prospective, multicenter trial that showed that intensive blood-glucose control using either sulphonylureas or insulin substantially decreased the risk of microvascular complications, but not macrovascular disease, in patients with type 2 diabetes. Between 1987 and 1991, UKPDS patients with hypertension were, in addition, randomly assigned by factorial design to tight control of blood pressure aiming at a blood pressure of < 150/85 mm Hg (with an ACE inhibitor, captopril, or a beta-blocker, atenolol, as main treatment) vs less-tight control aiming at a blood pressure of < 180/105 mm Hg. For tight compared with the less-tight control of blood pressure, there were relative risk reductions of 24% in diabetes-related endpoints (P = .005), 32% in deaths related to diabetes (P = .02), 44% in strokes (P = .01), and 37% for microvascular disease (P = .009).

Among the 5102 UKPDS patients with newly diagnosed type 2 diabetes mellitus, 1148 with hypertension were randomized to captopril ≤ 50 mg twice daily or atenolol ≤ 100 mg once daily (tight blood pressure control) or to a regimen without ACE inhibitors or beta-blockers (less tight control). Additional antihypertensive drugs allowed to achieve blood pressure targets included furosemide, slow-release nifedipine, methyldopa, and prazosin. At the end of the interventional trial, a total of 884 of these patients entered the post-trial monitoring program, during which physicians were advised to aim for the lowest blood pressure levels, but no attempt was made to maintain their previously randomized therapies. During the first 5 years of follow-up, patients were seen at annual visits to UKPDS clinics, or for patients who were unable to attend the clinic, annual questionnaires completed by patients and general practitioners were used. During Years 6 to 10, due to funding constraints, questionnaires were used for all patients.

At baseline the tight blood pressure control group had lower SBP (by 9 mm Hg, P < .001) and DBP (by 3 mm Hg, P < .001) than the less-tight blood pressure control group, but these differences had been lost by Year 1 and Year 2, respectively, of follow-up. By Year 3, the researchers say, it was already evident that the blood pressure differences had been lost. The significant relative risk reductions seen during the trial for any diabetes-related endpoint, diabetes-related death, stroke, and microvascular disease in the group receiving tight compared with less-tight blood pressure control diminished over time and were not significant at Year 10 of follow up: 7% for any diabetes-related end point (P = .31), 16% for diabetes-related death (P = .12), 23% for stroke (P = .12), and 16% for microvascular disease (P = .17). No risk reductions were seen during or after the trial for MI or death from any cause, but a risk reduction for peripheral vascular disease associated with tight blood-pressure control became significant at year 10 (P = .02), although few patients in this study had peripheral vascular disease.

In The New England Journal of Medicine, Prof. Holman and colleagues say that it is not surprising that the beneficial effects seen in study populations randomly assigned to blood pressure-lowering therapies are lost once the blood-pressure differences are lost. They point out that most trials of blood pressure reduction therapy show an early separation of the cumulative risk of macrovascular endpoints between study groups. They suggest that "the relatively rapid ‘on-effects’ of improved blood pressure lowering on cardiovascular risk would be reflected in similarly rapid ‘off-effects’ if blood-pressure control were to be relaxed." Alternatively, "post trial improvements in blood-pressure therapy in groups treated less aggressively during the trial would be likely to bring their cardiovascular risks into line with those treated more aggressively during the trial."

In either case, if blood pressure control is lost or diminished, no long-term differences in cardiovascular risk would be seen, as happened in the UKPDS follow-up. The researchers stress the importance of maintaining optimal blood pressure control in diabetic patients to maintain benefits in reducing the risk of macro- and microvascular disease.

Long-term follow-up of blood glucose control showed continuing benefit of earlier intensive glucose control, with emergent significant risk reductions for MI and all-cause mortality, despite loss of within-trial blood glucose and antihyperglycemic therapy differences. A legacy effect was seen also for earlier metformin therapy.

The results of the 10-year post trial monitoring program were presented by Rury R. Holman, MD (Oxford Centre for Diabetes, Endocrinology & Metabolism, Oxford, UK) at the 44th Annual Meeting of the European Association for the Study of Diabetes, held September 7-11, 2008 in Rome, Italy, and published simultaneously in The New England Journal of Medicine.