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Therapeutics

Tight blood pressure control reduced diabetes mellitus-related deaths and complications and was cost-effective in type 2 diabetes

ACP J Club. 1999 Jan-Feb;130:4-5. doi:10.7326/ACPJC-1999-130-1-004


Source Citations

UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ. 1998 Sep 12;317:703-13.

UK Prospective Diabetes Study Group. Cost effectiveness analysis of improved blood pressure control in hypertensive patients with type 2 diabetes: UKPDS 40. BMJ. 1998 Sep 12;317:720-6.


Abstract

Questions

In hypertensive patients with type 2 diabetes mellitus, can tight blood pressure control reduce morbidity and mortality, and is it cost-effective?

Design

Multicenter, randomized, controlled trial with median follow-up of 8.4 years. A cost-effectiveness analysis was done, and a simulation model was used to estimate life expectancy beyond the end of the trial.

Setting

20 hospital-based clinics in England, Scotland, and Northern Ireland.

Patients

1148 patients (mean age 56 y, 55% men) with type 2 diabetes and hypertension (systolic pressure ≥ 150 mm Hg, diastolic pressure ≥ 85 mm Hg, or both in patients receiving antihypertensive treatment; or systolic pressure ≥ 160 mm Hg, diastolic pressure ≥ 90 mm Hg, or both in patients not receiving antihypertensive treatment) who had been recruited to the U.K. Prospective Diabetes Study (UKPDS). Exclusion criteria were a clinical requirement for strict blood pressure control or β-blockade, severe vascular disease, severe concurrent illness or illness precluding β-blocker use, pregnancy, or unwillingness to participate. Follow-up was 96%.

Intervention

Patients were stratified for presence or absence of previous hypertensive treatment. 758 patients were allocated to tight blood pressure control aiming for a blood pressure of < 150/85 mm Hg by first-line use of captopril, 25 mg twice/d increasing to 50 mg twice/d if required (n = 400), or atenolol, 50 mg/d increasing to 100 mg/d if required (n = 358). 390 patients were allocated to less tight blood pressure control aiming for a blood pressure of < 180/105 mm Hg without the use of angiotensin-converting enzyme inhibitors or β-blockers. If target blood pressure values were not met, patients used furosemide, nifedipine, methyldopa, or prazosin.

Main cost and outcome measures

The cost-effectiveness of tight control was compared with less tight control on the basis of costs of treatment and the management of diabetes complications, costs per extra within-trial year free from diabetes-related end points, and costs per life-year gained. Costs (in 1997 pounds sterling) were based on those associated with the trial protocol and were transformed to reflect the costs of standard clinical practice.

Main outcomes were a first diabetes-related nonfatal or fatal predefined clinical end point, deaths related to diabetes, and all-cause mortality. Secondary outcomes were myocardial infarction, stroke, amputation or death from peripheral vascular disease, and microvascular disease.

Main results

Analysis was by intention to treat. Patients allocated to tight control had lower mean blood pressure over 9 years of follow-up than those allocated to less tight control (144/82 vs 154/87 mm Hg, P < 0.001). During follow-up, patients allocated to tight control had reduced risks for developing a diabetes-related clinical end point (P = 0.005), diabetes-related death (P = 0.019), stroke (P = 0.013), and microvascular disease (P = 0.009) than patients allocated to less tight control (Table). No differences existed for all-cause mortality, myocardial infarction, and amputations or deaths from peripheral vascular disease (Table).

Based on the use of resources associated with the trial protocol, over the median follow-up period tight control increased the total cost of treatment by £740/patient compared with less tight control but reduced the total cost of complications by £949/patient (a net savings of £209/patient, undiscounted values). By the simulation model, tight control increased the within-trial years free from end points by 0.23 years (discounted at 6%/yr) but did not increase life expectancy. Based on estimates of the cost of resources in standard clinical practice, the incremental cost per extra year free from end points was £1049 (costs and health effects discounted at 6%/yr) and £434 (costs discounted at 6% per year, and health effects not discounted); and the incremental cost per life-year gained was £720 (costs and health effects discounted at 6%/yr) and £291 (costs discounted at 6%/yr and health effects not discounted).

Conclusions

In hypertensive patients with type 2 diabetes mellitus, tight control of blood pressure (target blood pressure <150/85 mm Hg) using captopril or atenolol reduced the risk for diabetes-related complications or death, strokes, and microvascular disease. Tight control was cost-effective, had favorable cost-effectiveness ratios, and reduced the cost of complications.

Sources of funding: Medical Research Council; British Diabetic Association; U.K. Department of Health; National Institutes of Health; British Heart Foundation; Charles Wolfson Charitable Trust; Clothworkers' Foundation; Health Promotion Research Trust; Alan and Babette Sainsbury Trust; Oxford University Medical Research Fund Committee; Novo-Nordisk; Bayer; Bristol-Myers Squibb; Hoechst; Lilly; Lipha; Farmitalia Carlo Erba; Glaxo-Wellcome; Smith-Kline Beecham; Pfizer; Zeneca; Pharmacia and Upjohn; Roche; Boehringer Mannheim; Becton Dickinson; Owen Mumford; Securicor; Kodak; Cortecs Diagnostics.

For correspondence: Professor R. Turner, U.K. Prospective Diabetes Study Group, Diabetes Research Laboratories, Radcliffe Infirmary, Oxford OX2 6HE, England, UK. FAX 44-1865-723884 for the first report; Dr. A. Gray, Health Economics Research Centre, Institute of Health Sciences, Oxford University, Oxford OX3 7LF, England, UK. FAX 44-1865-226842 for the economic analysis.


Table. Tight vs less tight blood pressure control in hypertensive patients with type 2 diabetes melllitus*

Outcomes over 8.4 y of follow-up Tight control Less tight control RRR (95% CI) NNT (CI)
Any diabetes-related clinical end point 34% 44% 22% (9 to 32) 11 (6 to 29)
Diabetes-related death 11% 16% 32% (8 to 50) 20 (10 to 100)
All-cause mortality 18% 21% 17% (-6 to 35) Not significant
Myocardial infarction 14% 18% 20% (-5 to 39) Not significant
Stroke 5% 9% 42% (10 to 63) 27 (14 to 141)
Peripheral vascular stroke 1% 2% 49% (-32 to 80) Not significant
Microvasular disease 9% 14% 35% (9 to 54) 21 (11 to 94)

*Abbreviations defined in Glossary; RRR, NNT, and CI calculated from data in article.


Commentary

The UKPDS shows that meticulous blood pressure reduction is important in patients with type 2 diabetes. This finding has major implications for health care because of the projected dramatic increase in diabetes in the future and the clear relation between diabetes and hypertension. The Systolic Hypertension in the Elderly Program (SHEP) has shown that antihypertensive treatment reduces cardiovascular events in elderly patients with and without diabetes (1). The present trial consolidates this information and extends the findings to younger patients and to patients with newly detected diabetes. The results are consistent with the recently published Hypertension Optimal Treatment (HOT) study, in which intensive blood pressure lowering was more effective in reducing cardiovascular events among patients with diabetes than among those without diabetes (2). In addition, the UKPDS shows that intensive blood pressure control reduces microvascular complications, which is an outcome that has not been addressed in previous studies of hypertension management in patients with diabetes.

The mean blood pressure of 144/82 mm Hg achieved in the UKPDS is similar to the blood pressure achieved in the SHEP study. It is, however, higher than that attained in the HOT study, which showed that the lowest targeted diastolic blood pressure was most protective, especially among patients with diabetes. Taken together, these studies provide no evidence for any negative effect of blood pressure lowering. Therefore, assuming a curvilinear relation between cardiovascular disease and hypertension, the treatment goal should be 140/80 mm Hg or possibly lower. To achieve this goal, multi-drug treatment may be needed. In the UKPDS, almost one third of the intensively treated patients were receiving at least 3 drugs.

The UKPDS also showed that β-blockers and angiotensin-converting enzyme inhibitors were equally effective in preventing macrovascular and microvascular events (3). The SHEP study used chlorthalidone and the HOT study used felodipine as initial therapy. This shows that blood pressure reduction itself is more important than the pharmacologic tool by which reduction is achieved. However, the effectiveness of monotherapy with calcium channel blockers is uncertain and awaits further evidence (4).

The UKPDS investigators performed a cost-effectiveness analysis based on the use of the resources in the trial protocol. These costs were transformed to show the resources that would be needed for the same treatment in standard clinical practice. Tight blood pressure control in patients with type 2 diabetes was cost-effective. The analyses did not consider the full societal perspective because the indirect cost of morbidity and the increased future costs from increased life expectancy were not included in the analysis. However, the data are strong enough to support the overall conclusion from this broader perspective.

In summary, the UKPDS confirms that tight blood pressure control is key to the treatment of type 2 diabetes. Apart from protecting patients from unnecessary suffering, it is cost-effective. However, it should be emphasized that blood pressure control is just part of a holistic approach to the care of patients with diabetes. Comprehensive care should include glycemic control and meticulous evaluation and treatment of other cardiovascular risk factors, such as dyslipidemia and smoking.

Bjorn Almbrand, MD
Klass Malmberg, MDLars Rydén, MDInstitutionen für Medicin Vid Karolinska SjukhusetStockholm, Sweden


References

1. Curb JD, Pressel SL, Cutler JA, et al. Effect of diuretic-based antihypertensive treatment on cardiovascular disease risk in older diabetic patients with isolated systolic hypertension. Systolic Hypertension in the Elderly Program Cooperative Research Group. JAMA. 1996;276:1886-92.

2. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT study group. Lancet. 1998;351:1755-62.

3. UK Prospective Diabetes Study Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. BMJ. 1998;317:713-20.

4. Malmberg K, Ryden L, Wedel H. Calcium antagonists, appropriate therapy for diabetic patients with hypertension? Eur Heart J. 1998;19:1269-72.