Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38
Guarantor: R C Turner.
Abstract
Objective: To determine whether tight control of blood pressure prevents macrovascular and microvascular complications in patients with type 2 diabetes.
Design: Randomised controlled trial comparing tight control of blood pressure aiming at a blood pressure of <150/85 mm Hg (with the use of an angiotensin converting enzyme inhibitor captopril or a β blocker atenolol as main treatment) with less tight control aiming at a blood pressure of <180/105 mm Hg.
Setting: 20 hospital based clinics in England, Scotland, and Northern Ireland.
Subjects: 1148 hypertensive patients with type 2 diabetes (mean age 56, mean blood pressure at entry 160/94 mm Hg); 758 patients were allocated to tight control of blood pressure and 390 patients to less tight control with a median follow up of 8.4 years.
Main outcome measures: Predefined clinical end points, fatal and non-fatal, related to diabetes, deaths related to diabetes, and all cause mortality. Surrogate measures of microvascular disease included urinary albumin excretion and retinal photography.
Results: Mean blood pressure during follow up was significantly reduced in the group assigned tight blood pressure control (144/82 mm Hg) compared with the group assigned to less tight control (154/87 mm Hg) (P<0.0001). Reductions in risk in the group assigned to tight control compared with that assigned to less tight control were 24% in diabetes related end points (95% confidence interval 8% to 38%) (P=0.0046), 32% in deaths related to diabetes (6% to 51%) (P=0.019), 44% in strokes (11% to 65%) (P=0.013), and 37% in microvascular end points (11% to 56%) (P=0.0092), predominantly owing to a reduced risk of retinal photocoagulation. There was a non-significant reduction in all cause mortality. After nine years of follow up the group assigned to tight blood pressure control also had a 34% reduction in risk in the proportion of patients with deterioration of retinopathy by two steps (99% confidence interval 11% to 50%) (P=0.0004) and a 47% reduced risk (7% to 70%) (P=0.004) of deterioration in visual acuity by three lines of the early treatment of diabetic retinopathy study (ETDRS) chart. After nine years of follow up 29% of patients in the group assigned to tight control required three or more treatments to lower blood pressure to achieve target blood pressures.
Conclusion: Tight blood pressure control in patients with hypertension and type 2 diabetes achieves a clinically important reduction in the risk of deaths related to diabetes, complications related to diabetes, progression of diabetic retinopathy, and deterioration in visual acuity.
HDL=high density lipoprotein.
LDL=low density lipoprotein.
Acknowledgments
We appreciate the cooperation of the patients and many NHS and non-NHS staff at the centres. We thank Philip Bassett for editorial assistance, and Caroline Wood, Kathy Waring, and Lorraine Mallia for typing the manuscripts.
Notes
Editorials by Orchard and MogensenPapers pp 713, 720
Footnotes
Members of the study group are given at the end of the paper.
Funding: The UK prospective diabetes study and the hypertension in diabetes study was funded by grants from the Medical Research Council, British Diabetic Association, Department of Health, the United States National Eye Institute and the United States National Institute of Diabetes, Digestive and Kidney Disease in the National Institutes of Health, the British Heart Foundation, the Charles Wolfson Charitable Trust, the Clothworkers’ Foundation, the Health Promotion Research Trust, the Alan and Babette Sainsbury Trust, the Oxford University Medical Research Fund Committee, and pharmaceutical companies, including Novo-Nordisk, Bayer, Bristol-Myers Squibb, Hoechst, Lilly, Lipha, and Farmitalia Carlo Erba. GlaxoWellcome, SmithKline Beecham, Pfizer, Zeneca, Pharmacia and Upjohn, and Roche provided grants for health economics and epidemiological studies. Boehringer Mannheim, Becton Dickinson, Owen Mumford, Securicor, Kodak, and Cortecs Diagnostics gave additional help.
Conflict of interest: None.
References
- 1. Garcia MJ, McNamara PM, Gordon T, Kannell WB. Morbidity and mortality in diabetics in the Framingham population. Sixteen year follow-up. Diabetes. 1974;23:105–111.[PubMed]
- 2. Stamler J, Vaccaro O, Neaton JD, Wentworth DDiabetes, other risk factors, and 12 year cardiovascular mortality for men screened in the multiple risk factor intervention trial. Diabetes Care. 1993;16:434–444.[PubMed][Google Scholar]
- 3. Manson JAE, Colditz GA, Stampfer MJ, Willett WC, Krolewski AS, Rosner B, et al A prospective study of maturity-onset diabetes mellitus and risk of coronary heart disease and stroke in women. Arch Intern Med. 1991;151:1141–1147.[PubMed][Google Scholar]
- 4. Perneger TV, Brancati FL, Whelton PK, Klag MJEnd-stage renal disease attributable to diabetes mellitus. Ann Intern Med. 1994;121:912–918.[PubMed][Google Scholar]
- 5. Klag MJ, Whelton PK, Randall BL, Neaton JD, Brancati FL, Ford CE, et al Blood pressure and end stage renal disease in men. N Engl J Med. 1996;334:13–18.[PubMed][Google Scholar]
- 6. United Kingdom Prospective Diabetes Study GroupUK Prospective Diabetes Study 23: risk factors for coronary artery disease in non-insulin dependent diabetes. BMJ. 1998;316:823–828.[Google Scholar]
- 7. Hypertension in Diabetes Study GroupHDS 1: Prevalence of hypertension in newly presenting type 2 diabetic patients and the association with risk factors for cardio-vascular and diabetic complications. J Hypertens. 1993;11:309–317.[PubMed][Google Scholar]
- 8. Prescott-Clarke P, Primatesta P, editors. Health survey for England 1995. London: HMSO; 1997. [PubMed]
- 9. Harris MI, Cowie CC, Stern MP, Boyko EJ, Reiber GE, Bennett PH, editors. Diabetes in America. 2nd ed. Washington, DC: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 1995. [PubMed]
- 10. Hypertension in Diabetes Study GroupHDS 2: Increased risk of cardio-vascular complications in hypertensive type 2 diabetic patients. J Hypertens. 1993;11:319–325.[PubMed][Google Scholar]
- 11. United Kingdom Prospective Diabetes Study GroupUK Prospective Diabetes Study X: urinary albumin excretion over 3 years in diet-treated type 2 (non-insulin-dependent) diabetic patients, and association with hypertension, hyperglycaemia and hypertriglyceridaemia. Diabetologia. 1993;36:1021–1029.[PubMed][Google Scholar]
- 12. Nelson RG, Bennett PH, Beck GJ, Tan M, Knowler WC, Mitch WE, et al Development and progression of renal disease in Pima Indians with non-insulin-dependent diabetes mellitus. N Engl J Med. 1996;335:1636–1642.[PubMed][Google Scholar]
- 13. United Kingdom Prospective Diabetes Study GroupUK Prospective Diabetes Study 30: diabetic retinopathy at diagnosis of type 2 diabetes and associated risk factors. Arch Ophthalmol. 1998;116:297–303.[PubMed][Google Scholar]
- 14. Collins R, MacMahon SBlood pressure, antihypertensive drug treatment and the risks of stroke and of coronary heart disease. Br Med Bull. 1994;50:272–298.[PubMed][Google Scholar]
- 15. Collins R, Peto R, MacMahon S, Herbert P, Fiebach NH, Eberlein KA, et al. Blood pressure, stroke, and coronary heart disease. Part 2. Short-term reductions in blood pressure: overview of randomised drug trials in their epidemiological context. Lancet. 1990;335:827–838.[PubMed]
- 16. Medical Research Council Working PartyMRC trial of treatment of hypertension in older adults: principal results. BMJ. 1992;304:405–412.[Google Scholar]
- 17. Sanderson SHypertension in the elderly: pressure to treat? Health Trends. 1996;28(4):117–121.[PubMed][Google Scholar]
- 18. Parving HH, Andersen M, Smidt UH, Hommel E, Mathiesen ER, Svendsen PAEffect of antihypertensive treatment on kidney function in diabetic nephropathy. BMJ. 1987;294:1443–1447.[Google Scholar]
- 19. Mogensen C, Keane W, Bennett P, Jerums G, Parving H, Passa P, et al Prevention of diabetic renal disease with special reference to microalbuminuria. Lancet. 1995;346:1080–1084.[PubMed][Google Scholar]
- 20. Mogensen CESystemic blood pressure and glomerular leakage with particular reference to diabetes and hypertension. J Intern Med. 1994;235:297–316.[PubMed][Google Scholar]
- 21. Hypertension in Diabetes Study GroupHDS 3: Prospective study of therapy in type 2 diabetic patients—efficacy of ACE inhibitor and β-blocker. Diabet Med. 1994;11:773–782.[PubMed][Google Scholar]
- 22. United Kingdom Prospective Diabetes Study GroupUK prospective diabetes study VIII: study design, progress and performance. Diabetologia. 1991;34:877–890.[PubMed][Google Scholar]
- 23. United Kingdom Prospective Diabetes Study GroupUK prospective diabetes study 33: intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes Lancet 1998;352:837-53. [[PubMed]
- 24. British Diabetic AssociationDietary recommendations for diabetics for the 1980s. Hum Nutr Appl Nutr. 1982;36:378–394.[PubMed][Google Scholar]
- 25. Systolic Hypertension in the Elderly Program Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the systolic hypertension in the elderly program (SHEP) JAMA. 1991;265:3255–3264.[PubMed]
- 26. Dahlof B, Lindholm L, Hansson L, Scheriten B, Ekbom T, Wester POMorbidity and mortality in the Swedish trial in old patients with hypertension (STOP-Hypertension) Lancet. 1991;338:1281–1285.[PubMed][Google Scholar]
- 27. United Kingdom Prospective Diabetes Study GroupUK Prospective Diabetes Study XI: biochemical risk factors in type 2 diabetic patients at diagnosis compared witn age-matched normal subjects. Diabet Med. 1994;11:534–544.[PubMed][Google Scholar]
- 28. Manley SE, Burton ME, Fisher KE, Cull CA, Tumer RCDecreases in albumin/creatinine and N-acetylglucosaminidase/creatinine ratios in urine samples stored at −20°C. Clin Chem. 1992;38:2294–2299.[PubMed][Google Scholar]
- 29. UK Prospective Diabetes Study GroupEfficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. BMJ. 1998;317:713–720.[Google Scholar]
- 30. Curb JD, Pressel SL, Cutler JA, Savage P, Applegate WB, Black H, 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;276:1886–1892.[PubMed]
- 31. Hansson L, Zanchetti A, Carruthers SG, Dahlf B, Elmfeldt D, Julius S, et al Effect of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the hypertension optimal treatment (HOT) randomised trial. Lancet. 1998;351:1755–1762.[PubMed][Google Scholar]
- 32. Hypertension Detection and Follow-up Program Cooperative GroupMortality findings for stepped-care and referred-care participants in the Hypertension Detection and Follow-up Program, stratified by other risk factors. Prev Med. 1985;14:312–335.[PubMed][Google Scholar]
- 33. Klein R, Moss SE, Klein BE, Davis MD, DeMets DL. The Wisconsin Epidemiologic Study of Diabetic Retinopathy. XI. The incidence of macular edema. Ophthalmology. 1989;96:1501–1510.[PubMed]
- 34. Davies EG, Petty RG, Kohner EMLong term effectiveness of photocoagulation for diabetic maculopathy. Eye. 1989;3:764–767.[PubMed][Google Scholar]
- 35. British Multicentre GroupPhotocoagulation for proliferative diabetic retinopathy: a randomised controlled clinical trial using the xenon-arc. Diabetologia. 1984;26:109–115.[PubMed][Google Scholar]
- 36. Parving HH, Hommel E, Smidt UMProtection of kidney function and decrease in albuminuria by captopril in insulin dependent diabetics with nephropathy. BMJ. 1987;297:1086–1091.[Google Scholar]
- 37. Ravid M, Savin H, Jutrin I, Bental T, Lang R, Lishner MLong-term effect of ACE inhibition on development of nephropathy in diabetes mellitus type II. Kidney Int. 1994;45(suppl):S161–S164.[PubMed][Google Scholar]
- 38. Alberti KGMM, Gries FA, Jervell J, Krans HMA desktop guide for the management of non-insulin-dependent diabetes mellitus (NIDDM): an update. Diabetic Med. 1994;11:899–909.[PubMed][Google Scholar]
- 39. Canadian Diabetes Advisory BoardClinical practice guidelines. Can Med Assoc J. 1992;147:697–712.[Google Scholar]
- 40. Bauduceau B, Chatellier G, Cordonnier D, Marre M, Mimran A, Monnier L, et al. Hypertension arterielle et diabète. Membres des conseils d’administration et scientifiques de l’ALFEDIAM. Diabetes Metab. 1996;22:64–76.[PubMed]
- 41. RR Associates. Blood pressure and diabetes: everyone’s concern. London: British Diabetic Association; 1994. [PubMed]
- 42. American Diabetes AssociationStandards of medical care for patients with diabetes mellitus. Diabetes Care. 1998;21(suppl):S23–S31.[PubMed][Google Scholar]
- 43. Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood PressureSixth report. Arch Intern Med. 1997;157:2413–2446.[PubMed][Google Scholar]