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Micro & Macrovascular Residual Risk THROUGH LANDMARK STUDY

2 August 2014
UKPDS 38: despite significant benefits, “tight” blood pressure control does not prevent two thirds of major macrovascular and microvascular events in hypertensive patients with type 2 diabetes

Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998;317:703

UK Prospective Diabetes Study Group.
Summary
Comments & References
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STUDY SUMMARY
Objective Whether tight control of blood pressure (BP) prevents macro- and microvascular complications in patients with type 2 diabetes.
Study population
1148 hypertensive (BP 160/94 mmHg) 25-65 year old patients with type 2 diabetes; 758 allocated to tight BP control (<150/85 mm Hg) with captopril or atenolol as main treatment; 390 allocated to less tight control (<180/105 mm Hg)..
Primary endpoint
All cause mortality and fatalities and non­fatalities related to diabetes.
Secondary endpoint
fatal and non-fatal myocardial infarction (MI) or sudden death; stroke; amputation or death from peripheral disease, microvascular complications (retinopathy requiring photocoagulation, vitreous hemorrhage, and renal failure)
Study design
Randomized controlled trial.
Methods
At least 9 years follow-up analyzed using Cox's proportional hazards and Kaplan Meier models.
Main results

Tight vs less tight BP control achieved:

  • Mean blood pressure: 144/82 mm Hg vs 154/87 mm Hg(p<0.0001).

  • Significant reductions in relative risk including 24% in all diabetes-related endpoints, 32% in deaths related to diabetes, 44% in stroke (p=0.013), 37% in microvascular endpoints, and 34% in progression of retinopathy by ≥ 2 steps (p=0.0038).
Author's conclusion Tight blood pressure control in patients with hypertension and type 2 diabetes significantly reduces the risk of morbidity and mortality.

COMMENT

The prevalence of hypertension in patients with type 2 diabetes is higher than in the general population. Hypertensive diabetes patients are at higher risk of macrovascular disease (e.g. MI, stroke, peripheral vascular disease) and microvascular complications (impaired renal function, retinopathy, neuropathy) than normotensive patients with diabetes.1, 2
UKPDS 38 (the Hypertension in Diabetes Study arm of the UKPDS) was one of the first major trials to demonstrate clinical benefits of BP-lowering in hypertensive patients with diabetes.

It should be noted however that by current standards, target BP values defining the “tight” and “less tight” BP control arms would be in the range of uncontrolled hypertension. At 9 years, the proportion of patients achieving a target BP of <150/85 mm Hg was 56% in patients assigned tight control and 37% in those assigned less tight control. The mean
(1 standard deviation, SD) BP in patients under tight control was 144 (14) / 82 (7) mm Hg (n = 297) and those with less tight control was 154 (16) / 87 (7) mm Hg (n = 156; P <0.0001). 29% of patients allocated to tight control required three or more hypotensive treatments to achieve and maintain target BP throughout the study (Figure 1).
A contemporary view of the UKPDS 38 data would be that it compared two groups of high-risk patients with type 2 diabetes characterized by more or less severe hypertension while being on drug treatment.

However the reported differences in outcomes between groups were independent from glycemic control. Mean HbA1c values, were 6.9 and 6.8% at study entry, 7.2 and 7.2% at 1-4 years, and 8.3 and 8.2% at 5-8 years in the tight and less tight BP control group, respectively.
Since publication of the UKPDS 38, BP control has been considered as the second most important measure (after glycemic control) to reduce vascular risk in patients with diabetes. It is therefore important to revisit its results from a micro- and macrovascular residual risk perspective.

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Figure 1. Proportion of patients over 9 years who required no drugs, one drug, two drugs, or three or more drugs for treating hypertension to attain target blood pressure

Two-thirds of progression of retinopathy not prevented by 7.5 years of “tight” BP control and no significant benefit at 4.5 years
After a median 7.5-year follow-up, tighter control compared with less tight control left 63% of microvascular complications (Figure 2), 66% of progression of retinopathy by ≥ 2 steps, 65% of retinal photocoagulation, 53% of decreased vision, 71% of microalbuminuria, and 61% of proteinuria unaddressed, There was a non-significant trend toward reduced risk of fatal and non-fatal renal failure.

Some of the risk reduction observed with tighter BP control only became significant after 7.5 years of treatment, being non-significant at the intermediate assessment at 4.5 years. Such was the case for retinopathy progression by ≥ 2 steps and deterioration of vision (75% and 83% not prevented, respectively).
Interpretation of these results is limited by the goals set for tight blood pressure control at the time (1990s). Since then, however, evidence has accumulated showing a huge micro- and macrovascular residual risk in patients with type 2 diabetes receiving optimal standard of care, including glycemic control, blood pressure, and statin therapy.

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Figure 1: Kaplan Meier plots of proportions of patients who developed microvascular end points (mostly retinal photocoagulation), fatal or non­fatal myocardial infarction or sudden death, and fatal or non­fatal strokes

References
  1. Hypertension in Diabetes Study Group. J Hypertens 1993;11:309­17.
  2. Garcia MJ, McNamara PM, Gordon T, Kannell WB. Diabetes 1974;23:105­11.
Key words Type 2 diabetes – blood pressure control – macrovascular events – microvascular complications