Blood pressure control for diabetic retinopathy

Review question
We reviewed the evidence about the effect of blood pressure control to prevent diabetic retinopathy and/or to slow progression of diabetic retinopathy.

Background
Diabetes is characterized by high levels of blood glucose (sugar circulating in the blood) and is classified as either type 1 or type 2, depending on the underlying cause of increased blood glucose. A common complication in people with diabetes is diabetic retinopathy, often called 'diabetic eye disease,' which affects the blood vessels in the back of the eye. Diabetic retinopathy is a major cause of poor vision and blindness worldwide among adults of working age. Research has shown that control of blood glucose reduces the risk of diabetic retinopathy and prevents worsening of the condition once it develops. However, the current diabetes epidemic suggests that the rates of new and worsening diabetic retinopathy will increase without effective means of prevention and treatment in addition to blood glucose control. Simultaneous treatment to reduce blood pressure among diabetics has been suggested as one approach.

Study characteristics
We found 15 randomized controlled trials, conducted primarily in North America and Europe, to investigate the effects of methods to lower blood pressure (drug-based in 14 trials; lifestyle change in 1 trial) in 4157 type 1 and 9512 type 2 diabetics, ranging from 16 to 2130 participants in individual trials. The follow-up period ranged from one to nine years for included trials. Of the 15 trials, six were funded in full by one or more drug companies. Seven more studies received drug company support, usually in the form of study medications. The remaining two studies were conducted with support from government-sponsored grants and institutional support. The evidence is current to April 2014.

Key results
Overall, the included trials provided modest support for lowering blood pressure to prevent diabetic retinopathy, regardless of diabetes type or baseline blood pressure level. However, the evidence did not indicate that lowering blood pressure kept diabetic retinopathy from worsening once it had developed or that it prevented advanced stages of diabetic retinopathy that required laser or other treatment of affected eyes. Treatment to reduce the blood pressure of people with diabetes is warranted for other health reasons, but the available evidence does not justify reduction of blood pressure solely to prevent or slow diabetic retinopathy.

Quality of the evidence
Overall, the quality of the evidence was low to moderate based on the reported information. The quality was downgraded mainly because some studies did not report outcomes for all or most participants at follow-up time points, and results from different studies were not highly consistent.

Authors' conclusions: 

Hypertension is a well-known risk factor for several chronic conditions in which lowering blood pressure has proven to be beneficial. The available evidence supports a beneficial effect of intervention to reduce blood pressure with respect to preventing diabetic retinopathy for up to 4 to 5 years. However, the lack of evidence to support such intervention to slow progression of diabetic retinopathy or to prevent other outcomes considered in this review, along with the relatively modest support for the beneficial effect on incidence, weakens the conclusion regarding an overall benefit of intervening on blood pressure solely to prevent diabetic retinopathy.

Read the full abstract...
Background: 

Diabetic retinopathy is a common complication of diabetes and a leading cause of visual impairment and blindness. Research has established the importance of blood glucose control to prevent development and progression of the ocular complications of diabetes. Simultaneous blood pressure control has been advocated for the same purpose, but findings reported from individual studies have supported varying conclusions regarding the ocular benefit of interventions on blood pressure.

Objectives: 

The primary aim of this review was to summarize the existing evidence regarding the effect of interventions to control or reduce blood pressure levels among diabetics on incidence and progression of diabetic retinopathy, preservation of visual acuity, adverse events, quality of life, and costs. A secondary aim was to compare classes of anti-hypertensive medications with respect to the same outcomes.

Search strategy: 

We searched a number of electronic databases including CENTRAL as well as ongoing trial registries. We last searched the electronic databases on 25 April 2014. We also reviewed reference lists of review articles and trial reports selected for inclusion. In addition, we contacted investigators of trials with potentially pertinent data.

Selection criteria: 

We included in this review randomized controlled trials (RCTs) in which either type 1 or type 2 diabetic participants, with or without hypertension, were assigned randomly to intense versus less intense blood pressure control, to blood pressure control versus usual care or no intervention on blood pressure, or to different classes of anti-hypertensive agents versus placebo.

Data collection and analysis: 

Pairs of review authors independently reviewed titles and abstracts from electronic and manual searches and the full text of any document that appeared to be relevant. We assessed included trials independently for risk of bias with respect to outcomes reported in this review. We extracted data regarding trial characteristics, incidence and progression of retinopathy, visual acuity, quality of life, and cost-effectiveness at annual intervals after study entry whenever provided in published reports and other documents available from included trials.

Main results: 

We included 15 RCTs, conducted primarily in North America and Europe, that had enrolled 4157 type 1 and 9512 type 2 diabetic participants, ranging from 16 to 2130 participants in individual trials. In 10 of the 15 RCTs, one group of participants was assigned to one or more anti-hypertensive agents and the control group received placebo. In three trials, intense blood pressure control was compared to less intense blood pressure control. In the remaining two trials, blood pressure control was compared with usual care. Five of the 15 trials enrolled type 1 diabetics, and 10 trials enrolled type 2 diabetics. Six trials were sponsored entirely by pharmaceutical companies, seven trials received partial support from pharmaceutical companies, and two studies received support from government-sponsored grants and institutional support.

Study designs, populations, interventions, and lengths of follow-up (range one to nine years) varied among the included trials. Overall, the quality of the evidence for individual outcomes was low to moderate. For the primary outcomes, incidence and progression of retinopathy, the quality of evidence was downgraded due to inconsistency and imprecision of estimates from individual studies and differing characteristics of participants.

For primary outcomes among type 1 diabetics, one of the five trials reported incidence of retinopathy and one trial reported progression of retinopathy after 4 to 5 years of treatment and follow-up; four of the five trials reported a combined outcome of incidence and progression over the same time interval. Among type 2 diabetics, 5 of the 10 trials reported incidence of diabetic retinopathy and 3 trials reported progression of retinopathy; one of the 10 trials reported a combined outcome of incidence and progression during a 4- to 5-year follow-up period. One trial in which type 2 diabetics participated had reported no primary (or secondary) outcome targeted for this review.

The evidence from these trials supported a benefit of more intensive blood pressure control intervention with respect to 4- to 5-year incidence of diabetic retinopathy (estimated risk ratio (RR) 0.80; 95% confidence interval (CI) 0.71 to 0.92) and the combined outcome of incidence and progression (estimated RR 0.78; 95% CI 0.63 to 0.97). The available evidence provided less support for a benefit with respect to 4- to 5-year progression of diabetic retinopathy (point estimate was closer to 1 than point estimates for incidence and combined incidence and progression, and the CI overlapped 1; estimated RR 0.88; 95% CI 0.73 to 1.05). The available evidence regarding progression to proliferative diabetic retinopathy or clinically significant macular edema or moderate to severe loss of best-corrected visual acuity did not support a benefit of intervention on blood pressure: estimated RRs and 95% CIs 0.95 (0.83 to 1.09) and 1.06 (0.85 to 1.33), respectively, after 4 to 5 years of follow-up. Findings within subgroups of trial participants (type 1 and type 2 diabetics; participants with normal blood pressure levels at baseline and those with elevated levels) were similar to overall findings.

The adverse event reported most often (7 of 15 trials) was death, yielding an estimated RR 0.86 (95% CI 0.64 to 1.14). Hypotension was reported from three trials; the estimated RR was 2.08 (95% CI 1.68 to 2.57). Other adverse ocular events were reported from single trials.

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