Does blood pressure control prevent diabetic retinopathy or slow its progression?
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. Control of blood glucose reduces the risk of diabetic retinopathy and prevents worsening of the condition once it develops. Simultaneous treatment to reduce blood pressure among diabetics has been suggested as another approach to reduce the risks of development and worsening of diabetic retinopathy below the risks achieved by blood glucose control.
We found 29 randomized controlled trials (a type of study where participants are randomly assigned to one of two or more treatment groups), conducted primarily in North America and Europe, looking at the effects of several methods to lower blood pressure in 4620 type 1 and 22,565 type 2 diabetics, with 16 to 4477 participants in individual trials. The treatment and follow-up periods in these trials ranged from less than one year to nine years. Eight trials were funded in full by one or more drug companies. Ten other trials had received drug company support, usually in the form of study medications. The remaining 11 studies were conducted with support from government‐sponsored grants and institutional support or did not report funding source. The evidence is current to September 2021.
Overall, the evidence from 19 trials in which participants were treated for 5 years or longer provided modest support for lowering blood pressure to prevent diabetic retinopathy. However, lowering blood pressure did not keep diabetic retinopathy from worsening once it had developed, or prevent advanced stages of diabetic retinopathy that required treatment of the affected eyes. The evidence favored control of blood pressure for hypertensive type 2 diabetics for more outcomes than favored blood pressure lowering among participants with normal blood pressure. 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 in diabetics with normal blood pressures 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 because some studies did not report all of their prespecified outcomes, and results from different studies were not always consistent.
Hypertension is a well-known risk factor for several chronic conditions for which lowering blood pressure has proven to be beneficial. The available evidence supports a modest beneficial effect of intervention to reduce blood pressure with respect to preventing diabetic retinopathy for up to five years, particularly for hypertensive type 2 diabetics. However, there was a paucity of evidence to support such intervention to slow progression of diabetic retinopathy or to affect other outcomes considered in this review among normotensive diabetics. This weakens any conclusion regarding an overall benefit of intervening on blood pressure in diabetic patients without hypertension for the sole purpose of preventing diabetic retinopathy or avoiding the need for treatment for advanced stages of diabetic retinopathy.
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. Concurrent blood pressure control has been advocated for this purpose, but individual studies have reported varying conclusions regarding the effects of this intervention.
To summarize the existing evidence regarding the effect of interventions to control blood pressure levels among diabetics on incidence and progression of diabetic retinopathy, preservation of visual acuity, adverse events, quality of life, and costs.
We searched several electronic databases, including CENTRAL, and trial registries. We last searched the electronic databases on 3 September 2021. We also reviewed the reference lists of review articles and trial reports selected for inclusion.
We included randomized controlled trials (RCTs) in which either type 1 or type 2 diabetic participants, with or without hypertension, were assigned randomly to more intense versus less intense blood pressure control; to blood pressure control versus usual care or no intervention on blood pressure (placebo); or to one class of antihypertensive medication versus another or placebo.
Pairs of review authors independently reviewed the titles and abstracts of records identified by the electronic and manual searches and the full-text reports of any records identified as potentially relevant. The included trials were independently assessed for risk of bias with respect to outcomes reported in this review.
We included 29 RCTs conducted in North America, Europe, Australia, Asia, Africa, and the Middle East that had enrolled a total of 4620 type 1 and 22,565 type 2 diabetic participants (sample sizes from 16 to 4477 participants). In all 7 RCTs for normotensive type 1 diabetic participants, 8 of 12 RCTs with normotensive type 2 diabetic participants, and 5 of 10 RCTs with hypertensive type 2 diabetic participants, one group was assigned to one or more antihypertensive agents and the control group to placebo. In the remaining 4 RCTs for normotensive participants with type 2 diabetes and 5 RCTs for hypertensive type 2 diabetic participants, methods of intense blood pressure control were compared to usual care. Eight trials were sponsored entirely and 10 trials partially by pharmaceutical companies; nine studies received support from other sources; and two studies did not report funding source.
Study designs, populations, interventions, lengths of follow-up (range less than one year to nine years), and blood pressure targets varied among the included trials.
For primary review outcomes after five years of treatment and follow-up, one of the seven trials for type 1 diabetics reported incidence of retinopathy and one trial reported progression of retinopathy; one trial reported a combined outcome of incidence and progression (as defined by study authors). Among normotensive type 2 diabetics, four of 12 trials reported incidence of diabetic retinopathy and two trials reported progression of retinopathy; two trials reported combined incidence and progression. Among hypertensive type 2 diabetics, six of the 10 trials reported incidence of diabetic retinopathy and two trials reported progression of retinopathy; five of the 10 trials reported combined incidence and progression.
The evidence supports an overall benefit of more intensive blood pressure intervention for five-year incidence of diabetic retinopathy (11 studies; 4940 participants; risk ratio (RR) 0.82, 95% confidence interval (CI) 0.73 to 0.92; I2 = 15%; moderate certainty evidence) and the combined outcome of incidence and progression (8 studies; 6212 participants; RR 0.78, 95% CI 0.68 to 0.89; I2 = 42%; low certainty evidence). The available evidence did not support a benefit regarding five-year progression of diabetic retinopathy (5 studies; 5144 participants; RR 0.94, 95% CI 0.78 to 1.12; I2 = 57%; moderate certainty evidence), incidence of proliferative diabetic retinopathy, clinically significant macular edema, or vitreous hemorrhage (9 studies; 8237 participants; RR 0.92, 95% CI 0.82 to 1.04; I2 = 31%; low certainty evidence), or loss of 3 or more lines on a visual acuity chart with a logMAR scale (2 studies; 2326 participants; RR 1.15, 95% CI 0.63 to 2.08; I2 = 90%; very low certainty evidence). Hypertensive type 2 diabetic participants realized more benefit from intense blood pressure control for three of the four outcomes concerning incidence and progression of diabetic retinopathy.
The adverse event reported most often (13 of 29 trials) was death, yielding an estimated RR 0.87 (95% CI 0.76 to 1.00; 13 studies; 13,979 participants; I2 = 0%; moderate certainty evidence). Hypotension was reported in two trials, with an RR of 2.04 (95% CI 1.63 to 2.55; 2 studies; 3323 participants; I2 = 37%; low certainty evidence), indicating an excess of hypotensive events among participants assigned to more intervention on blood pressure.