The effect of antihypertensive treatment for diabetes patients may depend on the level of their systolic blood pressure (SBP) to begin with, a new meta-analysis suggests.
The review of 49 trials enrolling 73,738 participants, published online February 25 in the BMJ, "strongly supports blood-pressure treatment in people with diabetes mellitus if SBP is more than 140 mm Hg."
"If SBP is already less than 140 mm Hg, however, adding additional agents might be harmful," write Mattias Brunström and Bo Carlberg, MD, of the department of public health and clinical medicine, Umeå University, Sweden.
The analysis was performed to help answer the elusive question of appropriate blood-pressure targets in people with diabetes. For many years, the recommendation was to aim for less than 130/80 mm Hg, but more recent guidelines have backed off, raising the target to less than 140/90 mm Hg.
Now the conversation has shifted yet again, with publication last fall of the Systolic Blood Pressure Intervention Trial (SPRINT), which found lower rates of cardiovascular events and all-cause mortality associated with targeting SBP of less than 120 mm Hg vs less than 140 mm Hg in patients at increased cardiovascular risk but who did not have diabetes.
Whether or not the results of SPRINT should be extended to people with diabetes has proved controversial.
"Since the publication of SPRINT, [there have been discussions regarding whether] to lower blood-pressure targets in general and whether the results from SPRINT should be extrapolated to people with diabetes. Our results suggest that the current recommendation to treat people with diabetes to less than 140 mm Hg is appropriate and should not be changed because of SPRINT," Mr Brunström told Medscape Medical News.
But SPRINT co–principal investigator William C Cushman, MD, professor of medicine at the University of Tennessee, Memphis, told Medscape Medical News that the new meta-analysis findings don't add much to what is already known. "There have been a number of different meta-analyses done. At best, it's hypothesis-generating that it's not beneficial to treat lower levels, but [most of] the studies used to determine lower SBP levels weren't designed to test this specific question."
In fact, Dr Cushman said, the review included only one study that was designed to prospectively assess whether lower blood-pressure targets might benefit diabetes patients, Action to Control Cardiovascular Risk in Diabetes (ACCORD), which had begun prior to SPRINT and was the reason that SPRINT excluded diabetes patients.
While the initial ACCORD results showed a nonsignificant reduction in CV events after about 5 years of active intensive blood-pressure–lowering treatment, ongoing follow-up of those patients (ACCORDION) now suggests that some diabetes patients may significantly benefit from further blood-pressure lowering after all.
"There is suggestion within ACCORD for the possibility of benefit, although it certainly doesn't prove it.…At some point we need to do another trial in diabetics testing lower blood-pressure goals….We can't do a meta-analysis based on one trial," said Dr Cushman, who was the lead investigator for the ACCORD blood-pressure arm.
But Mr Brunström defended the meta-analysis approach, pointing out that this is the largest such review done to date to examine treatment effects at different blood-pressure levels in people with diabetes, and it included all trials from previous meta-analyses plus a large amount of unpublished data.
"Based on previous systematic reviews in nondiabetics…it is reasonable to assume that the effect of different antihypertensive drugs on cardiovascular disease is mainly due to blood-pressure lowering, and thus, results from outcome trials of antihypertensive drugs should be able to answer questions about blood-pressure lowering in general."
Moreover, Mr Brunström added, "we stratify our main analyses according to baseline systolic blood pressure, which is very close to the clinical situation."
A U-Shaped Relationship
Included in the meta-analysis were randomized controlled trials with a mean follow-up of 12 months or more and enrolling 100 or more participants with diabetes. To be included, the trials had to compare any antihypertensive agent against placebo, any two agents against one, or any blood-pressure target against another. Head-to-head comparisons and combined-treatment trials were excluded.
A total of 25 trials involving 26,625 participants were made up of diabetic subgroups from larger trials, while 24 trials with 47,113 participants included only those with diabetes. Among these were 12 unpublished studies with 8916 participants, obtained through contact with the authors, pharmaceutical companies, or authorities. The mean follow-up was 3.7 years.
For patients with baseline SBP greater than 150 mm Hg, antihypertensive treatment reduced the risk of all-cause mortality (relative risk [RR], 0.89), cardiovascular mortality (RR, 0.75), myocardial infarction (RR, 0.74), stroke (RR 0.77), and end-stage renal disease (RR, 0.82). In all cases, the 95% confidence interval did not cross 1.0.
Among the subjects with SBP 140 to 150 mm Hg, additional treatment reduced all-cause mortality (RR, 0.87), myocardial infarction (0.84), and heart failure (RR, 0.80). Again, those results were statistically significant.
However, for subjects with baseline SBP less than 140 mm Hg, further treatment significantly increased the risk for cardiovascular mortality (RR, 1.15), with a nonsignificant trend toward an increased risk for all-cause mortality (RR, 1.05). Differences in the other end points were not significant.
The concept of a J-shaped or U-shaped curve for the relation between blood pressure and cardiovascular disease has been shown previously in observational studies, Mr Brunström and Dr Carlberg write, noting that the most likely biological explanation is that intensive treatment impairs blood flow to end organs, leading to ischemia.
Informing the Guidelines
Mr Brunström said that the new findings call into question current American Diabetes Association guidelines suggesting lower blood-pressure targets for diabetes patients who are younger or who have albuminuria or additional atherosclerotic risk factors.
"The evidence behind these recommendations is not very strong…and based on the principle not to harm, one could question these recommendations in light of our study."
But Dr Cushman said he anticipates that new blood-pressure guidelines from the American College of Cardiology (ACC)/American Heart Association (AHA) will reflect the SPRINT results, despite the lack of direct data for diabetes patients.
"Admittedly, we don't exactly know what the goals should be in diabetes for SBP. What the recent guidelines have recommended is 140.…But I think after SPRINT, there will be a new set of guidelines. If [the ACC and AHA] recommend lower goals for diabetic patients again, it won't be a level A recommendation, but clinicians can look at it and decide if it sounds reasonable or not."
Until further data are available, Dr Cushman said, "I think the evidence is very clear that in diabetics we should treat SBP down to below at least 140 or 150 [mm Hg]. For 140 mm Hg, the evidence is rather indirect. But even this meta-analysis suggests we should treat people above 140 [mm Hg] to below."
This study was funded by Västerbotten County Council. The authors have no further relevant financial relationships. Both ACCORD and SPRINT were supported by the National Heart, Lung, and Blood Institute (NHLBI)/National Institutes of Health (NIH). Dr Cushman reports receiving institutional grant support from the NHLBI/NIH and Eli Lilly and participating in uncompensated consulting for Takeda.
BMJ.Published online February 25, 2016.Article
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