More uncertainty about appropriate BP targets in diabetic patients
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For patients with diabetes and moderately elevated blood pressure, aggressive antihypertensive therapy may do more harm than good, according to a meta-analysis published in The BMJ.
In diabetic patients with systolic blood pressure (SBP) less than 140 mm Hg at baseline, additional antihypertensive treatment increased the risk of cardiovascular mortality by 15%, reported co-authors Mattias Brunström, a doctoral student, and Bo Carlberg, MD, of Umeå University in Sweden.
Cardiovascular mortality was reduced when baseline SBP was greater than 150 mm Hg. When baseline SBP was 140-150 mm Hg, the effect of treatment on cardiovascular mortality was not significant, Brunström and Carlberg said.
"This systematic review and meta-analyses included a large amount of previously unpublished data, thereby increasing precision compared with previous research," Brunström and Carlberg said.
The study authors added that "our results, combined with those from the SPRINT trial, suggest that blood pressure treatment goals should be less aggressive in people with diabetes than without diabetes. This review 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."
But an independent expert told MedPage Today that these data were not enough to alter practice.
"Based on what I saw in this study, this will probably not change the way clinicians treat patients," said Tom Giles, MD, of Tulane University in New Orleans. "I think clinicians will take advantage of all the information available to them and conclude that lower BPs are better -- if they accommodate comorbidities and unwanted medical effects."
Study Details
The meta-analysis covered 49 clinical trials involving more than 73,000 patients. The investigators included randomized controlled trials of antihypertensive therapy with a mean follow-up of 12 months or more and at least 100 patients with diabetes. The mean follow-up was 3.7 years, and most of the patients had type 2 diabetes.
Included trials had to compare any antihypertensive agent against placebo, any two agents against one, or any blood pressure target against another. The investigators excluded strictly comparative trials, evaluating one agent against another, as well as trials with combined interventions. For 12 of the studies, Brunström and Carlberg obtained unpublished data by contacting study authors, pharmaceutical companies, or relevant authorities. Key results included the following:
If baseline SBP was less than 140 mm Hg, further treatment increased the risk of cardiovascular mortality (relative risk 1.15; 95% CI 1.00-1.32), with a tendency toward an increased risk of all-cause mortality (RR 1.05; 95% CI 0.95-1.16).
If baseline SBP was 140-150 mm Hg, additional treatment reduced the risk of all-cause mortality (RR 0.87; 95% CI 0.78-0.98), myocardial infarction (RR 0.84; 95 CI 0.76-0.93), and heart failure (RR 0.80; 95% CI 0.66-0.97). But the risk reduction with cardiovascular mortality was not statistically significant (RR 0.87; 95% CI 0.71-1.05).
If baseline SBP was greater than 150 mm Hg, antihypertensive treatment reduced the risk of all-cause mortality (RR 0.89; 95% CI 0.80-0.99), cardiovascular mortality (RR 0.75; 95% CI 0.57-0.99), myocardial infarction (RR 0.74; 95% CI 0.63-0.87), stroke (RR 0.77; 95% CI 0.65-0.91), and end stage renal disease (RR 0.82; 95% CI 0.71-0.94).
Speculation and Caveats
"The most likely biological explanation for our findings is that intensive treatment impairs blood flow to end organs, leading to ischemia," Brunström and Carlberg said. "In arterial stiffening, commonly present in people with diabetes, myocardial perfusion is increasingly dependent on SBP. This could, at least partly, explain the association between low SBP and worse treatment effect in our analyses."
"Another potential explanation for our findings is that low blood pressure leads to less coronary collateral circulation," they said. "This could explain not only an increased number of events with treatment but also a worse prognosis when having an event, as reflected by the possible increase in case fatality suggested by our analyses."
"Many treatment guidelines, both Swedish and international, will be redrawn in the next few years," Brunström said in a statement. "It has been discussed to recommend even lower blood pressure levels for people with diabetes -- maybe as low as 130. We are hoping that our study, which shows potential risks of such aggressive blood pressure lowering treatment, will come to influence these guidelines."
However, he added, "In practice, it is important to remember that undertreatment of high blood pressure is a bigger problem than overtreatment."
Giles said an important limitation of the meta-analysis is that the blood pressure data was obtained primarily by office measurements, which increasing evidence suggests is unreliable. The same problem plagued hypertension trials such as SPRINT and ACCORD, said Giles, who recently authored an editorial in Hypertension advocating ambulatory blood pressure monitoring to confirm office measurements.
SPRINT and ACCORD yielded conflicting results. SPRINT reported improved outcomes with more aggressive hypertension treatment in high-risk patients, excluding those with diabetes. ACCORD reported only a nonsignificant trend toward improvement with aggressive treatment in patients with diabetes.
Clinicians should be wary of changing their clinical practice based on meta-analyses such as the one by Brunström and Carlberg, Giles cautioned. "It's all smoke and mirrors," he scoffed. "It's not research, it's sitting at a computer dredging through data."
In diabetic patients with systolic blood pressure (SBP) less than 140 mm Hg at baseline, additional antihypertensive treatment increased the risk of cardiovascular mortality by 15%, reported co-authors Mattias Brunström, a doctoral student, and Bo Carlberg, MD, of Umeå University in Sweden.
"This systematic review and meta-analyses included a large amount of previously unpublished data, thereby increasing precision compared with previous research," Brunström and Carlberg said.
The study authors added that "our results, combined with those from the SPRINT trial, suggest that blood pressure treatment goals should be less aggressive in people with diabetes than without diabetes. This review 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."
But an independent expert told MedPage Today that these data were not enough to alter practice.
"Based on what I saw in this study, this will probably not change the way clinicians treat patients," said Tom Giles, MD, of Tulane University in New Orleans. "I think clinicians will take advantage of all the information available to them and conclude that lower BPs are better -- if they accommodate comorbidities and unwanted medical effects."
The meta-analysis covered 49 clinical trials involving more than 73,000 patients. The investigators included randomized controlled trials of antihypertensive therapy with a mean follow-up of 12 months or more and at least 100 patients with diabetes. The mean follow-up was 3.7 years, and most of the patients had type 2 diabetes.
Included trials had to compare any antihypertensive agent against placebo, any two agents against one, or any blood pressure target against another. The investigators excluded strictly comparative trials, evaluating one agent against another, as well as trials with combined interventions. For 12 of the studies, Brunström and Carlberg obtained unpublished data by contacting study authors, pharmaceutical companies, or relevant authorities. Key results included the following:
If baseline SBP was less than 140 mm Hg, further treatment increased the risk of cardiovascular mortality (relative risk 1.15; 95% CI 1.00-1.32), with a tendency toward an increased risk of all-cause mortality (RR 1.05; 95% CI 0.95-1.16).
If baseline SBP was 140-150 mm Hg, additional treatment reduced the risk of all-cause mortality (RR 0.87; 95% CI 0.78-0.98), myocardial infarction (RR 0.84; 95 CI 0.76-0.93), and heart failure (RR 0.80; 95% CI 0.66-0.97). But the risk reduction with cardiovascular mortality was not statistically significant (RR 0.87; 95% CI 0.71-1.05).
Speculation and Caveats
"The most likely biological explanation for our findings is that intensive treatment impairs blood flow to end organs, leading to ischemia," Brunström and Carlberg said. "In arterial stiffening, commonly present in people with diabetes, myocardial perfusion is increasingly dependent on SBP. This could, at least partly, explain the association between low SBP and worse treatment effect in our analyses."
"Another potential explanation for our findings is that low blood pressure leads to less coronary collateral circulation," they said. "This could explain not only an increased number of events with treatment but also a worse prognosis when having an event, as reflected by the possible increase in case fatality suggested by our analyses."
"Many treatment guidelines, both Swedish and international, will be redrawn in the next few years," Brunström said in a statement. "It has been discussed to recommend even lower blood pressure levels for people with diabetes -- maybe as low as 130. We are hoping that our study, which shows potential risks of such aggressive blood pressure lowering treatment, will come to influence these guidelines."
Giles said an important limitation of the meta-analysis is that the blood pressure data was obtained primarily by office measurements, which increasing evidence suggests is unreliable. The same problem plagued hypertension trials such as SPRINT and ACCORD, said Giles, who recently authored an editorial in Hypertension advocating ambulatory blood pressure monitoring to confirm office measurements.
SPRINT and ACCORD yielded conflicting results. SPRINT reported improved outcomes with more aggressive hypertension treatment in high-risk patients, excluding those with diabetes. ACCORD reported only a nonsignificant trend toward improvement with aggressive treatment in patients with diabetes.
Clinicians should be wary of changing their clinical practice based on meta-analyses such as the one by Brunström and Carlberg, Giles cautioned. "It's all smoke and mirrors," he scoffed. "It's not research, it's sitting at a computer dredging through data."
The study was funded by the Västerbotten County Council of Sweden.
No researchers disclosed financial relationships with industry.
Giles is a speaker or consultant for Allergan, AstraZeneca, and Boehringer Ingelheim.
No researchers disclosed financial relationships with industry.
Giles is a speaker or consultant for Allergan, AstraZeneca, and Boehringer Ingelheim.
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