Lowering BP Boosts CV Health Irrespective of Diabetes: Meta-analysis

A 5-mm Hg reduction in systolic blood pressure provides a lower risk of major CV events that is comparable in patients with or without type 2 diabetes, according to a meta-analysis from the Blood Pressure Lowering Treatment Trialists’ Collaboration (BPLTTC) that provides fodder for the ongoing debate about how best to manage BP in this setting.

Though the relative risk reduction was slightly smaller in patients with diabetes (HR 0.94 vs 0.89), the absolute risk reduction was similar (-1.54% vs -1.61%) due to their higher cardiovascular risk at baseline, lead author Milad Nazarzadeh, MSc (University of Oxford, England), and colleagues report in a paper published recently online in the Lancet Diabetes & Endocrinology.

Senior author Kazem Rahimi, MD (University of Oxford), said that clinical decisions about treatment ultimately come down to effects on absolute, not relative, risk. “If the population that we see in clinic is roughly similar to the risk profile of what we have included in previous clinical trials, then it shouldn’t matter if someone has diabetes” when implementing antihypertensive therapy, Rahimi told TCTMD. He acknowledged that that is a big assumption when treating patients in everyday practice, where there is wide variability in risk. If patients have a lower risk, then the absolute risk reduction with any amount of BP-lowering will be less.

Nevertheless, “I think the message for clinicians should be at this stage: we can assume, on average, despite the weaker relative risk reduction, the absolute risk differences are similar and therefore clinical practice should not change,” Rahimi said. “The only thing that it should change is we should not worry about what an individual’s baseline blood pressure is because the same applies to people with diabetes—reducing blood pressure wherever you start will give you a similar effect on cardiovascular events.”

Moreover, there should not be different BP thresholds for initiating treatment or targets for guiding therapy based on diabetes status, “because those are clearly refuted by the findings that we have,” Rahimi said. “We should be guided by the risk of individuals of suffering a cardiovascular event, and if tolerable and if acceptable, we should offer the same strategies for blood pressure reduction irrespective of presence or absence of diabetes.”

An Ongoing Controversy

There isn’t broad agreement on the optimal way to manage hypertension in patients with type 2 diabetes, and the controversy is fueled by discrepant results from prior studies, including ACCORD and SPRINT. The trials both evaluated the impact of intensive versus standard BP control, but only SPRINT, which included nondiabetic patients, demonstrated a significant benefit when aiming for a systolic BP goal below 120 mm Hg.

Those trials were followed by multiple meta-analyses, which also produced conflicting results. One indicated that antihypertensive treatment provided clinical benefits in patients with diabetes when baseline systolic BP was 140 mm Hg or greater, but was harmful—with an increased risk of CV mortality—at lower baseline BP levels. And in another, lowering BP reduced major CVD and all-cause death overall, with a stronger relationship seen in patients with a baseline systolic BP of 140 mm Hg or higher (and no clear association at lower thresholds).

“That is the situation . . . that has led to people making differing recommendations and leaving the decision ultimately to the judgment of individuals,” Rahimi said.

The BPLTTC previously explored the interaction between antihypertensive treatment and diabetes in a meta-analysis that predates ACCORD and SPRINT, published in 2005. In it, antihypertensive therapy was associated with a lower risk of major CV events, with similar results in patients with or without type 2 diabetes. Yet it “had limited statistical power, analyses were not standardized for varying magnitudes of blood pressure-lowering, and stratification by baseline blood pressure levels was not performed,” the investigators note.

This new effort from the group looks at patient-level data pooled from 51 randomized trials of antihypertensive treatment that either compared BP-lowering therapies with placebo or active comparators or investigated intensive versus standard control. They were published between 1981 and 2014 and included a total of 358,533 participants (mean age 65 years; 58% men); 29% of patients had known type 2 diabetes. At baseline, mean BP was 149/84 mm Hg among those with type 2 diabetes and 153/88 mm Hg among nondiabetic patients.

The primary outcome was major CV events, a composite of first-time fatal/nonfatal stroke or cerebrovascular disease, fatal/nonfatal ischemic heart disease, or heart failure causing death or requiring hospitalization. Over a median of 4.2 years of follow-up, this occurred at a rate of 14.3 per 100,000 person-years among patients with type 2 diabetes and 8.5 per 100,000 person-years among those without diabetes.

A 5-mm Hg reduction in systolic BP reduced the risk of major CV events in both groups, with a weaker relative effect in patients with type 2 diabetes (P = 0.0013 for interaction):

• Type 2 diabetes (HR 0.94; 95% CI 0.91-0.98)
• No diabetes (HR 0.89; 95% CI 0.87-0.92)

The discrepancy between groups was mostly related to the effects on ischemic heart disease, which wasn’t reduced as much in patients with diabetes. There also was little effect on all-cause and CV mortality in that subset.

The absolute impact on major CV events was similar in both groups, however.

In addition, “the difference in relative risk reduction was not related to the baseline blood pressure or allocation to different drug classes,” the investigators note. “Therefore, the adoption of differential blood pressure thresholds, intensities of blood pressure-lowering, or drug classes used in people with and without type 2 diabetes is not warranted.”

Disagreement Remains

But it appears unlikely that the new analysis will convince everybody. In a critical review published earlier this year in the Journal of Hypertension, representatives of the European Society of Hypertension (ESH) raised a number of issues with the BPLTTC’s prior meta-analysis assessing BP-lowering for prevention of CVD across different levels of blood pressure.

Asked to comment on the latest meta-analysis, lead author of the critique, Reinhold Kreutz, MD, PhD (Charité – Universitätsmedizin Berlin, Germany), immediate past president of the ESH, said via email: “This is nothing new, but a repetition of a highly questionable methodology to a subgroup of patients, providing hypotheses that have never been addressed nor proven in specific trials.”

Another author of the ESH paper, Costas Thomopoulos, MD (Helena Venizelou Hospital, Athens, Greece), also cautioned against reading too much into the findings. “The results cannot be taken seriously because studies with a different design were used to deliver data (mixing up apples and oranges),” he told TCTMD in an email. “More specifically, some studies were performed without a BP reduction, while others with a substantial BP reduction. Also, too many statistical or clinically oriented methodological assumptions were made to create a database eligible for any kind of statistical experiment.”

Rahimi defended the BPLTTC’s methods, however, noting that his group addressed the various concerns in a paper in the Journal of Hypertension. There, he said, “we point by point address really the misunderstanding of that eminent group in terms of how research works and how these complicated meta-analyses work. Basically, in a nutshell, all the points were unfortunately based on a misunderstanding of statistics and the scientific way of doing these analyses as opposed to any weakness of the work that we have done.”

Though some of the particulars can be debated, there was agreement that BP-lowering therapy should be offered to all hypertensive individuals irrespective of diabetes status. Thomopoulos noted that prior data has shown patients with diabetes consistently have greater absolute reductions in major CV events compared with their nondiabetic counterparts. But, he added, this latest BPLTTC meta-analysis cannot inform decisions about how much BP should be lowered.

“Regarding thresholds, in newly diagnosed hypertensive patients with diabetes mellitus (thus without previous treatment), patients should be treated with a fixed-drug combination to reduce systolic/diastolic blood pressure to less than 140/80 mm Hg,” Thomopoulos advised. “Although there is no robust evidence so far, the untreated threshold to begin pharmacological antihypertensive treatment cannot be different between patients with or without diabetes mellitus.”

When it comes to targets, “a systolic blood pressure a few mm Hg above or below the target of 130 optimizes treatment benefits whenever diabetes mellitus is present,” he said. “However, a further reduction of systolic blood pressure to values from 120 to 130 mm Hg may be attempted for those without diabetes mellitus to maximize the benefit. There is no evidence to support systolic blood pressure reduction to less than 120 mm Hg in patients with or without diabetes mellitus.”

In an accompanying editorial, Luis Ruilope, MD, PhD, and Gema Ruiz-Hurtado, PhD (both Hospital Universitario 12 de Octubre, Madrid, Spain), highlight the need to move beyond in-office BP measurement and to learn more about the effects of newer drugs in order to enhance discussions about BP control.

“It is our opinion that the conclusions of the current meta-analysis and, in part, the criticism of the members of the ESH both make valid points that need to be considered in clinical practice, but these conclusions are based on an inadequate evaluation of blood pressure levels and do not take into account the recently described effects on renal function and cardiovascular disease of [sodium-glucose cotransporter 2] inhibitors and finerenone,” they write.