SPRINT, ACCORD-BP, EMPA-REG: A Few Notes on BP Control in Diabetes

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A few facts on hypertension and diabetes are in order to set the stage for this short discussion on the implications of these 3 pivotal studies. Eighty to 90% of persons with type 2 diabetes (T2DM) will also have hypertension.¹ T2DM itself triples the risk of cardiovascular disease (CVD) at any level of systolic blood pressure-even at pre-hypertension levels.¹ The presence of hypertension in T2DM increases CV risk by a factor of 4.¹ Reducing blood pressure in patients with T2DM has been shown to lower CV risk.² In fact, blood pressure control is the most effective intervention in controlling CV risk in T2DM patients when compared to management of other common risk factors.¹

Which leads to the million dollar question: how low should we go when lowering blood pressure in T2DM?

At the turn of this new century, a target of <130/<80 mm Hg was recommended-a value based primarily on observational studies.¹ Controversy remains and some guidelines still recommend a systolic target of 140 mm Hg.¹ In 2018, results of 3 specific studies are critical to addressing the question of blood pressure targets in T2DM: SPRINT,^1,3 ACCORD-BP,^1,4 and the EMPA-REG OUTCOME trial (and this last study is different).^1,5

ACCORD-BP

ACCORD-BP (n=4733) was designed as a factorial trial to investigate the effects of intensive glycemic control, intensive blood pressure management (systolic < 119.3 mm Hg [systolic intensive average], systolic <133.5 mm Hg [systolic standard average]),  and intensive lipid reduction (multiple therapies) on cardiovascular outcomes.^1,4 After nearly 5 years of follow-up, patients receiving intensive therapy had significant reductions in stroke, but more adverse events (eg, hypotension and/or syncope).^1,4 However, in a post hoc analysis of ACCORD-BP, intensive BP control (systolic <120 mm Hg) with intensive glucose control  (A1c <6.0%), reduced the rate of CV events compared to other risk factor approaches (HR 0.71).^1,6
 

SPRINT

The SRPINT Trial (n= 9,361)³ was designed to determine targets for systolic blood pressure that would reduce CV morbidity and mortality among patients at increased CV risk but who did not have diabetes. The study was terminated early because adverse CV outcomes were lower in the intensive control group (<120 mm Hg systolic)^1,3 vs the standard control group (<140 mm Hg systolic). So, intensive systolic control helped reduce CV risk in both ACCORD-BP and SPRINT. However, since SPRINT did not enroll persons with T2DM (or persons age <50 years or status post-stroke), the results can’t be generalized or compared to outcomes in ACCORD-BP.1 There were other important differences between the 2 studies as well:  statistical power in SPRINT was greater, and although T2DM patients were excluded from SPRINT, other high risk groups-the elderly and those with chronic kidney disease not included in ACCORD-BP-were enrolled in SPRINT.¹
 

EMPA-REG OUTCOME

EMPAG-REG OUTCOME (n=7,028)⁵ was a CV outcomes study of the antihyperglycemic agent empagliflozin, an SGLT2 inhibitor, and substantially different in design from both ACCORD-BP and SPRINT. It compared 2 doses of empagliflozin to placebo in T2DM patients characterized as “very well treated in terms of comprehensive care,” including similar hypertension management strategies and medications at enrollment.¹ After 3-year follow-up, the pooled empagliflozin patients demonstrated decreased risk of MI, stroke, cardiovascular death, admissions for heart failure, worsening or incipient nephropathy, and all cause mortality compared to placebo (HR 0.86).⁵ SGLT-2 inhibitors have a diuretic effect and blood pressure among study enrollees taking the drug was lower than patients in the placebo group already taking antihypertensive agents.⁵ Since some of the benefit across all outcomes was achieved within weeks of enrollment, it is unlikely A1c changes were responsible.¹ The EMPA-REG trial patients experienced mild, but sustained declines in blood pressure of 4 mm Hg systolic and 1.5 mm Hg  diastolic. In fact, the pooled empagliflozin recipients had blood pressure readings of 131.3/75.1 mm Hg versus placebo values of 135.3/76.6 mm Hg. The lower blood pressures were not associated with increased adverse events. Observers have said that the EMPAG-REG OUTCOME trial “might indeed be the one associated with the lowest incidence of cardiovascular events in patients with T2DM.”¹

Thinking forward

Data regarding systolic BP targets in T2DM patients of 140, 130, and 120 mm Hg are confusing and need more study. However, 2 things are clear. Comprehensive care for patients with T2DM includes blood pressure, lipid, and A1c control. Both ACCORD-BP and EMPA-REG support a clinical approach in patients with T2DM that takes hypertension and other risk factors into consideration simultaneously. Second, in EMPA-REG, the extra benefit (in addition to glycemic control) of lower blood pressure cannot be ignored. Further studies will probably be designed with multiple risk factor interventions as well as a lower blood pressure target (ie, systolic <130 or <120 mm Hg) as the approach to managing the CV complications so common in T2DM.

References:

1.) Sarafidis PA., Lazaridis AA., Ruiz-Hurtado G., & Ruilope LM. Blood pressure reduction in diabetes: lessons from ACCORD, SPRINT, and EMPA-REG OUTCOME. Nature Reviews/Endocrinology 2017; 13:365-374.
2.) Adler A., Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36) prospective observational study. BMJ 2000; 321:412-419.
3.) The Sprint Research Group: A randomized Trial of intensive versus standard blood pressure control. N. Engl. J. Med. 2015; 373:2103-2116.
4.) Cushman WC. Effects of intensive blood pressure control in type 2 diabetes mellitus. N Engl J Med. 2010; 362:1575-85.
5.) Zinman B. Empagaflozin, cardiovascular outcomes, and mortality in type 2 diabetics. N Engl J Med. 2015; 373:2117-2128.
6.) Margolis KL, O’Connor PJ, Morgan TM, et. al. Outcomes of combined cardiovascular risk management strategies in Type 2 Diabetes: the ACCORD randomizecd trial. Diabetes Care 2014; 37:1721-28.