PracticeUpdate: Cardiology

HYPERTENSION

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Impact of empagliflozin on BP in patients with type 2 diabetes and hypertension Comment by Jan N Basile MD T he recently reported Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes (EMPA-

heart failure was also seen. Subsequently, the phase 3, randomised, placebo-controlled 12- week EMPA-REG hypertension trial ( Diabetes Care 2015;38:420–428) investigated the efficacy and safety of empagliflozin in patients with T2DM and stage 1 hypertension receiving either empagliflozin 10 mg (n=276) or 25 mg (n=276) compared with placebo (n=271) for change in blood pressure (BP) based on 24- hour ambulatory BP monitoring (ABPM). This smaller hypertension-specific trial from within the overall study found that treatment with empagliflozin was associated with significant and clinically meaningful reductions in both

systolic BP (SBP) and diastolic BP (DBP) throughout the 24-hour period compared with placebo. In addition, like in the overall trial, improvements in glucose control and reductions in weight were also seen. Now,inasubstudyoftheEMPA-REG hyperten- sion trial ( Hypertension http://dx.doi.org/10.1161/ HYPERTENSIONAHA.116.07703 ; published online October 10, 2016), the BP-lowering effects of empagliflozin in these patients with T2DM and stage 1 hypertension taking 10 and 25 mg of active drug were analysed based on if they were taking none, one, or two or more anti- hypertensive medications and the effect on BP specifically if they were or were not taking diu- retics or angiotensin-converting enzyme (ACE) inhibitor/angiotensin receptor blocker (ARB) background therapy. The investigators found that the favourable BP-lowering effect of empa- gliflozin on 24-hour SBP and DBP compared with placebo was irrespective of the number of antihypertensives used at baseline and regard- less of if they were or were not specifically on a background of diuretics (all types pooled together due to the small number of thiazide vs loop users) and ACE inhibitor/ARB use. In summary, empagliflozin reduces BP when used alone or when combined with commonly used antihypertensive agents, including both diuretics and RAS-blocking drugs in those with T2DM and stage 1 hypertension. Dr Basile is from the Seinsheimer Cardiovascular Health Program, Medical University of South Carolina, Ralph H Johnson VA Medical Center, Charleston, and SC President-Elect American Society of Hypertension 2018–2020.

REG OUTCOME) trial ( N Engl J Med 2015;373:2117–2128) found that, in patients with type 2 diabetes mellitus (T2DM) at high-risk for cardiovascular (CV) disease, empagliflozin when added to standard of care reduced the 3-point composite of death from CV causes, nonfatal MI, and nonfatal stroke compared with placebo. Of note, only the 38% relative risk (RR) reduction in death from CV causes was significant. Furthermore, a 35% RR reduction in first hospitalisation for

Impact of empagliflozin on blood pressure in patients with type 2 diabetes mellitus and hypertension by background antihypertensive medication Hypertension Take-home message • This 12-week study evaluated the effect of empagliflozin 10 mg or 25 mg on systolic blood pressure and diastolic blood pressure readings over a 24-hour period in patients with type 2 diabetes mellitus. The results were analyzed based on co-treatment with other antihypertensives, specifically diuretics or ACE inhibitors/ARBs. The results showed that empagliflozin at both treatment doses reduced systolic and diastolic blood pressure regardless of number or type of co-treatment antihypertensive medications. • The researchers concluded that empagliflozin shows promise as an adjunct treatment option for reducing blood pressure in patients with type 2 diabetes. Abstract

of empagliflozin was not significantly different between subgroups by number of antihypertensives for changes in SBP (interaction P value 0.448) or DBP (interaction P value 0.498). Empagliflozin reduced 24-hour mean SBP/DBP irrespective of diuretic or angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use, with no significant difference between subgroups by use/no use of diuretics (interaction P values 0.380 [systolic]; 0.240 [diastolic]) or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (interaction P values 0.900 [systolic]; 0.359 [diastolic]). In conclusion, in patients with type 2 diabetes mellitus and hypertension, empagliflozin for 12 weeks reduced SBP and DBP versus placebo, irrespective of the number of antihypertensives and use of diuretics or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers. Hypertension 2016 Oct 10;[Epub ahead of print], Mancia G, Cannon CP, Tikkanen I

In the EMPA-REG BP trial, empagliflozin 10 mg and 25 mg once daily reduced glycohemoglobin, blood pressure (BP), and weight versus placebo in patients with type 2 diabetes mellitus and hypertension. Patients received placebo (n=271), empagliflozin 10 mg (n=276), or empagliflozin 25 mg (n=276) for 12 weeks (n=full analysis set). This present analysis investigated changes from baseline to week 12 in mean 24-hour systolic BP (SBP) and diastolic BP (DBP) in patients receiving 0, 1, or ≥2 antihypertensive medications and patients receiving/not receiving diuretics or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers. Compared with placebo, empagliflozin 10 mg and 25 mg reduced mean 24-hour SBP/DBP in patients receiving 0 (10mg: −3.89/−2.58mmHg; 25mg: −3.77/−2.45mmHg), 1 (10mg: −4.74/−1.97mmHg; 25mg: −4.27/−1.81 mmHg), or ≥2 (10 mg: −2.36/−0.68 mmHg; 25 mg: −4.17/−1.54 mmHg) antihypertensives. The effect

Association of systolic BP variability with mortality, coronary heart disease, stroke, and renal disease Comment by Jeffrey Whittle MD, MPH

Association of systolic blood pressure variability with mortality, coronary heart disease, stroke, and renal disease Journal of the American College of Cardiology Take-home message • The authors evaluated 2,865,157 US veterans to assess the association between visit-to-visit systolic blood pressure variability (SBPV) and all-cause mortality, cardiovascular events, and end-stage renal disease (ESRD). • Results showed that the higher the variability (measured in standard deviation quar- tiles), the greater the association with all-cause mortality, CHD, stroke, and ERSD. Abstract

T hese investigators examined the association of systolic blood pressure variability (SBPV) with risk of mortality, incident coro- nary heart disease, stroke, and end-stage renal disease in a large cohort of US veterans. In each case, higher SBPV increased the risk of the adverse event. This finding has been noted in multiple prior studies, generally with more selected populations; but this study used BP measures obtained during routine practice throughout the period of follow-up. Rather than focus on methodological concerns, the reader should recognise the growing weight of evidence that blood pressure variability predicts adverse events, whether it is measured visit to visit over years (as in this study), over the course of days to weeks of home blood pressure measurements, or during a single 24-hour ambulatory blood pressure recording. It is also clear that we don’t have much reason to change our clinical practice in response to this information. Certainly, the increased risk might be a cause for more aggressive treatment, but this same variability might increase the risk of adverse events with treat- ment. While some drug classes, in particular calcium channel blockers, clearly are associated with less SBPV, they are not, on balance, more protective against adverse outcomes than other drugs with the opposite effect on SBPV, notably ACE inhibitors, when similar reductions in SBP are achieved. This is a result that should stimulate research but not change current clinical practice.

sociodemographic characteristics, baseline eGFR, comorbidities, body mass index, SBP, diastolic BP, and antihypertensive medication use. RESULTS Several sociodemographic variables (older age, male sex, African- American race, divorced or widowed status) and clinical characteristics (lower baseline eGFR, higher SBP and diastolic BP), and comorbidities (presence of diabetes, hypertension, cardiovascular disease, and lung disease) were all associated with higher intraindividual SBPV. The multivariable adjusted hazard ratios and 95% confidence intervals for SD quartiles 2 through 4 (compared with the first quartile) associated with all-cause mortality, CHD, stroke, and ESRDwere incrementally higher. CONCLUSIONS Higher SBPV in individuals with and without hypertension was associated with increased risks of all- cause mortality, CHD, stroke, and ESRD. Further studies are needed to determine interventions that can lower SBPV and their impact on adverse health outcomes. J Am Coll Cardiol 2016 Sep 27;68:1375- 1386, Gosmanova EO, Mikkelsen MK, Molnar MZ, et al.

BACKGROUND Intraindividual blood pressure (BP) fluctuates dynamically over time. Previous studies suggested an adverse link between greater visit-to-visit variability in systolic blood pressure (SBP) and various outcomes. However, these studies have significant limitations, such as a small size, inclusion of selected populations, and restricted outcomes. OBJECTIVES This study investigated the association of increased visit-to-visit variability and all-cause mortality, cardiovascular events, and end-stage renal disease (ESRD) in a large cohort of U.S. veterans. METHODS From among 3,285,684 U.S. veterans with and without hypertension and normal estimated glomerular filtration rates (eGFR) during 2005 and 2006, we identified 2,865,157 patients who had 8 or more outpatient BP measurements. Systolic blood pressure variability (SBPV) was measured using the SD of all SBP values (normally distributed) in 1 individual. Associations of SD quartiles (<10.3, 10.3 to 12.7, 12.7 to 15.6, and ≥15.6 mmHg) with all- cause mortality, incident coronary heart disease (CHD), stroke, and ESRD was examined using Cox models adjusted for

Dr Whittle is Director of Health Services Research, Clement J Zablocki VA Medical Center in Wisconsin and Professor, Division of General Internal Medicine, Department of Medicine, Medical College of Wisconsin.

VOL. 1 • No. 3 • 2016