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Effect of antihypertensive treatment at different blood pressure levels in patients with diabetes mellitus: systematic review and meta-analyses

BMJ 2016; 352 doi: https://doi.org/10.1136/bmj.i717 (Published 25 February 2016) Cite this as: BMJ 2016;352:i717

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Redefining Blood Pressure Targets against SPRINT in Patients with Diabetes?

Brunstrom M, et al evaluated the effect of antihypertensive treatment on mortality and cardiovascular morbidity in people with diabetes mellitus, at different blood pressure levels.

They observed that antihypertensive treatment reduces the risk of mortality and cardiovascular morbidity in people with diabetes mellitus and a systolic blood pressure more than 140 mm Hg. If systolic blood pressure is less than 140 mm Hg, however, further treatment is associated with an increased risk of cardiovascular death, with no observed benefit.1

Diabetes is the worst risk factor for most diseases including cardiovascular disease. It is well known that diabetes increases the risk of cardiovascular disease 3 times higher than other risk factors.2 Those with diabetes and hypertension are particularly susceptible to vascular injury.

Emdin CA, et al determined the subgroup specific associations between usual blood pressure (BP) and risk of peripheral arterial disease, and examined the relation between peripheral arterial disease and a range of other types of vascular disease in a large contemporary cohort. They observed that a 20 mm Hg higher than usual systolic BP was associated with a 63% higher risk of peripheral arterial disease (hazard ratio 1.63) and peripheral arterial disease was associated with an increased risk of 11 different vascular events, including ischaemic heart disease, heart failure, aortic aneurysm, and chronic kidney disease, but not haemorrhagic stroke.3 Therefore, to control BP is important to prevent vascular injury.

The next question is the most optimal BP target level in people with hypertension. Because observational studies with a low risk of confounding have shown a linear relationship between BP and cardiovascular risk down to 115/75 mm Hg.4 To answer in people with diabetes, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial was performed and showed surprising results - no significant overall difference in cardiovascular events between patients with type 2 diabetes assigned to a systolic BP target of less than 120 mm Hg and those assigned to a target of less than 140 mm Hg.5 Therefore, the Eighth Joint National Committee took a targeted approach to the consideration of previous trials and concluded that systolic BP targets should be below 140 mm Hg, or below 150 mm Hg in those 60 years of age or older.6

Nonetheless, other trials reported benefits in persons with diabetes and those without diabetes that lower BP goals produced larger reductions in total major cardiovascular events.7 Indeed, the Systolic Blood Pressure Intervention Trial (SPRINT) reported that among patients at high risk for cardiovascular events but without diabetes, targeting a systolic BP of less than 120 mm Hg, as compared with less than 140 mm Hg, resulted in lower rates of fatal and nonfatal major cardiovascular events and death from any cause, although significantly higher rates of some adverse events were observed in the intensive-treatment group.8 Its editorial disclosed that the effects on individual outcomes in SPRINT and the ACCORD trial are generally consistent and the main differences were that the ACCORD trial had less statistical power than SPRINT, and
its primary outcome included a higher proportion of events that are less sensitive to BP reduction and suggested current guidelines and guideline processes require revision.9

So, is the SPRINT study enough to finish this debate regarding optimal BP targets? Some observational studies with a greater potential for confounding, involving persons at increased risk, have suggested a J-shaped curve. Brunstrom M, et al reiterated this fact. Furthermore, physicians should keep in mind that rates of serious adverse events of hypotension, syncope, electrolyte abnormalities, and acute kidney injury or failure, but not of injurious falls, were higher in the intensive treatment group than in the standard treatment group.8

Again, to control BP is important. Various strategies to reduce residual cardiovascular risk in hypertensive patients included treating BP to lower target goals and using different classes of anti-hypertensive medications, but still considerable residual risk remained. In contrast, controlling hypercholesterolemia in hypertensive patients by statins is very effective in reducing residual cardiovascular risk by 35% to 40%.10 Also, cross-talk between hypercholesterolemia and renin angiotensin system (RAS) exists at multiple steps of insulin resistance and endothelial dysfunction. In this regard, combined therapy with statins and RAS blockers demonstrate additive/synergistic effects on endothelial dysfunction and insulin resistance in addition to lowering cholesterol levels and blood pressure when compared with either monotherapy in patients.11,12 This is mediated by both distinct and interrelated mechanisms. Therefore, combined therapy with statins and RAS blockers may be important in developing optimal management strategies in patients with hypertension, hypercholesterolemia, diabetes, metabolic syndrome, or obesity to prevent vascular risk.13-15

REFERENCES
1. Brunström M, Carlberg B. Effect of antihypertensive treatment at different blood pressure levels in patients with diabetes mellitus: systematic review and meta-analyses. BMJ 2016;352:i717.

2. Koh KK. To take or not to take metformin to prevent diabetes? That is the question. BMJ 2015, Published on 22 February 2015, http://www.bmj.com/content/350/bmj.h454/rr

3. Emdin CA, Anderson SG, Callender T, et al. Usual blood pressure, peripheral arterial disease, and vascular risk: cohort study of 4.2 million adults. BMJ 2015;351:h4865.

4. Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. BMJ 2009; 338: b1665.

5. Cushman WC, Evans GW, Byington RP, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 2010; 362: 1575-85.

6. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014;311:507-20.

7. Turnbull F, Neal B, Algert C, et al. Effects of different blood pressure-lowering regimens on major cardiovascular events in individuals with and without diabetes mellitus: results of prospectively designed overviews of randomized trials. Arch Intern Med 2005; 165: 1410-9.

8. The SPRINT Research Group. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med 2015;373:2103-16.

9. Perkovic V1, Rodgers A. Redefining blood-pressure targets--SPRINT starts the marathon. N Engl J Med 2015;373:2175-8.

10. Egan BM, Li J, Qanungo S, Wolfman TE. Blood pressure and cholesterol control in hypertensive hypercholesterolemic patients: National health and nutrition examination surveys 1988-2010. Circulation 2013;128:29-41.

11. Koh KK, Quon MJ, Han SH, et al. Additive beneficial effects of losartan combined with simvastatin in the treatment of hypercholesterolemic, hypertensive patients. Circulation 2004;110:3687-92.

12. Koh KK, Quon MJ, Han SH, et al. Vascular and metabolic effects of combined therapy with ramipril and simvastatin in patients with type 2 diabetes. Hypertension 2005;45:1088-93.

13. Koh KK. Quon MJ. Targeting converging therapeutic pathways to overcome hypertension. Int J Cardiol 2009;132:297-9.

14. Lim S, Sakuma I, Quon MJ, Koh KK. Potentially important considerations in choosing specific statin treatments to reduce overall morbidity and mortality. Int J Cardiol 2013;167: 1696-1702.

15. Koh KK, Lim S, Choi H, et al. Combination pravastatin and valsartan treatment has additive beneficial effects to simultaneously improve both metabolic and cardiovascular phenotypes beyond that of monotherapy with either drug in patients with primary hypercholesterolemia. Diabetes 2013;62:3547-552.

Competing interests: No competing interests

01 March 2016
Kwang Kon KOH
Professor of Medicine
Department of Cardiovascular Medicine, Gachon University, Gil Medical Center
774 Beongil 21, Namdongdaero, Namdong-Gu, Incheon, Korea 21565