Lipid-lowering Drugs in Hypertension
Of all the lipid-lowering drugs, only statins have been properly tested in large clinical trials in hypertensive patients showing their ability to reduce CV morbidity and mortality.17
Effects of Statins on Blood Pressure and Renal Function – Pathophysiological Mechanism
By blocking the synthesis of 3-hydroxy-3-methylglutaryl coenzyme A reductase, statins induce consistent and predictable reductions in circulating LDL-cholesterol and triglycerides, and have a small effect on high-density lipoprotein (HDL)-cholesterol. In addition, these agents exhibit ancillary actions attributed to reductions in isoprenoid cholesterol intermediates and reductions in dolichols, geranylgeranoic acid and farsenylfarsenoic acid. These actions may provide a pleiotropic mechanism by which statins exert actions on blood pressure as well as target organ damage associated with hypertension. Statins improve endothelial function by increasing the bioavailability of nitric oxide, promoting reendothelialisation, reducing oxidative stress and inhibiting inflammatory responses.18 Increased angiotensin II sensitivity predisposes to hypertension and plaque instability. The increased sensitivity to angiotensin II in healthy young subjects with isolated hypercholesterolaemia can be partly restored by therapy to reduce the levels of LDL-cholesterol using statins. There is evidence that statins downregulate angiotensin II type 1 (AT1)-receptor expression.19
Clinical trials have demonstrated that aggressive treatment with statins improves serum creatinine, glomerular filtration rate and urate levels.20,21 This effect is probably another consequence of improved blood flow following treatment with statins. The beneficial effect of statins in preventing renal dysfunction has also been documented and seems to be independent of their lipid-lowering effect.22 Statins significantly reduce albuminuria or proteinuria and are associated with a small reduction in the rate of kidney function loss, particularly in populations with CV disease.23
Effects of Statins on Blood Pressure in Clinical Studies
Most of the studies report a small reduction in blood pressure; however, the blood pressure-lowering effect of statins is not consistent.
The effect on blood pressure (BP) varied from neutral to most favourable (Δ systolic BP 8–13 mmHg; Δ diastolic BP 5.0–7.8 mmHg) in a review by Milionis et al., including studies within a broad spectrum of patients (normotensives, hypertensives, individuals with normal lipids and dyslipidaemia, diabetic patients) published up to 2005.24
A meta-analysis of all studies published up to 2005 and reporting BP data during treatment with statins included 20 randomised controlled trials (828 patients) lasting from one to 12 months.25 Systolic BP was significantly lower in patients on statins than in those on placebo or a comparative lipid-lowering drug (mean difference: -1.9 mmHg; 95 % CI -3.8 to -0.1). The effect was greater when the analysis was restricted to studies with a baseline systolic BP >130 mmHg (Δ systolic BP -4.0 mmHg; 95 % CI -5.8 to 2.2). There was a trend toward lower diastolic BP in patients receiving statin therapy compared with controls: -0.9 mmHg (95 % CI -2.0 to 0.2) overall and -1.2 mmHg (95 % CI -2.6 to 0.1) in studies with a baseline diastolic BP >80 mmHg.
The University of California San Diego (UCSD) Statin Study, a randomised, double-blind, placebo-controlled trial with 973 patients allocated equally to simvastatin (20 mg), pravastatin (40 mg) or placebo for six months, showed a modest but significant BP reduction (2.4–2.8 mmHg for both systolic blood pressure [SBP] and diastolic blood pressure [DBP]) with both statins.26 As this effect was seen in patients not receiving antihypertensive treatment (most patients were normotensive), these results are compatible with the above possibility that statins exert a small BP-lowering effect that can be detected only when they are given alone.
By contrast, in the Plaque Hypertension Lipid-Lowering Italian Study (PHYLLIS), a randomised, placebo-controlled, double-blind study including 508 patients with mild hypertension and hypercholesterolaemia, administration of a statin (pravastatin 40 mg once daily) in hypertensive patients with BP effectively reduced by concomitant antihypertensive treatment did not have an additional BP-lowering effect.27 The strengths of this study were a 2.6-year follow-up and ambulatory BP monitoring in addition to clinic BP measurement.
A recent meta-analysis of 40 studies and 51 comparison groups (22,511 controls and 22,602 patients) reported a decrease in mean SBP in the statin group by 2.62 mmHg (95 % CI -3.41 to -1.84; p<0.001) and DBP by 0.94 mmHg (95 % CI -1.31 to -0.57; p<0.001). In studies including hypertensive patients, the decrease in BP with statins was slightly greater (SBP -3.07 mmHg; 95 % CI -4 to 2.15 and DBP 1.04 mmHg; 95 % CI -1.47 to -0.61).28