Epidemiologic observations from large, nationally representative samples consistently show a considerable gap between the growing population of Americans diagnosed with hypertension[1] and those reaching BP goals.[2] Although rates of hypertension treatment and control have increased somewhat in recent years, approximately two-thirds of hypertensive adults receiving treatment, and one-third overall, reach the BP goals recommended by the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7).[2,3] The most recently reported national BP control rates[3] fall far short of the 'healthy people 2010' goal of 50% of all hypertensive adults reaching recommended targets.[4]
Results of clinical trials indicate that what were once thought to be small differences in BP and time to BP control may translate into important differences in clinical outcomes.[5] The recognition that months and millimeters matter imparts a sense of urgency to treat hypertensive patients to goal within the first few months of therapy. In view of the accumulating and definitive evidence that lowering BP substantially reduces the risk of cardiovascular and renal events, and with the many therapeutic options available, it behooves clinicians to reflect on two key questions: (i) why rates of BP control remain low; and (ii) what strategies are most likely to improve control rates. These questions are even more critical for hypertensive patients at high risk for poor clinical outcomes, including those with altered lipid and glucose metabolism, diabetes mellitus, and/or chronic kidney disease, for whom the BP target is <130/80 mmHg.[3,6] This paper will briefly discuss some of the issues that account for the failure to achieve goal BP in many patients at risk for cardiovascular disease and will focus on the potential benefits of using thiazide diuretics in combination with inhibitors of the renin-angiotensin system (RAS) to address this deficiency.
1. Why Are BP Goals so Difficult to Attain?
Several explanations have been posited as to why efforts to control BP fall short of national targets. For some time, attention has focused on a lack of patient adherence to antihypertensive therapy,[7] but, recently, the issue of 'therapeutic inertia' among healthcare providers has come to light.[8] Therapeutic inertia has been defined as the failure of healthcare providers to initiate or intensify therapy when indicated. Clinicians may accept BP levels in their patients higher than those currently recommended and consequently fail to make appropriate medication adjustments, even in clinical trial settings.[9] Reasons cited for this behavior include an overestimation by the clinician of the care actually being provided, rationalization by the clinician that results obtained in large trials do not necessarily apply to individual patients in a typical clinical setting, and lack of practice structure needed to identify therapeutic shortcomings.[10] Clinicians also may hesitate to increase dosages or add another agent to the regimen out of concern about adverse effects commonly associated with antihypertensive therapy.
Another potential explanation for poor rates of BP control is the common practice of titrating the dose of single-agent therapy to maximum effect before adding another agent. Although this approach is consistent with traditional medical training and makes intuitive sense, most patients with hypertension, particularly those with high-risk or severe hypertension, will require combination therapy to reach their BP goal.[3,11,12] Because multiple mechanisms underlie the pathophysiology of hypertension, combinations of antihypertensive medications that have complementary therapeutic mechanisms are consistently more effective than monotherapy.[3] In addition, rationally chosen combinations provide maximum BP reduction and is appropriate treatment to improve clinical outcomes.
2. Strategies to Improve BP Control: Combination Therapy
Recognizing that the majority of patients in clinical trials required two or more antihypertensive agents to reach goal, JNC-7 recommends that, when BP is >20/10 mmHg above the desired goal and in all patients at high risk, consideration be given to initiating treatment with combination therapy.[3] Because the underlying pathophysiology of hypertension and its co-morbidities is multifactorial, combining drugs from antihypertensive classes with complementary mechanisms of action, such as diuretics or calcium channel antagonists (CCAs) with agents that block the RAS, offers utility in getting patients to their BP goals in an efficient and timely manner.
Diuretics were among the first and remain among the most effective treatments for elevated BP, and JNC-7 recommends thiazide diuretics as initial therapy for all patients with uncomplicated hypertension.[3] At low doses, thiazide diuretics usually do not produce changes in renal function,[13] and in clinical trials of patients with and without diabetes mellitus treatment with diuretics appears to protect against cardiovascular events to a degree comparable with β-adrenoceptor blockers (β-blockers), CCAs, or ACE inhibitors.[14] In an analysis of patients with diabetes mellitus in ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial), there was no difference in the occurrence of cardiovascular events with the use of a diuretic, CCA, or ACE inhibitor over a mean follow-up of approximately 5 years.[15]
One concern raised with use of thiazide diuretics is the association with a decrease in insulin sensitivity[16,17] and an increase in the incidence of new-onset diabetes mellitus. It is well established that hypertension and insulin resistance often coexist.[18-20] Data obtained from large observational studies suggest there is a higher incidence of new-onset type 2 diabetes mellitus in hypertensive patients who are chronically treated with thiazide diuretics (with or without β-blocker use), compared with placebo or ACE inhibitors or angiotensin receptor antagonists.[21,22] When new-onset type 2 diabetes mellitus is assessed as new cases per 1000 patients treated for 1 year, the absolute incidence among patients treated with diuretics or β-blockers compared with patients who use an alternative drug (or placebo) averages between 5.6 ± 2.3 new cases per 1000 patients per year.[23] New-onset diabetes mellitus among treated hypertensive patients has been shown to confer cardiovascular risk similar to that associated with pre-existing diabetes mellitus - approximately 3-fold the risk of persons who remain normoglycemic during antihypertensive therapy.[24]
While the association between thiazide use and glucose intolerance is well documented,[25] the severity and significance of the findings are uncertain. Another unresolved issue is whether glucose intolerance is a direct effect of the drug or a consequence of thiazide-induced hypokalemia. In a recent review of more than 50 trials in which thiazides were compared with other drugs or placebo a significant inverse relationship was found between the decrease in potassium and increase in glucose level.[25] For every 1 mEq/L decrease in potassium there was approximately a 10 mg/dL increase in glucose. Further strengthening the argument that hypokalemia plays an important role in the genesis of glucose intolerance is the observation that prevention of hypokalemia with potassium supplements prevents the development of thiazide-induced glucose intolerance.[26] In addition, changes in glucose levels can be normalized following potassium repletion in hypokalemic patients.
The mechanism of thiazide-induced hyperglycemia is thought to be the result of decreased insulin release from the pancreatic β cell. ATP-sensitive K+ channels couple β-cell metabolism to electrical activity and thereby play an essential role in the control of insulin secretion.[27] The involvement of K+ in this process at least raises the possibility that K+ depletion might alter β-cell insulin release. Impaired insulin release that is reversible with drug discontinuation or potassium supplements is in contrast to the persistent insulin resistance typical of patients with type 2 diabetes mellitus. This difference in mechanism of glucose intolerance may help explain the lack of convincing evidence that thiazide-induced diabetes mellitus increases the incidence of morbid or fatal cardiovascular events.[28]
Accumulated evidence supports the primary importance of BP lowering for reducing cardiovascular risk in persons with and without diabetes mellitus using the range of antihypertensive drug classes.[14] However, in patients with diabetes mellitus or chronic kidney disease, JNC-7 and American Diabetes Association guidelines recommend treatment with an agent that blocks the RAS, either an ACE inhibitor or an ARB.[3,11] RAS blockade plays a role in the repair of vascular injury and has been shown to delay deterioration in glomerular filtration rate and worsening of albuminuria.[3,11,29] The renoprotective effects of RAS blockade have been demonstrated in several landmark trials in patients with impaired renal function and type 1 or type 2 diabetes mellitus.[30-33] In patients with type 2 diabetes mellitus and overt nephropathy, the use of an ARB reduced the composite outcome of doubling the serum creatinine concentration, end-stage renal disease, and death independent of BP reduction.[31,33] In addition, RAS blockade has been shown to reduce the risk of cardiovascular events in patients at high risk.[34,35]
A recent nested case-control study of a diabetic population found that the long-term use of ACE inhibitors actually lead to a higher risk of renal failure.[36] In this type of analysis one cannot exclude the possibility that ACE inhibitor treated patients lived longer and therefore had greater opportunity to develop end-stage renal disease. In addition, ACE inhibitors may have been prescribed to individuals with hypertension that was more difficult to control. The study provided no database as to the absolute level of BP and whether there were significant differences between patients treated with ACE inhibitors versus other classes of drugs. Lastly, no information was provided as to the presence or absence of proteinuria in the various groups of patients. As reviewed recently, patients excreting large amounts of urinary protein who are otherwise deemed to be optimally treated should still be considered at high risk for renal disease progression.[37] Additional measures that decrease urinary protein excretion will reduce this risk.
Although clinical trial results indicate generally comparable cardiorenal protection provided with ACE inhibitors and ARBs, the more favorable tolerability of ARBs allows for higher dosing without a substantial increase in adverse effects.[38] This may offer an advantage, as some evidence suggests that higher doses of ARBs are associated with improved renal outcomes in patients with type 2 diabetes mellitus.[32] In diabetic patients with microalbuminuria, treatment with a 300 mg dose of irbesartan significantly reduced the progression to overt nephropathy (relative risk [RR] 0.32; p < 0.001) and to a greater extent than the 150 mg dose (RR 0.56; p = 0.05) versus placebo.[32] The reduction in risk of new-onset diabetes mellitus by approximately 25% with agents that inhibit the RAS versus β-blockers, diuretics, and placebo[39] provides an additional rationale for treating patients at risk for diabetes mellitus and kidney disease with ACE inhibitors or ARBs.[5,32,35] ARBs have beneficial effects on glucose metabolism that appear to be independent of bradykinin-mediated mechanisms.[5]
3. Rationale for Renin-Angiotensin System Blockade in Combination with Thiazide Diuretics
The combination of a diuretic with an agent that inhibits the RAS is a logical one (table I).[40-42] Thiazide diuretics lower BP via sodium excretion and volume reduction, making thiazides most effective in patients with salt- or volume-sensitive hypertension.[40] Thiazide-induced volume reduction may activate the RAS as a compensatory mechanism and, in turn, promote renin release and formation of angiotensin II; thus, RAS activation in response to diuretic therapy may limit the hypotensive action of the diuretic.[40,43] ACE inhibitors and ARBs counteract angiotensin II-mediated activation of the RAS and sympathetic nervous system, and provide BP control via their powerful vasodilatory effects. The combination of a RAS inhibitor and a thiazide diuretic effectively lowers BP in patients with renin- or salt-sensitive hypertension; among those with salt-sensitive hypertension, the BP-lowering effects of an ARB are enhanced when it is combined with even minimally natriuretic doses of hydrochlorothiazide.[43] RAS inhibition normalizes the pressure-natriuresis gradient and allows sodium balance to be maintained at lower arterial pressures.[44]
Table I. Benefits of...Image Tools
ACE inhibitors and ARBs reduce urinary protein excretion and slow the progression of chronic kidney disease. This beneficial effect on renal disease progression is greater in patients with higher urinary protein excretion at the onset of treatment.[45] The amount of proteinuria remaining during therapy is proportional to the subsequent rate of renal function loss, suggesting that interventions designed to further lower urinary protein excretion will enhance renal outcomes. Restricting dietary salt intake and using effective diuretic therapy have been shown to augment the antiproteinuric effect of RAS blockade, which provides additional rationale for the use of these two drug classes together.[46,47] Thiazide diuretics can be used for this purpose when the estimated glomerular filtration rate is >30 mL/minute; however, loop diuretics should be utilized in patients with more severe renal insufficiency.
ARBs offer utility in combination regimens due to the low rate of adverse events associated with this class compared with other antihypertensive classes;[48,49] for example, ARBs demonstrate a lower incidence of cough and angioedema than ACE inhibitors.[38] Because of their complementary mechanisms of action, the combination of an ARB with hydrochlorothiazide provides significantly greater BP reductions than either component as monotherapy.[50-55] Furthermore, a dose-dependent effect of ARB/hydrochlorothiazide has been observed through the approved dose range with losartan (up to 100 mg),[55,56] valsartan (up to 320 mg),[57,58] and olmesartan (up to 40 mg)[54] in combination with hydrochlorothiazide 12.5-25 mg, without a substantial increase in adverse events. In the recently reported Val-MARC (Valsartan-Managing Blood Pressure Aggressively and Evaluating Reductions in hs-CRP) trial,[58] the median change in SBP with the combination valsartan/hydrochlorothiazide (≤320/12.5 mg/day) was -25 mmHg versus -18 mmHg with valsartan monotherapy (≤320 mg/day) at 6 weeks (p < 0.001); median change in DBP was -14 mmHg versus -9 mmHg, respectively (p < 0.001). The greater reduction observed with combination therapy was statistically significant as early as the second week.[58]
In addition to increased BP-lowering efficacy with the combination of a diuretic and an agent that blocks the RAS, evidence suggests that combination therapy mitigates some of the adverse events associated with these drug classes when given as monotherapy.[13,59] A recent analysis of 59 clinical trials of diuretic treatment for hypertension found a significant inverse relationship between potassium and glucose values (Pearson's correlation coefficient -0.54; p < 0.01), suggesting a potential mechanism for the increased incidence of new-onset diabetes mellitus observed with diuretics.[25] RAS blockade inhibits urinary potassium secretion and thereby counteracts potassium wasting as well as aldosterone secretion associated with diuretic monotherapy. Hyperkalemia remains a common concern voiced by clinicians regarding the use of agents that block the RAS in patients with or at risk for chronic kidney disease; however, the risk of hyperkalemia can be minimized with the addition of a low-dose diuretic.[59]
Despite the evidence for a beneficial effect of RAS blockade on the kidney, some clinicians remain concerned by the observed changes in markers of renal function with these agents. A small, nonprogressive increase in serum creatinine may be observed with any antihypertensive therapy as a result of BP lowering, and this effect may be more pronounced with ACE inhibitors or ARBs. However, because of changes in renal autoregulation that occur in chronic kidney disease, this increase, rather than signaling structural injury, reflects a favorable hemodynamic effect of antihypertensive agents in the kidney. A slight rise in serum creatinine concentrations in patients with well controlled BP is an indicator that intraglomerular pressure has been reduced.[13] Thiazide diuretics will not cause the degree of volume contraction seen with more potent loop diuretics and therefore are less likely to be associated with an increased serum creatinine concentration when combined with RAS blockade. The long-term renoprotective effects of RAS inhibitors are maintained when used in combination with thiazide diuretics and may be possibly enhanced through better BP control and further reductions in urinary protein excretion.[29,31-33]
Concerns about adverse effects may discourage clinicians from treating hypertension aggressively in high-risk patients, but are not a reason to discontinue antihypertensive treatment. On the contrary, patients with or at risk for chronic kidney disease are more likely to lose renal function as a result of poorly controlled hypertension than from antihypertensive therapy.[13] Clinicians should not be deterred from continuing antihypertensive treatment, because it is precisely patients at highest risk - those with diabetes mellitus or impaired renal function - who will derive the greatest benefit from combined therapy employing RAS blockade.[59]
4. Conclusion
Despite advances in hypertension awareness and treatment, BP control remains far short of national targets. Combination treatment with agents that have complementary mechanisms of action will be needed to help most patients achieve their BP goals and is advocated by current hypertension guidelines. Combination therapy with an agent that inhibits RAS and a thiazide diuretic provides additive BP-lowering efficacy with potentially greater tolerability than monotherapy. This strategy can help patients achieve their individual BP goals and maintain adherence with treatment. Persistence with antihypertensive therapy on the part of patients and providers is essential, as incremental reductions in BP protect against cardiovascular, cerebrovascular, and renal events.
Acknowledgments
Dr Palmer has received speaker honoraria from Novartis, Astellas, and Boehringer Ingelheim. No sources of funding were used to assist in the preparation of this review.
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