Are There Pleiotropic Effects of Antihypertensive Medications or Is It All About the Blood Pressure in the Patient With Diabetes and Hypertension?

Abstract

Many small studies with varied surrogate end points and numerous preclinical data have suggested the likelihood of there being specific benefits that exceed simple blood pressure control with drug classes such as angiotensin‐converting enzyme inhibitors, angiotensin receptor blockers, and calcium channel blockers, which may be particularly relevant to the patient with diabetes and hypertension. Large clinical trials, however, have provided only token support for this idea. Likewise, meta‐analyses that have incorporated varied clinical trials, albeit with somewhat heterogeneous data, have not been particularly forthcoming in their support of this concept. In the patient with diabetes and hypertension, tight blood pressure control, more so than using a specific drug class, is the most important aspect of therapy. J Clin Hypertens (Greenwich). 2011;13:301–304. © 2011 Wiley Periodicals, Inc.

In addition to the current debate as to the optimum blood pressure (BP) for preventing cardiovascular (CV) events in the patient with diabetes and hypertension, ¹ another area of some dispute is whether certain antihypertensive medications provide a CV and/or renal benefit free of their BP‐lowering effects, a seeming pleiotropic effect. ¹ Pleiotropic effects are actions of a drug other than those for which the agent was specifically intended and may be variably related to the primary mechanism of drug action. ² , ³

Pleiotropic Effect: Antihypertensives

A number of antihypertensive drug classes have been suggested to have pleiotropic effects, with angiotensin‐converting enzyme (ACE) inhibitors, ⁴ , ⁵ , ⁶ , ⁷ , ⁸ angiotensin receptor blockers (ARBs), ⁹ , ¹⁰ , ¹¹ and calcium channel blockers (CCBs) ⁸ , ¹² , ¹³ , ¹⁴ being most commonly brought up. In that regard, it is the extent to which drugs in each of these antihypertensive medication classes provides benefits, in excess of the absolute level of BP reduction, which is debated in the patient with hypertension. ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ For an antihypertensive drug class marked by negative metabolic/hormonal effects, pleiotropism can still exist; however, it is only under select circumstances. Such is the case for the secondary prevention of coronary heart disease (CHD)–related events with β‐blockers where the event rate reduction is in excess of what might be expected from BP reduction alone.

Pleiotropism and Renin‐Angiotensin System Activation

Much of the positive discussion concerning ACE inhibitors and ARBs as to pleiotropism centers on their capacity to block the protean manifestation of renin‐angiotensin system (RAS) activity, either in its circulating or its locally tissue‐active form. The pathophysiologic effects of angiotensin II (Ang II), the main effector of the RAS, which potentially lead to CV disease, include vasoconstriction, thrombogenicity, increased production of reactive oxygen species (ROS), vascular smooth muscle growth, myocyte hypertrophy, fibrosis, and maladaptive remodeling of tissues. Moreover, RAS activation serves as the starting point for the release and increased activity of a number of hormonal mediators, inflammatory substances, and cytokines. ² Primary RAS activation will also trigger formation of a number of secondary messengers and/or activate pathways, which expand on its untoward vascular/tissue effects. These processes occur variably in the patient with diabetes and hypertension. ²⁰ In addition, CCBs have been suggested to have pleiotropic effects. Some of the more commonly proposed mechanisms include a reduction in vascular inflammation as well as ROS, increased nitric oxide bioavailability, and a decrease in migration and proliferation of smooth muscle cells. ²¹

Clinical Trials and Pleiotropism

For a drug to qualify as “going beyond the numbers,” supporting clinical trial evidence can present in any of three possible ways: first, a drug’s effectiveness in reducing CV outcomes must be in excess of (discordant) what might be expected from the BP reduction alone; second, evidence supporting this concept can be obtained (but less reliably so) from clinical trials where BP reduction was superior in one treatment arm and the alternative treatment limb was observed to have better outcomes; and third, from clinical trials where BP reduction was inferior with one treatment and outcomes were equivalent to what was seen with the alternative and superior BP‐lowering treatment limb. ² , ³

Whether pleiotropic effects exist for antihypertensive medications and in particular the ACE inhibitor and/or ARB drug classes remains an attention‐grabbing question but one that cannot be readily resolved. If ACE inhibitors and/or ARBs are to offer any particular benefit beyond BP reduction, the mechanism would likely relate to positive effect(s) on intermediate end points such as left ventricular hypertrophy, vascular structure, endothelial function, risk biomarkers (indirect), and/or improving the metabolic milieu by reducing the risk of new‐onset diabetes development. In reality, however, the impact of these drug classes on such intermediate end points is of limited relevance unless meaningful BP reduction has also taken place. If and when meaningful BP reduction occurs, intermediate end points are for the most part favorably impacted and as such the drug class in use devolves into a secondary consideration. Patients treated with an ACE inhibitor, ARB, or CCB typically do not receive one drug therapy, so the issue of pleiotropic effect also becomes one of comparing drug‐based regimens to the other. Finally, class effect is an underappreciated issue relative to pleiotropism in that dose, tissue exposure, intraclass pharmacokinetic differences (particularly drug compartmentalization), and location of pleiotropic effect (brain, heart, kidney, and vasculature) will influence its expression (or not).

The clinical trials that can offer information concerning BP reduction and outcomes, with or without an element of pleiotropism, are numerous and a thorough discussion of each is beyond the scope of this commentary; therefore, the reader is directed to a recently published insightful point‐counterpoint on this topic. ²²

BP Control and Pleiotropism

Many drug options are available for the pharmacologic management of hypertension in the patient with diabetes. The current approach, recommended by the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) and the European Society of Hypertension do not support a pleiotropic effect for any antihypertensive class in the diabetic patient with uncomplicated early‐stage hypertension. ²³ , ²⁴ Alternatively, the American Diabetes Association states categorically that pharmacologic therapy for patients with diabetes and hypertension should be with a regimen that includes either an ACE inhibitor or an ARB. ²⁵ JNC 7 further opines that the “question of which class of agent is superior for lowering BP is somewhat moot because the majority of diabetic patients will require ≥2 drugs to achieve BP control.” ²³ The opinion of various guideline‐promulgating committees advise the choice of a starting antihypertensive should be based on the characteristics of the patient, in particular, the presence of concomitant illnesses such as diabetic nephropathy and/or systolic heart failure (HF) wherein the choice of an ACE inhibitor or an ARB is better supported by experimental evidence.

How does one reconcile the multiple diverse opinions on pleiotropism for RAS inhibitors? For a pleiotropic effect of an antihypertensive medication to be viewed as being genuine, it must be assessed in the context of the time‐wise precision of BP control, which bears on interpretation of the degree to which BP differences exist(ed) between head‐to‐head treatments. The best long‐term outcome for hypertensive patients is typically seen when antihypertensive therapy has controlled BP effectively throughout a 24‐hour cycle of treatment ²⁶ ; however, outcomes trials have for the most part relied on office‐based BP determination, an ascertainment technique not ideally suited for the detection of BP differences, either in the latter part of the day or during sleep hours. ²⁷

End‐of‐study or early on–in‐study differences in BP (−2 mm Hg to −4‐mm Hg) between treatment arms of head‐to‐head studies may seem small, when in reality they are but the “tip of the iceberg” relative to between‐group BP differences. Such differences, although controlled for in analyses, still may not correctly weight the time of day impact of BP change for progression of a disease or occurrence of an event. ²⁷ For example, in the Heart Outcomes Protection Evaluation (HOPE) trial, ramipril dosing could have occurred in the evening hours and the BP response (as determined by ambulatory blood pressure monitoring) was more pronounced (decrease of 17/8 mm Hg) during the nighttime hours. ²⁸ By way of comparison, the office‐based readings in the HOPE study found but a 3/2‐mm Hg BP difference between the ramipril and placebo groups. ⁶ This small between‐group in‐office BP effect is not entirely unexpected considering that measurements could have been taken 12 hours or more following dosing and thus represented an approximated trough effect for evening dosing.

Therefore, the effects on CV morbidity and mortality seen with ramipril in the HOPE study may have related more so to effects on BP patterns over the 24‐hour period. Importantly, a peak medication effect during the sleep hours (the likely case in the HOPE study) could have been expected to expose the patient to drug (and a BP‐lowering effect) when such is most desirous; that is, when nocturnal hypertension (if a patient is a nondipper or a “reverse” dipper) and/or the next day’s early morning surge in BP occurs. The latter is the point in time when CV and stroke event rates are statistically the highest. ²⁹

Conclusions

Findings from the large drug vs drug trials, which included sizable numbers of patients with diabetes and hypertension, suggest that choosing a best first drug for hypertension treatment is not as important as is better BP control. In pooled analyses, when the achieved BP is similar, drugs such as thiazide‐type diuretics perform equally well as ACE inhibitors, ARBs, and CCBs. If BP‐independent differences favoring one antihypertensive drug class over another actually exist, they have been surprisingly difficult to unearth with any sort of regularity. The exceptions to this “all drugs being equal” approach relates to the use of either ACE inhibitors or ARBs in the case of diabetic nephropathy, systolic forms of HF, and stroke, where outcomes evidence exists supporting the preferential use of either of these two drug classes for their BP‐independent effects. Considering that multidrug therapy is required in many patients with hypertension and diabetes, the wrangling as to which drug class is best to start with is moot as the clinician is now more and more called upon to decide on the best drug combination and not the best monotherapy.