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Hypertension in Diabetes

Page history last edited by Dhemy Padilla 14 years, 2 months ago


The Web diabetesmanager




Darren Allcock, DO

Stephen A Brietzke, MD

James R Sowers, MD




Last Author Revision: 2010 






Hypertension and type 2 diabetes mellitus (T2DM) are commonly occurring conditions which collectively increase morbid and mortal cardiovascular and kidney disease events.  Associated with the rising incidence of obesity in industrialized countries, the rate of diabetes and hypertension continue to increase every year.  Additionally, as the incidence of hypertension grows, so does that of resistant hypertension.  Clustering together in this overweight and obese populations are T2DM, hypertension, dyslipidemia, chronic kidney disease, obesity, and other pathologies.  An effective treatment regimen will address all facets of the individual patient’s health derangements. This chapter will focus chiefly on the treatment of hypertension in association with T2DM


With goals of reducing risk for both diabetic renal disease and cardiovascular disease, the American Diabetes Association currently advocates a goal blood pressure of < 130/80 mm Hg for all patients with DM.  Justifying this goal is the observation that untreated hypertension produces vascular endothelial damage in myriad end-organs.  Since diabetes itself causes oxidative stress and endothelial dysfunction, it is not surprising that DM and hypertension together produce synergistic cardiovascular and renal damage, perhaps more multiplicative than additive.  Resulting disease states to be delayed, attenuated, or prevented by an aggressive diagnostic and treatment approach to hypertension in DM are coronary artery disease, left ventricular hypertrophy, kidney disease, and stroke.  Accordingly, an appropriate antihypertensive regimen will not only reduce blood pressure to goal, but will help reduce end-organ damage and adverse cardiovascular and renal events.



In this chapter we will examine treatment strategies of hypertension in patients with T2DM by drug class, critically examining advantages and disadvantages of each.  Past and ongoing research continues to demonstrate distinct advantages of certain pharmacologic classes in this target population.



ACE Inhibitors (Angiotensin-converting enzyme inbibitors)


Currently, Angiotensin-converting enzyme (ACE) inhibitors are prescribed almost reflexively as initial antihypertensive treatment in DM.  The body of evidence favoring their use has accumulated from multiple observational and interventional studies over a period of many years.  Benefits of this class of drugs extend to virtually every site of end-organ damage.  ACE inhibitors have been shown to reduce risk for all-cause mortality, myocardial infarction, stroke, diabetic retinopathy progression, onset and progression of microalbuminuria, progression of azotemia, and congestive heart failure.  Among other outcomes, data from the HOPE (Heart Outcomes Prevention Evaluation) trial demonstrated beneficial effects of ramipril on left ventricular structure and function [1], and prevented or delayed progression of microalbuminuria [2][2].  The EUCLID (EURODIAB Controlled Trial of Lisinopril in Insulin-Dependent Diabetes Mellitus) trial demonstrated a dramatic 50% reduction in retinopathy progression associated with the use of lisinopril vs. placebo, in type 1 diabetic patients [3].  So strong is the evidence for the efficacy of ACE inhibitors for prevention of target organ damage in diabetics that more recent trials, such as the ONTARGET (Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial) have not used a placebo arm, but have only been able to compare other agents with ACE inhibitors.  Some (but not all) studies suggest favorable effects of ACEI’s in decreasing risk for T2DM in patients at high risk; these studies include the HOPE trial [4], the CAPP (Captopril Prevention Project) [5], ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) [6], and ANBP-2 (Australian National Blood Pressure Study 2) [7].  There has been some suggestion of beneficial effects on lipid profile associated with the use of ACE inhibitors, but this evidence is even less convincing.


In general, ACEI’s enjoy a relatively favorable side effect profile, making members of this class well tolerated in most patients.  Side effects include dry cough, possibly secondary to increased bradykinin, and nasal stuffiness. In patients with long standing diabetes, diabetic nepropathy and autonomic dysfunction (hyporeninemic hypoaldosteronism/ type 4 renal tubular acidosis), hyperkalemia may occur..  While uncommon, the most serious reaction seen in association with ACE inhibitor use is angioedema.  If this reaction is observed, the entire class of medications should be permanently avoided, as re-challenge could result in life-threatening upper airway obstruction.


Combining multiple outcomes benefits with highly effective antihypertensive efficacy, low economic cost, and a generally favorable side effect profile,  it is not surprising that ACEI’s have become drugs of first choice for treatment of hypertension in DM.  For now, this class will remain the benchmark by which newer classes of antihypertensive agents are judged, and will likely remain a mainstay of therapy well into the future.



ARBs (Angiotensin-converting enzyme inhibitors)


As the ARBs exert similar salutary effects as ACEI’s on the renin-angiotensin-aldosterone axis, it is logical that they are most often compared with ACEI’s, or even “lumped” into the same category by practicing clinicians. The main advantage the ARBs have over other antihypertensive agents is their excellent side effect profile. Generally, studies within the past decade identify comparable outcomes data when ACEI’s and ARB’s are compared head-to-head. Much data has come from the ONTARGET, which has compared the ARB telmisartan with the ACEI ramipril, as well as the combined use of the two.  This trial established general non-inferiority of telmisartan to ramipril.  The telmisartan group had slightly greater reduction in blood pressure, but had statistically equivalent rates of reduction in death from cardiovascular causes, myocardial infarction, stroke, and hospitalization for heart failure.  Additionally, the telmisartan group had substantially lower occurrence of both cough and angioedema.  However, corresponding to the greater reduction in blood pressure, there was an increased incidence of hypotension-related symptoms [8].  These results of class comparison are quite similar to those found previously in the VALIANT (Valsartan in Acute Myocardial Infarction Trial) [9].  A very noteworthy aspect of ONTARGET, and possibly the most important question that it answered, was in regard to renal protection.  Telmisartan therapy was found to reduce proteinuria and provide statistically equivalent nephroprotective benefit to ramipril.  However, the combination of these two medications was inferior to either drug individually for preventing or slowing renal dysfunction [10].


As with ACEI’s, hyperkalemia is a potential adverse drug reaction but the risk of cough is much less, and the angioedema is far less frequent.  Hyperkalemia is less likely and less severe when combined with a thiazide diuretic.  This class of drugs has a very favorable side effect profile, and is generally tolerated quite well by almost all patients.  Cost is considerably greater than for ACEI’s, as there are as yet no generically available ARB’s.  Regardless, the ARBs are also a first-line choice in the treatment of hypertension and prevention of renal complications in diabetic patients, especially those who have developed cough with an ACE inhibitor.





Diuretics--specifically, thiazide-type diuretics--have been in common use for the treatment of hypertension for many decades, both as monotherapy and as frequent add-on agents.  They are, in fact, still considered first-line agents.  Numerous studies demonstrate efficacy in reducing blood pressure and clinical outcomes benefits.  The NORDIL (Nordic Diltiazem) study found diuretics to be equal in efficacy to beta-blockers and the calcium channel blocker diltiazem in reducing the risk of myocardial infarction, cardiovascular death, and stroke [11].  There is additionally specific evidence that thiazide diuretics provide benefit to elderly patients.  This was demonstrated for elderly diabetic patients in the STOP Hypertension-2 (Swedish Trial in Old Patients with Hypertension-2), where the combination of hydrochlorothiazide and amiloride was found to be statistically equivalent to beta-blockers, ACE inhibitors, and calcium channel blockers in reducing cardiovascular death [12].  Although not specific to diabetic patients, further evidence in favor of diuretic use in elderly hypertensives was provided more recently by HYVET (Hypertension in the Very Elderly Trial), which found significant benefit with indipamide, with or without the addition of the ACE inhibitor perindopril [13] with regard to cardiovascular outcomes.


Many practitioners have come to have some degree of concern for the use of diuretics in the treatment of hypertension due to the numerous potential adverse drug reactions.  Among these are volume depletion and hypokalemia.  While the chance of dehydration and resulting risk of renal dysfunction or syncope do merit screening out patients who are high risk of variable oral intake, the overall incidence of clinically significant hypokalemia is very low when these drugs are used at doses no higher than 25mg daily for hydrochlorothiazide or chlorthalidone.  This risk is further reduced when the thiazide diuretic is combined with another medication, such as an ACE inhibitor, ARB, potassium-sparing diuretic, or aldosterone antagonist.  Other purported concerns for worsening insulin resistance and unfavorable lipid profile are not borne out when lower-dose (25 mg/day or less) are use.  With good efficacy in lowering blood pressure and reducing evidence of target-organ damage, thiazide-type diuretics such as hydrochlorothiazide diuretics remain good choices for the treatment of hypertension in diabetic patients.  More evidence is forthcoming to enable optimal drug choice.  In patients with DM and hypertension, there is less nocturnal drop in blood pressure than is observed in other hypertensive patients.  Thus, a longer-acting agent, with antihypertensive action persisting into the nocturnal hours, might hypothetically be a preferred drug for treating DM-related hypertension.  Chlorthalidone, in comparison with hydrochlorothiazide, has a significantly longer duration of action and would appear advantageous for this reason [14].  Consequently, chlorthalidone should probably become the preferred diuretic agent in the treatment of hypertension.



Calcium Channel Blockers


There is considerable heterogeneity in calcium channel blockers, especially between the dihydropyridine  (amlodipine, felodipine, isradipine, nicardipine, nifedipine) and non-dihydropyridine agents (verapamil, diltiazam).  While the non-dihydropyridines are effective in reducing blood pressure, they are more commonly used in the setting of cardiac dysrhythmias for their anti-dysrhythmic effects.  The dihydropyridines, such as amlodipine and felodipine, find more use in the treatment of hypertension in T2DM.  One of the most noteworthy trials conducted recently on calcium channel blockers was the ACCOMPLISH (Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension) trial.  This study compared the combination of benazepril and amlodipine with the combination of benazepril and hydrochlorothiazide.  The amlodipine group was found to have fewer cardiovascular events in individuals who were at high risk for such events, including T2DM patients [15].  These findings of the ACCOMPLISH trial have already influenced many practitioners to be much quicker to add a dihydropyridine calcium channel blocker as a second or third-line agent for patients at high risk for cardiac events.  Generally well-tolerated, common adverse effects of calcium channel blockers include peripheral edema, and rarely, hyperprolactinemia.  Dihydropyridine calcium channel blockers and chlorthalidione are indicated as the second line drugs of choice, added to the ACEI’s or ARBs in persons with diabetes and hypertension.



Adrenergic Receptor Antagonists


The adrenergic receptor agents mostly fall into one three categories:  the “traditional” beta-blockers, the alpha-blockers (α1), and the combined alpha and beta-blockers.  Beta-blockers have been used for many years in the treatment of hypertension.  The more β1-selective agents, such as atenolol, metoprolol, and bisoprolol have taken the forefront due to their cleaner mechanism of action and overall lower side effect profile.  Numerous trials attest to efficacy of beta-blockers in reducing target-organ damage.  While they have been clearly shown to improve nearly all parameters over placebo, the comparative evidence against other antihypertensive agents seems somewhat conflicting.  In a long-term follow-up study, atenolol has been shown to provide comparable reduction in cardiovascular endpoints to captopril [16].  However, a more recent trial has demonstrated the inferiority of atenolol to losartan with regard to cardiovascular endpoints [17].  The reason for these differences is not entirely clear, but highlights the controversy surrounding the proper place of these agents in therapy for the patient without active heart disease.


Aside from their coincident use in treating symptoms of benign prostatic hyperplasia, pure alpha1 receptor antagonists have generally played little role in the treatment of hypertension in this population,.  Although alpha-blockers have modest beneficial effects on insulin resistance and lipid profiles [18], the doxazosin arm of the ALLHAT trial was discontinued due to significantly increased combined cardiovascular disease risk compared with other antihypertensive drugs assessed in the trial [19].


The third group of adrenergic receptor agents to be considered is the combined alpha and beta-blockers, chiefly carvedilol.  Studies to date demonstrate that carvedilol provides most of the benefits seen with both the alpha-blockers and beta-blockers, without very many of the adverse reactions observed with either.  While carvedilol is already in very wide use for patients with congestive heart failure, it is worth considering as a second-line agent for T2DM patients without (but at high risk for) ischemic heart disease.


The newest adrenergic receptor antagonist on the market is nebivolol.  While most similar to the β1-selective beta-blockers in its mechanism of action, nebivolol has a second property.  In addition to being the most β1-selective agent on the market, nebivolol also exhibits nitric oxide-dependent vasodilating properties.  In a recent study, this property resulted in decreased endothelial cell stiffness and growth of endothelial cells [20].  Ongoing research suggests numerous beneficial pleiotropic effects, but clinical trials published to date show nebivolol to be comparable to to atenolol with regard to magnitude of blood pressure reduction and aortic stiffness [21].  While additional pleiotropic effects are potentially exciting, further studies will be needed to determine whether its higher cost is justified by superior clinical outcomes.



Aldosterone Antagonists


Aldosterone, and activation of the renin-angiotensin-aldosterone axis, may have a substantial role in the pathogenesis of T2DM, obesity, and the metabolic syndrome.  The aldosterone antagonists spironolactone and eplerenone have clear efficacy in delaying mortality and reducing decompensation of heart failure in patients with NYHA Class III and IV heart failure.  Aldosterone has been shown to contribute significantly to the development of insulin resistance and declining pancreatic β-cell function [22].  Spironolactone has utility as an add-on agent for reduction of blood pressure in patients with resistant hypertension, a problem encountered frequently in T2DM and metabolic syndrome [23].  Adverse drug effects include hyperkalemia and, in men, anti-androgen effects of decreased potency, decreased libido, and gynecomastia.  The possibility of hyperkalemia should not be underestimated, especially since most patients starting an aldosterone antagonist are already taking either an ACE inhibitor or an ARB.  A low dose (25 mg daily, or less) should be started and frequent monitoring performed until the effects for the individual patient are observed.  Anti-androgen effects of spironolactone are avoided by eplerenone.  Each of these agents appears to provide excellent benefit as an add-on agent for resistant hypertension.  At present, they are probably underutilized in this population.



Renin Inhibition


Aliskiren, a direct renin inhibitor, is one of the newer antihypertensive agents on the market, and appears to have great potential.  Studies to date demonstrate impressive blood pressure lowering and reduction in markers of end-organ damage.  It has been shown to be superior to hydrochlorothiazide in obese patients in the degree of blood pressure reduction, and with fewer adverse effects [24][25].  Aliskiren has been shown equivalent to an ARB in reducing of left ventricular mass in patients with hypertension-relatedleft ventricular hypertrophy [26].  Additionally, the combination of aliskiren and an ARB may have a synergistic effect in reducing both cardiovascular and renal injury [27].  Although not studied, to date, it would be reasonable to assume a similar synergistic effect when aliskiren is combined with an ACEI.  While this agent’s precise place in clinical practice remains to be determined, it appears to be quite promising.  The most beneficial use of aliskiren will most likely be in individuals whose hypertension is not yet adequately controlled on an ACE inhibitor or ARB and who are at high risk of end-organ damage, such as those patients with T2DM or obesity.



Future Options – Endothelin antagonists


Although not yet generally available for prescription, another potentially exciting drug is the selective endothelin type A antagonist darusentan.  As an endothelin receptor antagonist, darusentan has been shown to effectively reduce both systolic and diastolic blood pressure in patients with resistant hypertension by causing arterial vasodilation [28].  If this drug does come to market, it may quickly become one of the more powerful agents for the treatment of resistant hypertension.



Other Aspects


Finally, as further evidence of the complex physiologic interactions underlying hypertension in patients with T2DM, animal studies have been conducted which test the effects of simvastatin in a T2DM mouse model.  These mice had significant hypertension and endothelial dysfunction, both of which resolved after addition of simvastatin [29].  While statins are not traditionally considered as antihypertensive agents, the demonstration of an antihypertensive effect highlights the interconnected nature of Hypertension, dyslipidemia, vascular damage, and T2DM. In fact meta-analysis of statin trials indicates that they lower systolic blood pressure somewhere between 2 and 4 mm Hg [30].



Summary of Treatment Recommendations


The proper treatment of hypertension in patients with diabetes frequently becomes quite complex, and as such, the approach must be multi-factorial.  Due to their well-chronicled efficacy in attenuating end-organ damage and delaying or preventing adverse cardiovascular endpoints, especially in the setting of renal dysfunction, ACEI’s and ARBs remain the most rational first choice for most patients.  Blood pressure < 130/80 mm Hg is often not achieved with monotherapy.  Generally considered first-line agents on their own, thiazide diuretics are excellent agents as the first add-on to ARB or ACEI therapy, as are dihydropyridine calcium channel blockers.  When making this decision for the first add-on, there is evidence that amlodipine provides some degree of benefit over the thiazides.  When a thiazide is selected, chlorthalidone has been demonstrated to have superior antihypertensive effect in comparison with hydrochlorothiazide.


When the T2DM patient’s blood pressure remains uncontrolled on maximally-tolerated doses of three oral agents, a diagnosis of resistant hypertension is established.  Additive therapy to be considered includes carvedilol, nebivolol, aliskiren, and the aldosterone antagonists spironolactone and eplerenone.  It is quite likely that darusentan will soon be added to this list, as well.





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