Optimal Therapy in Hypertensive Subjects with Diabetes Mellitus

Gianpaolo Reboldi & Giorgio Gentile & Fabio Angeli &Paolo Verdecchia

# Springer Science+Business Media, LLC 2011

Abstract Diabetes and its micro- and macrovascularcomplications represent a worldwide epidemic that willplace an enormous financial burden on poorer countries inthe years to come. In patients with diabetes and hyperten-sion, the main determinant of the cardiovascular and renalbenefits of antihypertensive drugs is the blood pressure(BP) level achieved under treatment. Quite recently, theparadigm of a BP target <130/80 mm Hg in these patientshas been questioned by a number of trials, including datafrom the Action to Control Cardiovascular Risk in Diabetes(ACCORD) blood pressure–lowering arm and from thediabetic cohort of International Verapamil SR-TrandolaprilStudy (INVEST). At the same time, even if the key role ofBP control is unquestionable, a growing number ofpublished trials suggest that different antihypertensivecombinations may offer specific cardio-, vasculo-, andrenoprotective advantages that go beyond BP reduction perse. The present review focuses on the most recent and

important literature that explored the “optimal” antihyperten-sive therapy in patients with type 2 diabetes and concomitanthypertension, and it discusses in detail the various areas ofuncertainty, including the specific renoprotective effects ofrenin-angiotensin system blocking agents and the long-termeffects of angiotensin-converting enzyme/angiotensin recep-tor blocker combinations on the progression of diabeticnephropathy.

Keywords Diabetes mellitus . Hypertension . Diabeticnephropathies . Drug therapy . Combination .

Antihypertensive agents

Introduction

The diabetes epidemic continues to grow, particularly ineconomically developing and newly industrialized nations.According to the International Diabetes Federation (IDF)Atlas, there were an estimated 285 million patientsworldwide with diagnosed diabetes in the year 2010, andthis number is projected to rise to 438 million in 2030, 90%of whom will have a type 2 diabetes [1]. The middle- andlow-income countries of Asia (eg, India, China) and sub-Saharan Africa are among the World Health Organization(WHO) global regions that are expected to experience adisproportionate increase in the prevalence of diabetes. Thecommon explanation for this epidemic is the increasingadoption of the Western lifestyle, which not only predis-poses to diabetes, but also favors the development ofobesity and hypertension. Unsurprisingly, cardiovascularmortality accounts for about 86% of all premature deathsamong diabetic patients [2].

About 40% of newly diagnosed type 2 diabetes patientsare also hypertensive, and this rate further increases with

G. Reboldi (*) :G. GentileDepartment of Internal Medicine, University of Perugia,Via E. Dal Pozzo,06126 Perugia, Italye-mail: paolo@unipg.it

G. Gentilee-mail: ggentile@unipg.it

F. AngeliDivision of Cardiology, Hospital S Maria della Misericordia,Piazzale G. Menghini,06132 Perugia, Italye-mail: fangeli@cardionet.it

P. VerdecchiaDivision of Internal Medicine, Hospital of Assisi,Via Valentin Müller, 1,06132 Assisi, Italye-mail: verdec@tin.it

Curr Atheroscler RepDOI 10.1007/s11883-011-0160-9

aging and in the presence of micro- or macroalbuminuria[3]. Concomitant hypertension doubles total mortality andstroke risk, triples the risk of coronary heart disease, andsignificantly hastens the progression of diabetic nephropa-thy, retinopathy, and neuropathy [3]. In such patients, adifference of 5 mm Hg in either systolic blood pressure ordiastolic blood pressure increases the risk of cardiovascularevents or death by 20% to 30% [4].

Blood pressure (BP) reduction is a major priority inpreventing clinical events in patients with type 2 diabetesand hypertension, both of which carry a very high risk ofcardiovascular and renal outcomes, including stroke,coronary heart disease, left ventricular hypertrophy, andend-stage renal disease .

Unfortunately, BP control is very poor among diabeticpatients and is usually reached in only one third of thesepatients. Two or more antihypertensive drugs are usuallyrequired in order to achieve and maintain a desirable BPcontrol. In these patients, combination therapy maycontribute to achieve BP goals in a relatively short time,with equivalent or better tolerability than higher dosemonotherapy [5].

The present review focuses on the most recent andimportant literature that explored the optimal antihyperten-sive therapy in patients with type 2 diabetes and concom-itant hypertension.

Metabolic Effects of Antihypertensive Drugs: What WeAlready Know and Insights from Recent Trials

Although the effects of intensive glycemic control oncardiovascular outcomes in diabetic patients are still thesubject of much debate [6, 7], compelling evidence in bothtype 1 [8, 9] and type 2 [10, 11] diabetes patients indicatesthat intensive glycemic control decreases the risk ofmicrovascular complications, especially diabetic nephropa-thy, which is the first cause of renal replacement therapyboth in the United Kingdom and the United States [12].Thus, antihypertensive drugs should be at least neutral, ifnot beneficial, in terms of glycemic control.

Diuretics are very effective in lowering BP [13] but theymay cause metabolic adverse effects (hyperglycemia,hyperuricemia, dyslipidemia, and hypokalemia), increasinga patient’s likelihood of developing diabetes or worseningglycemic control in those already with diabetes [14]. Thediabetogenic effects of thiazides are most likely multifac-torial, and a clear non–K+-dependent component is alsoevident [15].

Renin-angiotensin system (RAS) blocking agents mayincrease insulin secretion and improve its actions on whole-body and skeletal muscle glucose disposal; in addition, theymay decrease sympathetic activity and promote favorable

effects on the adipose tissue, such as adipocyte differenti-ation and increased adiponectin levels [16]. Angiotensin-converting enzyme (ACE) inhibitors improve insulinsensitivity via the bradykinin pathway [17], whereas certainangiotensin receptor blockers (ARBs), such as telmisartanand irbesartan, may have a potential antidiabetic effect,through the AT1R antagonism and peroxisome proliferator–activated receptor γ (PPAR-γ) activation [18]. In a studyinvolving 308 hypertensive patients with diabetes mellitus,low-dose telmisartan (40 mg daily), candesartan (8 mgdaily), and valsartan (80 mg daily) had a neutral effect onseveral metabolic parameters (fasting plasma glucose,fasting insulin, glycated hemoglobin, serum lipids, adipo-nectin, high-sensitivity C-reactive protein, and plasminogenactivator inhibitor-1), with comparable effects between thethree groups [19].

Calcium channel blockers (CCBs), particularly newerlong-acting dihydropyridines, may also provide favorablemetabolic effects [20] through two separate mechanisms.Firstly, these drugs induce vasodilation and enhanceskeletal muscle blood flow, with consequent increaseddelivery of insulin and glucose and enhanced non-oxidative pathways of glucose utilization. Secondly, CCBscan also improve insulin sensitivity at the cellular level bydecreasing the cytosolic-free calcium concentrations [21].

Traditional β-blockers, both nonselective β1 and β2antagonists (ie, propranolol) and β1-selective antagonists(ie, metoprolol), have vasoconstrictive properties due to theconsequent unopposed α1-adrenergic activity, and they mayhave negative metabolic effects on insulin resistance [22];conversely, newer vasodilating β-blockers (ie, nebivolol,carvedilol) appear to be associated with better metabolicprofiles [23].

RAS blocking agents have been combined with other drugclasses in patients with type 2 diabetes and hypertension.Because these drugs may theoretically mitigate the alterationsin glucose metabolism induced by diuretics, a few trials haveexplored the metabolic effects of RAS blocking agent/diureticcombinations in diabetic subjects, leading to differentconclusions. Two studies raised concerns about the metaboliceffects of an ACE inhibitor/diuretic combination therapy inhypertensive type 2 diabetes patients [24, 25], whereas othertrials, including the large randomized trial Action in Diabetesand Vascular Disease: Preterax and Diamicron MR Con-trolled Evaluation (ADVANCE), did not show any deterio-ration in glycemic control in type 2 diabetes patients treatedwith ACE inhibitors plus diuretics [26] or ARBs plusdiuretics [27].

On the other hand, available evidence strongly supportsthe metabolic benefits of a RAS blocking agent/CCBcombination, particularly in patients with prediabetes(glucose intolerance, metabolic syndrome, or history ofgestational diabetes) or diabetes mellitus [28].

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In the TRAVEND trial [29], 103 patients with type 2diabetes, microalbuminuria, and BP not controlled onmonotherapy were randomized to either verapamil sus-tained release (SR)/trandolapril or enalapril/hydrochlorothi-azide. The ACE/CCB combination allowed a bettermetabolic control than the ACE/diuretic combination, asalso observed when verapamil/trandolapril was comparedwith atenolol plus chlorthalidone (glycated hemoglobin[HbA1c] of 7.9% vs 8.6%; P=0.001) in 463 hypertensivediabetic patients [30]. Similarly, in elderly hypertensivepatients with type 2 diabetes, treatment with delapril/manidipine caused no changes in metabolic parameters,whereas an increase in HbA1c was found in the olmesartan/hydrochlorothiazide arm [31].

Finally, the large The Glycemic Effects in DiabetesMellitus: Carvedilol-Metoprolol Comparison in Hyperten-sives (GEMINI) trial [32•] randomized 1235 subjects withtype 2 diabetes and hypertension, already treated with RASblocking agents (ACE inhibitors or ARBs), to either atraditional β-blocker (metoprolol) or a newer β-blocker(carvedilol). After 5 months of treatment, carvedilol had noadverse effect on metabolic control, whereas metoprololincreased HbA1c by 0.15%. Moreover, the addition ofcarvedilol for BP control resulted in a significant decreasein triglyceride, total cholesterol, and non–high-densitylipoprotein (HDL) cholesterol levels, whereas the use ofmetoprolol resulted in a significantly greater rate ofinitiation of statin therapy or an increase in the dose ofexisting statin therapy [33]. Finally, insulin-stimulatedendothelial function was preserved during treatment withcarvedilol whereas it was blunted during treatment withmetoprolol [34]. However, although a favorable metabolicprofile might be considered in selecting a specific β-blocker, these agents, both traditional and newer, have well-established indications in diabetes patients with a previousmyocardial infarction, rhythm disorders, or heart failurebecause of their proven effectiveness in reducing mortality[28].

Blood Pressure Lowering and CardiovascularOutcomes in Hypertensive Diabetes Patients: What WeAlready Know and Insights from Recent Clinical Trials

In patients with type 2 diabetes and concomitant hyperten-sion, the main determinant of the cardiovascular benefits ofantihypertensive drugs is the BP level achieved undertreatment, rather than a specific drug class (ACE inhibitors,ARBs, CCBs, diuretics, or β-blockers) [35]. However, the“optimal” blood pressure target for people with diabetes isstill uncertain. A systematic review published by Vijan andHayward [36] in 2003 identified three randomized con-trolled trials (RCTs) comparing specific BP targets in

people with diabetes [37–39]. The first RCT randomized1148 subjects with newly diagnosed type 2 diabetes (meanage of 56 years, mean baseline BP of 160/94 mm Hg) toeither an intensive BP target of <150/85 mm Hg or a non-intensive target of <180/105 mm Hg [37]. Achieved BPvalues were 144/82 mm Hg and 154/87 mm Hg in the twotarget groups, respectively. The intensive-target control armreduced the risk of any cardiovascular outcome, ascompared with the non-intensive target after 8.4 years offollow-up (relative risk [RR] 0.66; 95% CI, not reported).The risk of any diabetes endpoint (cardiovascular endpointsplus renal failure, amputation, cataract extraction, vitreoushemorrhage, retinal photocoagulation, or blindness in oneeye) was significantly reduced in the intensive target group,as compared with the non-intensive target group (50.9/1000person-years vs 67.4/1000 person-years; RR 0.76; 95% CI,0.62–0.92). Moreover, the risk of diabetes-related death(13.7/1000 person-years vs 20.3/1000 person-years; RR0.68; 95% CI, 0.49–0.94) or microvascular endpoints (12.0/1000 person-years vs 19.2/1000 person-years; RR 0.63;95% CI, 0.44–0.89) were significantly reduced in theintensive target group as compared with the non-intensivegroup. The second RCT randomly assigned 470 patientswith type 2 diabetes (mean age of 58 years, mean baselineBP of 155/98 mm Hg) to a diastolic BP target of either75 mm Hg or 80 to 89 mm Hg [38]. The mean achieved BPwas 132/78 mm Hg in the intensive group and 138/86 mmHg in the less-intensive group. A difference in overallmortality was reported (6% with intensive target versus11% with less-intensive target; P=0.037), but there were nosignificant differences in any cardiovascular endpoints(including cardiovascular mortality), rate of progression ofrenal disease (intensive vs less-intensive control: RR 1.38;95% CI, 0.84–2.27), or retinopathy (RR 0.88; 95% CI,0.68–1.15). The third RCT conducted a pre-specifiedsubgroup analysis in 1501 diabetic patients (mean age of61.5 years; diabetes type unspecified; mean baseline BP of170/105 mm Hg) assigned to diastolic BP targets of 90 mmHg, 85 mm Hg, and 80 mm Hg, respectively [39].Achieved BP values were 144/85 mm Hg, 141/83 mmHg, and 140/81 mm Hg in the three target groups (90, 85,and 80 mm Hg, respectively). A target of 80 mm Hgsignificantly reduced both major cardiovascular event rates(11.9/1000 person-years; RR 0.49; 95% CI, 0.29–0.81) andcardiovascular mortality (3.7/1000 person-years; RR 0.33;95% CI, 0.14–0.78) as compared with a target of 90 mmHg (24.4/1000 person-years and 11.1/1000 person-years,respectively).

Even if achieved systolic BP in the three aforementionedtrials was never lower than 130 mm Hg, current guidelinesalso consistently recommend to begin or to intensify drugtreatment of diabetic patients when BP is <140/90 mm Hg,with the aim to reduce BP to <130/80 mm Hg [13, 40]. In

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this regard, a recently published critical analysis ofavailable trials has shown that such recommendation isnot supported by solid evidence [41], and this position hasbeen subsequently endorsed by a consensus document ofthe European Society of Hypertension [42], which hasemphasized that although lowering BP to <140/90 mm Hgis unquestionably protective in diabetes, the beneficialeffects of tighter BP control are still inconclusive [42].The findings of the recently published Action to ControlCardiovascular Risk in Diabetes (ACCORD) trial [43••],which compared a tighter (<120 mm Hg) with a less tight(<140 mm Hg) systolic BP goal in patients with diabetes,leave open the question about the optimal BP target forthese patients. The incidence of the primary endpoint (acomposite of fatal and non-fatal cardiovascular events) didnot differ significantly (hazard ratio [HR] 0.88; 95% CI,0.73–1.06; P=0.20) between the two groups, and neitherdid the incidence of myocardial infarction. On the otherhand, the incidence of stroke, a pre-specified secondaryoutcome, was lower in the more aggressively treated groupas compared with the <140-mm Hg arm (HR 0.63; 95% CI,0.41–0.96), but this evidence should not be regarded asconclusive, given the small number of observed strokes[43••]. Recently, Cooper-DeHoff et al. [44••] and Bakris etal. [45] performed a secondary analysis of the diabeticcohort of the large International Verapamil SR-Trandolapril(INVEST) study. There were 6400 patients with baselinediabetes, hypertension, and coronary artery disease ran-domized to a non-dihydropyridine CCB (verapamil SR) ora β-blocker (atenolol). If target BP (<130/85 mmHg) wasnot achieved, trandolapril and hydrochlorothiazide wererecommended as primary and secondary add-on agents inthe verapamil-SR group, and the sequence was reversed inthe atenolol group [45]. The analysis of these two studiesfocused on the impact of BP control on coronary arterydisease outcomes. Patients were assigned to three groupsaccording to their average systolic BP while taking studymedication: 1) tight control (BP<130 mm Hg; 35.2% ofpatients); 2) usual control (BP 130 mm Hg to <140 mmHg; 30.8% of patients); or 3) uncontrolled (BP≥140 mmHg; 34% of patients). The primary outcome was acomposite of all-cause mortality, nonfatal myocardialinfarction, and nonfatal stroke, all of which were alsoanalyzed independently as secondary outcomes. During16,893 patient-years of follow-up, the primary outcomeoccurred in 12.7% of patients in the tight-control group(adjusted HR 1.11; 95% CI, 0.93–1.32), 12.6% of theusual-control group (reference), and 19.8% of the uncon-trolled group (adjusted HR 1.46; 95% CI, 1.25–1.71; Pvalue for trend <0.001). The tight-control and usual-controlgroups did not differ from each other for each individualsecondary outcome, but had significantly lower event ratesthan the uncontrolled group. A non-statistically significant

higher all-cause mortality rate was also observed in thetight-control group, as compared with the usual-controlgroup (11.0% vs 10.2%, adjusted HR 1.20; 95% CI, 0.99–1.45; P=0.06), which became statistically significant forsystolic BP values <110 mmHg (adjusted HR 2.18; 95%CI, 1.17–4.09; P=0.02) [44••]. This finding is consistentwith the non-significant all-cause mortality increase ob-served in the intensive arm of ACCORD (HR 1.07; 95%CI, 0.85–1.35) [43••], but it should be interpreted with greatcaution, given the fact that the analyses of Cooper-DeHoffet al. [44••] and Bakris et al. [45] were not defined a prioriand were observational in nature. In particular, given thefact that INVEST enrolled patients with concomitant CAD,these data could lead to the misleading assumption that theobserved mortality excess is partly explained by a J-shapedrelationship between the degree of BP reduction and therisk of myocardial infarction. In this respect, we performeda series of analyses (unpublished data), showing that a moreaggressive reduction of BP, although not providing addi-tional benefit, does not increase the risk of myocardialinfarction in patients with diabetes and hypertension.

However, at the very least, the findings of Cooper-DeHoffet al. [44••] confirm the ACCORD findings of no additionalbenefits for a very tight BP control in patients with diabetesand hypertension. It could be argued that an aggressive BPcontrol (systolic BP<130 or even <120 mm Hg) could slowthe progression of atherosclerosis, as shown by the StopAtherosclerosis in Native Diabetics Study (SANDS) [46], inwhich 548 subjects with type 2 diabetes and no priorcardiovascular disease (CVD) events, aged 40 years or older,were randomized to reach aggressive targets of low-densitylipoprotein cholesterol (LDL-C) of≤70 mg/dL and systolicBP of≤115 mm Hg versus standard targets of LDL-C of≤100 mg/dL and systolic BP of≤130 mm Hg. Anyway, theaggressive control group also achieved much lower LDLvalues (72 vs 104 mg/dL), which could have accounted forthe greater regression of carotid intimal-media thickness(IMT) and the greater decrease in left ventricular mass,whereas clinical CVD events did not differ significantlybetween the two groups (1.6/100 in the intensive group and1.5/100 person-years in the less-intensive group; P=0.87),and adverse events were more common in the aggressivegroup, as observed in ACCORD [43••, 46].

Blood Pressure Lowering and Renal Outcomesin Hypertensive Diabetes Patients: What We AlreadyKnow and Insights from Recent Clinical Trials

Patients with type 2 diabetes and hypertension are at highrisk for chronic kidney disease (CKD), that ultimately leadsto end-stage renal disease (ESRD), requiring renal replace-ment therapy (RRT). In the past decades, most of these

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patients died of cardiovascular causes before reachingESRD [47]. However, continuous improvement in themanagement of diabetes and other cardiovascular riskfactors means that diabetic patients are now living longerand are more likely to develop ESRD, requiring dialysistreatment. In a poorly determined [48], but probably smallproportion of cases, the true cause of ESRD is representedby hypertensive nephropathy (nephrosclerosis) [49], where-as diabetic nephropathy represents the underlying cause ofESRD in most patients. Diabetic nephropathy has become aworldwide epidemic, being the leading cause of RRT in theUnited States, Europe, and Japan, as well as in anincreasing number of economically developing and newlyindustrialized nations [12]. In accordance with theseobservations, a global study of 32,208 patients with type2 diabetes (Developing Education on Microalbuminuria forAwareness of renal and cardiovascular risk in Diabetes[DEMAND]) showed an overall prevalence of micro-albuminuria of 39% [50]. The prevalence of microalbumi-nuria, a powerful and independent risk factor for bothclinical diabetic nephropathy and cardiovascular events, ishighest in the Hispanic and Asian populations [51].

Along with intensive glycemic control [8, 10], antihyper-tensive treatment is a cornerstone of the prevention andtreatment of diabetic nephropathy. The aim of primaryprevention of diabetic nephropathy is to prevent theprogression from normo- to microalbuminuria (ie, incipientnephropathy). Secondary prevention aims to reduce orprevent progression from micro- to macroalbuminuria (ie,overt nephropathy). Tertiary prevention aims to slow downthe progression from overt nephropathy to ESRD [52]. Avery large number of trials and systematic reviews haveinvestigated the effects of antihypertensive drugs, alone or incombination, in primary, secondary, and tertiary prevention ofdiabetic nephropathy (type 1 or type 2 diabetes) [53–56].Despite all this evidence, there are still many areas ofuncertainty and lively debate. The most important is probablyrepresented by the renoprotective effects of RAS blockingagents in diabetic nephropathy. In 1992, Bjorck et al. [57]suggested that ACE inhibitors offer renoprotection in type 1diabetes patients with diabetic nephropathy (ie, an effectprotecting the kidney function above and beyond what wasoffered by similar BP reduction with other antihypertensiveagents). This finding was later confirmed and extended by theCollaborative Study Group [55]. Subsequently, RAS block-ade was investigated in type 2 diabetic patients using ARBs,and a renoprotective effect was again demonstrated, both insecondary and in tertiary prevention [54, 56, 58]. Therenoprotective effect of RAS blocking agents has a soundpathophysiologic rationale. The intrarenal RAS has a centralrole in the pathophysiology of hypertensive and diabeticnephropathy and in the relationship between nephropathy andcardiovascular disease. Angiotensin II, the main effector of

the RAS and a potent vasoconstrictor, promotes cell growth,inflammation, and fibrosis, acting not only as a vasoactivepeptide but also as a cytokine. Angiotensin II stimulatesproduction of superoxide anions, which inactivate nitricoxide, a vasodilator with antigrowth effects that counterbal-ance the actions of angiotensin II. Stimulation of theangiotensin II type 2 receptor is associated with increasedproduction of nitric oxide, bradykinin, and cyclic guanosinemonophosphate (cGMP) in renal interstitial fluid [59].However, the greater proportion of type 1 receptors in thekidney results in a disequilibrium between angiotensin II andnitric oxide (oxidative stress), leading to endothelial dysfunc-tion and the development of renal injury. Oxidative stresscontributes to the chronic inflammation associated with CKDand is associated with hyperglycemia and the developmentand progression of diabetic nephropathy [60].

Nevertheless, the specific renoprotective role of RASblocking agents in patients with diabetic nephropathy hasbeen challenged by a number of publications in the past fewyears [61–63], causing an ongoing and bitter debate [64]. Inparticular, whether the benefits of these drugs are related tosystemic BP reduction, glomerular capillary pressure reduc-tion, nonhemodynamic effects, or all of the above remains animportant topic of discussion. The benefit from RASinhibitors in delaying the development and progression ofrenal disease may be a result of their BP-lowering effects, ofspecific renoprotective effects, or both. A meta-analysis ofclinical trial data [62] concluded that the effect of RASinhibition on renal outcomes is related to the BP-loweringeffects, as a larger benefit was found with greater meandifferences in systolic BP reductions. However, many othertrials concluded that the renoprotective effects of RASinhibition are independent of the BP-lowering effect, asvarious treatments resulted in similar BP reductions. Thebeneficial effects of RAS inhibition have been attributed tothe central role of the RAS in the pathophysiology of renaldisease and the ability of RAS inhibitors to restore thebalance between angiotensin II and nitric oxide, therebyalleviating oxidative stress and chronic inflammation in thekidney [65, 66].

The debate on this topic has been recently fueled by thepublication of data from the Ongoing Telmisartan Alone andin Combination with Ramipril Global Endpoint Trial(ONTARGET). In patients with diabetic nephropathy in theONTARGET study [67••], dual RAS blockade (telmisartanplus ramipril) did not offer any benefit on the primary renaloutcome (dialysis, doubling of serum creatinine, and death);the only benefit provided by dual RAS blockade was agreater reduction in urinary albumin excretion, a findingconsistent with a recent meta-analysis investigating combi-nation therapy with ACE inhibitors and ARBs for diabeticnephropathy [68] and with two recently published trials inAsian type 2 diabetes patients with nephropathy [69, 70]. On

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the other hand, ONTARGET raised concerns about dual-agent blockade of the renin–angiotensin–aldosterone system,particularly about the potential increase in the incidence ofhyperkalemia and decrease in the glomerular filtration rate.The greater incidence of reversible deterioration of renalfunction requiring acute dialysis is consistent with ahemodynamically mediated renal event, resulting from dualRAS blockade in volume-depleted subjects or in patientswith atherosclerotic renovascular disease and/or nephroscle-rosis. A strict monitoring of renal function might preventadverse events and let us safely achieve the potential benefitsof dual RAS blockade in patients at high cardiovascular risk[71]. Meanwhile, it has been suggested that clinicians shouldlook past the experimental rationale for dual RAS blockadeon renal outcomes, and use ACE inhibitor/ARB combina-tions in selected patients, until additional data of efficacy andsafety are made available [72]. In this respect, the VeteranAffairs Nephropathy In Diabetes Study (VA NEPHRON-D),a multicenter, prospective, randomized, parallel group trial,will examine the long-term effect of an ACE/ARB combi-nation on the progression of diabetic nephropathy [73••].Approximately 1850 patients with type 2 diabetes, overtnephropathy, and estimated glomerular filtration rate (eGFR)between 30 and 89.9 mL/min/1.73 m2 will receive open-label losartan (100 mg/daily) for 2 weeks and then will berandomized to receive either blinded-study ACE inhibitor(lisinopril 10 mg/daily) or matching placebo. Randomizationwill be stratified by baseline albuminuria (<1 vs≥1 g/dcreatinine) and eGFR<60 mL/min/1.73 m2 (stage 3) versus≥60 mL/min/1.73 m2 (stage 2). The primary endpoints are 1)time to reduction in eGFR of >50% (if baseline <60 mL/min/1.73 m2); 2) time to reduction in eGFR of 30 mL/min/1.73 m2 (if baseline≥60 mL/min/1.73 m2); 3) time toprogression to ESRD (need for dialysis, renal transplant, oreGFR <15 mL/min/1.73 m2); or 4) death. The secondaryendpoint is time to change in eGFR or ESRD. Tertiaryendpoints are cardiovascular events, slope of change ineGFR, and change in albuminuria at 1 year. Specific safetyendpoints are serious hyperkalemia (potassium>6 mEq/L,requiring admission, emergency room visit, or dialysis), all-cause mortality, and other serious adverse events. Theprimary and secondary endpoints in this study can be viewedas a combination of a surrogate endpoint (change in kidneyfunction) with harder events (end-stage renal disease ordeath). VA NEPHRON-D will help answer the questionsraised from ONTARGET [67••].

Treating Diabetic Patients with Hypertension in ClinicalPractice: Beyond BP Targets

There is no doubt that BP control plays a central role inreducing the risk of cardiovascular and renal outcomes in

patients with diabetes mellitus with or without coexistingCKD [35, 74]. However, our previous discussion about thedifferent targets for the treatment of hypertension indiabetic subjects may appear pointless, if not purelyacademic, when two thirds of these patients have uncon-trolled or poorly controlled hypertension [13]. Becausesuccessful treatment of these patients in the real world willoften require a combination therapy [37], either withseparate drugs or with fixed-dose combinations, the choicebetween different antihypertensive combinations that mayoffer specific cardio-, vasculo-, and renoprotective advan-tages that go beyond BP reduction per se is not trivial.

Available evidence favors treatment of diabetic patientswith hypertension with an RAS blocking agent (ACEinhibitor or ARB) combined with a CCB or a thiazide-typediuretic [74, 75]. In particular, there is growing evidencethat combinations including a CCB may provide additionalbenefits in these high-risk patients. In this regard, Weber etal. [76••] recently published a pre-specified analysis of thediabetic cohort of the Avoiding Cardiovascular EventsThrough Combination Therapy in Patients Living withSystolic Hypertension (ACCOMPLISH) study. In thisstudy, there were 6946 patients with diabetes randomizedto either benazepril plus amlodipine or benazepril plushydrochlorothiazide. A subgroup of 2842 diabetes patientsat very high risk (previous cardiovascular or stroke events)was also analyzed. The primary outcome was a compositeof cardiovascular death, myocardial infarction, stroke,hospitalized angina, resuscitated arrest, and coronaryrevascularization. Mean achieved BPs in the benazeprilplus amlodipine and benazepril plus hydrochlorothiazidegroups were 131.5/72.6 and 132.7/73.7 mm Hg, respec-tively. The authors demonstrated a striking superiority ofthe benazepril/amlodipine combination, as compared withbenazepril/hydrochlorothiazide, in reducing the primaryoutcome during the 30 months of follow-up (307 vs 383primary events; HR 0.79; 95% CI, 0.68–0.92; P=0.003).For the diabetic patients at very high risk, there were 195and 244 primary events, respectively (HR 0.77; 95% CI,0.64–0.93; P=0.007). Finally, in the whole diabetic cohort,there were clear coronary benefits with the benazepril/amlodipine combination, including both acute clinicalevents (P=0.013) and revascularizations (P=0.024). Nounexpected adverse events were observed. An interestingpoint to note is that the mean BP difference between thetwo arms across the study was −1.2/-1.1 mm Hg (systolic/diastolic) in favor of the benazepril/amlodipine group. Thisvery small difference cannot explain the significant differ-ence between the two treatment groups in the risk of thecomposite primary endpoint [77]. ACCOMPLISH alsoexamined the effects of benazepril plus amlodipine andbenazepril plus hydrochlorothiazide on a prespecified renaloutcome, a composite of doubling of serum creatinine and

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ESRD [78]. The benazepril/amlodipine combination wasstrikingly superior to benazepril/hydrochlorothiazide (113vs 215 events of CKD progression; HR 0.52; 95% CI,0.41–0.65; P<0.0001).

A caveat is the fact that ACCOMPLISH was premature-ly stopped when the independent data safety monitoringcommittee observed a difference in the incidence of theprimary endpoint between the two study arms that exceededthe pre-specified stopping point and recommended thetermination of the trial [75]. Therefore, the excellent resultsof the benazepril/amlodipine combination may potentiallyrepresent an overestimation of reality, as has been proven tobe the case with early truncation of trials [79]. Additionally,when including doubling of serum creatinine in a compositerenal endpoint, one should assess the doubling of GFR,starting with the serum creatinine several weeks post-randomization/post-titration to exclude the acute hemody-namic effect. In ACCOMPLISH, benazepril plus hydro-chlorothiazide induced a distinct fall in GFR within12 weeks, whereas addition of the CCB to the ACEinhibitor increased GFR slightly. After this acute hemody-namic change in GFR, the subsequent long-term slope wassimilar between the two treatment groups. Thus, theconclusion of ACCOMPLISH that the addition of a CCBis better than the addition of a diuretic to an ACE inhibitoris mainly (if not solely) based on the hemodynamic and notthe structural effects. Also, although the use of a compositerenal endpoint is appealing because it increases statisticalpower, the composite should be interpreted cautiously whenthe results are driven by a single component of thecomposite. In ACCOMPLISH, the endpoint was complete-ly driven by the doubling of serum creatinine, with nodifference in end-stage renal disease. This point highlightsthe need for a prespecified balance in the incidence of thecomponents of the renal composite endpoint [80].

Conclusions

The hypothesis that overly aggressive BP control (< 130/80 mmHg) allows us to obtain additional clinical benefits inpatients with diabetes mellitus and concomitant hyperten-sion is not supported by compelling evidence at the presenttime. Given the fact that most hypertensive diabetespatients need two or more drugs in order to obtainreasonable BP control, a combination therapy based onRAS blocking agents plus CCBs or thiazide diuretics mightbe a sound and evidence-based first-line choice [5] . Inparticular, a growing number of published trials using RASblocking agent/CCB combinations showed that such asso-ciations are able to reduce the risk of major fatal andnonfatal cardiovascular events as compared with diuretic-based combinations [75], providing at the same time greater

renoprotection, as expressed by the slope of GFR reduction[81••], and better metabolic control [29]. Of course, thisdoes not imply that other combinations are generallyineffective and harmful. Combination therapy shouldalways be tailored to the individual patient, balancingbenefits and harms in view of specific therapeutic targetsand long-term adherence. Finally, emphasis should beplaced on treating other cardiovascular risk factors (smok-ing, dyslipidemia, etc.) and obtaining behavior changes(eating habits, physical activity, etc.) to further reduce long-term cardiovascular risk in diabetic patients with hyperten-sion. Cooperation between general practitioners and spe-cialists (cardiologists, nephrologists, and diabetologists), aswell as the intervention of multidisciplinary teams (groupmedical clinics) and self-management interventions, may beboth feasible and effective in fighting the deadly duo ofdiabetes and hypertension [82–85].

Disclosure Gianpaolo Reboldi has received honoraria from WoltersKluwer Health Italy, Sanofi-Aventis, and NovoNordisk. He has receivedpayment for the development of educational presentations and/orspeaking fees from Wolters Kluwer Health Italy, Sanofi-Aventis,NovoNordisk, and Boehringer-Ingelheim. He has had travel and/oraccommodations expenses paid for by Sanofi-Aventis, NovoNordisk,Pfizer, and Boehringer-Ingelheim.

Giorgio Gentile has received payment for the development ofeducational presentations and/or speaking fees from Boehringer-Ingelheim.

Paolo Verdecchia has received honoraria from Sanofi-Aventis,Novartis, and Boehringer-Ingelheim. He has received payment for thedevelopment of educational presentations and/or speaking fees fromSanofi-Aventis, Novartis, and Boehringer-Ingelheim.

Fabio Angeli reports no potential conflict of interest relevant to thisarticle.

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