ABSTRACT. The most important factor that prevents the progressionof renal damage in diabetes mellitus, beside the improvementof blood glucose control, is tight BP control. The tenet oftight BP control may be defined as the lowest BP level one canaccomplish using antihypertensive therapy that is at the sametime compatible with the absence of untoward side effects. Infact, both the Framingham Heart Study in nondiabetic normalsubjects and the United Kingdom Prospective Diabetes Study intype 2 diabetic patients showed that systolic values as lowas 108 to 111 mmHg and diastolic values as low as 70 to 71 mmHgare significantly associated with decreased cardiovascular mortalityand morbidity. However, 45 to 50% of the patients with type2 diabetes mellitus and hypertension have systolic BP levelsabove 140 mmHg during antihypertensive therapy, particularlywhen using monotherapy. Thus the issue regarding the choiceof which drugs one should use to treat hypertension became criticalfrom a clinical point of view. Pharmaceutical compounds, whichinhibit the renin-angiotensin system, have become the first-choicetreatment in patients with diabetes mellitus and incipient andadvanced renal complications. The present brief review analyzesthe effects of calcium channel blockers (CCB) on cardiovascularand renal complications in diabetes mellitus. The review discussedthose studies that directly and blindly compared CCB with angiotensin-convertingenzyme (ACE) inhibitors and with angiotensin II AT1 receptorblockers (ARB). Furthermore, size of the population recruitedin each trial was used as a criterion of priority in the selectionof the reports from the available literature. From the pointof view of cardiovascular complications, the results of thesestudies showed a slightly better benefit of CCB on stroke, whereasACE inhibitors better prevented the occurrence of myocardialinfarction and congestive heart failure. On the other hand,recent observations demonstrated that also ACE inhibitors andARB are effective in the primary and secondary prevention ofstroke, although these studies did not directly compare thesecompounds with CCB. With regard to the outcome of renal complications,both ARB and ACE inhibitors more effectively prevented the progressionof renal damage among the patients with overt nephropathy thanCCB. On the contrary, both CCB and ACE inhibitors were equallyeffective on blunting the decay of GFR in diabetic patientswho do not have overt proteinuria. However, ACE inhibitors andARB more markedly decreased the rate of albumin excretion ratein the range of both microalbuminuria and macroalbuminuria.Recent advances in the understanding of the pathogenesis ofabnormalities of albumin excretion rate and of atherosclerosisare also discussed. Both mechanical stress, mainly secondaryto systolic hypertension, and elevated circulating and tissuelevels of angiotensin II, partially independent from each other,cause excessive generation of superoxide compounds. This chainreaction of events in turn leads to disorders of structuralcomponents of glomerular filter and to damage of the vascularwall. Systolic BP control (<130 mmHg) is not adequately accomplishedin the majority of the patients treated only with ACE inhibitorsand ARB, even in association with diuretics. Poor BP controlmay lead to excessive systemic mechanical stress at the vascularlevel despite satisfactory inhibition of angiotensin II effects.In conclusion, one can suggest that CCB are useful and oftenindispensable pharmaceutical compounds, beside ACE inhibitorsand ARB, to accomplish tight BP control (<130/85 mmHg), atarget that is unlikely to be successfully maintained in theoverall population of type 2 diabetic patients only by ACE inhibitorsor ARB, as monotherapy. However, ACE inhibitors and ARB mightbe considered first-choice drugs in the treatment of hypertensionin diabetes mellitus, mainly because of a better renoprotection.E-mail: noscia@tin.it
The VIth Joint National Committe indicated cut-off levels of130 mmHg for systolic and 85 mmHg for diastolic BP to formulatethe diagnosis of arterial hypertension in diabetes mellitus(1). Moreover, the United Kingdom Prospective Diabetes Study(UKPDS) trial (2) has demonstrated that the levels of systolicand diastolic BP have a strong continuous graded and etiologicallysignificant positive association with microvascular and macrovascularcomplications in type 2 diabetes (2). Furthermore in the UKPDS,any reduction in BP was likely to reduce the risk of complications,with the lowest risk being in those with systolic BP less than120 mmHg (2). On the basis of such findings, it has been statedthat the target of BP control should be maintained as low aspossible compatibly with the absence of side effects of theantihypertensive therapy itself (3).
More recently, support of this view, also in nondiabetic subjects,has been provided by further analysis of the follow-up studiesof the Framingham Heart Study (4). In fact, Vasan et al. (4)investigated the association between BP category at baselineand the incidence of cardiovascular disease on 12-yr follow-upstudies among 6859 participants in the Framingham Heart Studywho were initially free of hypertension and cardiovascular disease.Men and women were divided into three categories according toBP characteristics at baseline — 1st optimal BP levels:systolic 108 to 111 mmHg, diastolic 70 to 71 mmHg; 2nd normalBP level: systolic 122 to 122 mmHg, diastolic 77 to 78 mmHg;3rd high normal BP level: systolic 132 to 131 mmHg, diastolic81 to 83 mmHg.
The 10-yr cumulative incidence of cardiovascular disease insubjects 35 to 64 yr of age with high normal BP was associatedwith a value of adjusted hazard ratio for cardiovascular diseaseof 2.5 in women and 1.6 in men compared with the subjects withoptimal BP. A trend toward a significant reduction of cardiovascularmortality was observed also in the cohort of subjects in theintermediate normal BP category, although the difference wasNS (4). As regards the relationship between BP levels and renalcomplications, Klag et al. (5) reported some years ago thatan increase in diastolic BP levels as low as 5 mmHg from 85to 80 mmHg and of systolic BP levels as low as 6 mmHg from 130to 124 mmHg at baseline was associated with a significant increaseof the occurrence of end-stage renal disease during a 16-yrperiod of follow-up in 332,544 subjects who were screened between1973 and 1975 for entry into the Multiple Risk Factor IntervenvionTrial (MRFIT) (5).
On the basis of such findings, the recent report of the WorldHealth Organization and of the International Society of Hypertensionemphasized the rationale for expecting high-risk subjects withouthypertension to benefit from BP lowering and the need for clinicaltrials to investigate this possibility (3). Thus the argumentsconcerning the comparison between individual pharmaceuticalcompounds as regards their putative superiority in the preventionof macrovascular and microvascular complications may be seenas an academic rather than practical issue, because the achievementof these levels of BP will almost always require combinationtherapy, particularly using inhibitors of the renin angiotensinsystem, calcium channel blocker, diuretics, and -blockers. Howeverone should raise the question of the real meaning of BP controlin diabetes mellitus. Indeed the results of several recent largetrials showed that the patterns of BP control accomplished,using multiple antihypertensive therapies, are far higher thanthose indicated above.
Tight BP control in the UKPDS (2) aiming at a BP of <150/85mmHg using at least two antihypertensive drugs in most of thepatients resulted in average systolic levels of 144 mmHg anddiastolic levels of 82 mmHg. The Heart Outcomes Prevention EvaluationStudy in Diabetes Mellitus (MICROHOPE) used relatively elevateddoses of the angiotensin-converting enzyme (ACE) inhibitor,ramipril, and observed a systolic BP level of 139.8 mmHg anda diastolic BP level of 76.7 mmHg, although half as much ofthe recruited diabetic patients were not hypertensive at baseline(6). The LIFE study recently compared the effects of losartanwith those of atenolol in 1195 patients with diabetes, hypertension,and signs of ventricular hypertrophy on electrocardiograms (7).Mean BP at the end of the follow-up was 146/79 mmHg in the losartanand 148/79 mmHg in the atenolol groups (7). Of note, 85% and82% of the patients in both groups of treatments had diastolicBP levels below 90 mmHg, whereas only 38% and 34% respectivelyhad systolic BP below 140 mmHg (7). Also the 1501 diabetic patientswho were treated by felodipine, a dihydropyrinic calcium channelantagonist, along with other antihypertensive agents in theHypertension Optimal Treatment (HOT) randomized trial, despitea marked reduction of diastolic BP levels below 90 mmHg in mostof the patients, showed average values of systolic BP between143.7 and 139.7 mmHg (8). Similar findings have been reportedby the Irbesartan Diabetic Nephropathy Trial (IDNT) (9), whichstudied the effects of angiotensin II AT1 receptors blockers(ARB), irbesartan, and of calcium channel blockers (CCB), amlodipine,in type 2 diabetic patients with overt proteinuria, and by theSwedish Trial in Old Patients (STOP-2) in elderly diabetic patients,which compared ACE inhibitors with CCB (10). On the whole, theseresults show that about half as many of the patients who sofar participated in carefully conducted antihypertensive trialshad systolic BP levels above 140 mmHg.
The aim of the present review will be the discussion of therole of CCB in the treatment of hypertension in diabetes mellitusby the light of the results of recent large trials on this item.However, the issue of the target of BP control will be furthermorediscussed at the end of the present brief review.
Calcium Channel Blockers and Cardiovascular Protection in Diabetes Mellitus
To demonstrate that antihypertensive therapy decreases mortalityrequires a very large trial or a high-risk population or a meta-analysison several trials. Contrasting results have been reported onthe cardiovascular effects of CCB on cardiovascular morbidityand mortality in the overall population and in diabetic patients.The Systolic Hypertension in Europe Study, which recruited ahigh-risk elderly population, was stopped prematurely becauseof the large beneficial effect of the CCB, nitrendipine, oncardiovascular mortality (10). Moreover, overall mortality reductionduring CCB therapy was particularly ameliorated in the diabeticthan in nondiabetic hypertensive patients (10). The beneficialeffects of CCB, dihydropyridinic drugs, on cardiovascular complicationswere also more clearly evident in diabetic than nondiabeticpatients in the Hypertension Optimal Treatment (HOT) study (8).More recently, the results of the Heart Outcomes PreventionEvaluation (HOPE) study report that the ACE inhibitor, ramipril,given to people with diabetes mellitus lowered the risk of majorcardiovascular outcomes by 25 to 30% (6). The conclusions ofthis latter study have been criticized to some extent on thebasis of the observation that the relative risk reduction insubgroups, without microalbuminuria and previous cardiovasculardisease despite high numbers of patients does not reach statisticalsignificance (11). Furthermore, Taylor (12) recently pointedout that detailed inspection of the characteristics of the patientgroups suggests problems of randomization. Specifically, theplacebo group contained an excess of patients with major adverserisk factors, thus accounting for the worse outcome of the placebogroup.
Despite these putative drawbacks, it has to be said that ACEinhibitors have become a mainstay as first-choice treatmentof hypertension in diabetes mellitus, particularly when abnormalitiesof albumin excretion rate are present. This view stems mainlyfrom the findings that ACE inhibitors as well as ARB delay theonset of overt proteinuria and end-stage renal disease in type1 and type 2 diabetes (9,13,14).
Thus we decided to take into consideration, in the present briefreview, only those trials that used a prospective, randomized,double-blind, intention-to-treat design to compare CCB and compoundsinhibiting the renin-angiotensin hormonal system. The size ofthe population studied by the reports was a further criterionof choice for the inclusion in the present review. Three recenttrials had the above-mentioned characteristics (9,10,15). Onefurther study (16) with similar design, the FACET study (n =380; fosinopril versus amlodipine) found a higher incidenceof stroke among those assigned to amlodipine. However, thisstudy was unblinded, partly crossover, and suffered from asymmetriesin the treatment groups. Furthermore, the combination of fosinopriland amlodipine scored best, which was not emphasized by theauthors (16). Nevertheless, this latter report too was takeninto consideration in the analysis of the present review. Table 1reports the main characteristics and the results of the threetrials we have chosen, according to the above described criteria,IDNT (Irbesartan versus Amlodipine Diabetic Nephropathy Trial)(9), ABCD (Apropriate BP Control Diabetes Trial, Nisoldipineversus Enalapril) (15), FACET (Fosinopril versus AmlodipineCardiovascular Events Trial), (16) and STOP-2 (ACE versus CCBin Elderly Hypertensive Patients) (10).
Table 1. Main characteristics at entry of the selected studies, which describe a comparison between inhibitors of the renin angiotensin system and dihydropyridinic calcium channel blockers (CCB) on death and on myocardial infarction in type 2 diabetic patients with arterial hypertension
From a general point of view, it has to be highlighted thatthe treatment with dihydropyridinic CCB, when specifically comparedwith ARB, provided the same results concerning the incidenceof major cardiovascular events, cardiovascular death, and totalmortality. With regard to the comparison between ACE and CCB,no difference in total mortality was observed by Hansson etal. (10). On the contrary, the ABCD trial (n = 470; enalaprilversus nisoldipine) had to be stopped prematurely because ofa significantly higher incidence of myocardial infarctions amongthose assigned to nisoldipine. However myocardial infarctionwas a secondary end point in this trial. In addition, baselinecharacteristics of the treatment groups were different, reportingwas incomplete, and more than half of the participants werenot compliant with study medication. The relative risk of myocardialinfarction and congestive heart failure was significantly lowerwith ACE inhibitors than CCB in the report of Hansson et al.(10) in the overall population but not in the subgroup of diabeticpatients. These conclusions are seemingly at slight odds withthose from a meta-analysis of randomized controlled trials usingCCB compared with other first-line antihypertensive therapiesfrom Pahor et al. (17). These latter authors in fact analyzednine eligible trials including 27,743 participants. CCB andother drugs achieved similar control of both systemic and diastolicBP. Compared with patients assigned diuretics, -blockers, ACEinhibitors, or clonidine (n = 15,044), those assigned CCB (n= 12,699) had a significantly higher risk of acute myocardialinfarction, congestive heart failure, and major cardiovascularevents (17). On the contrary, in the overviews comparing differentantihypertensive regimens (eight trials; 37,872 patients withhypertension), several, different in cause, specific effectswere seen between CCB-based therapy and other regimens, buteach was of borderline significance (18).
In the attempt to reconcile these apparently contrasting conclusions,Opie (19) recently suggested that the conclusions of Pahor etal. (17) were strongly influenced by the inclusions of the ABCDand FACET studies (15,16), which were small trials with veryfew events, whereas no such difference was detected in the othermuch larger studies with many more events. On the whole, webelieve that we share the ideas of Opie (19) that CCB comparedwith conventional therapy reduced nonfatal stroke by an averageof 25% and increased nonfatal acute myocardial infarction by18%. Similar conclusions were drawn by a further recent meta-analysison this item (19). In the attempt to explain these findings,one can suggest that the CCB could have two types of effectsthat reduce the occurrence of stroke. First, they delay theprogression of carotid atherosclerosis (20-22). Second, theyhave platelet inhibitor capacities, which play a role on a differentsite from aspirin and therefore may have antithrombotic qualitiesthat could help to prevent stroke. As regards the putative increaseof myocardial infarction, one might suggest that CCB increaseadrenergic stimulation. This latter side effect could be mainlyassociated with dihydropyridinic CCB rather than with non-dihydropyridinicCCB. This latter view might also explain the better outcomeconcerning myocardial infarction of ACE inhibitors and -blockers,which both have antiadrenergic effects. Thus the same authorssuggested that CCB cause a small increase in myocardial infarction,approximately balanced by fewer stroke episodes when comparedwith ACE inhibitors and conventional therapy. However, notethe relative statistical weakness or even absence of statisticaldifference (Table 2) of such data (20,21). The role of the compoundscapable to inhibit the activity of the renin-angiotensin systemin the primary and secondary prevention of stroke in type 2diabetes has to be discussed again after the reports of theProgress Study (23), as far as secondary prevention is concerned,and of the Life study (7), as far as primary prevention is concerned.The Progress Study described a period of 4 yr of follow-up in762 type 2 diabetic patients with a positive history for cerebrovasculardiseases during treatment with the ACE inhibitor, perindopril,or placebo. The reduction of the incidence rate of new strokeepisodes was particularly evident when perindopril treatmentwas associated with indapamide diuretic therapy (23). The Lifestudy (7) evaluated the effects of losartan, an antagonist ofangiotensin II AT1 receptors against those of atenolol, a -blockercompound, during a 4-yr follow-up period in 1195 patients withdiabetes mellitus, arterial hypertension, and cardiac hypertrophybut without history of cerebrovascular events. Losartan significantlyreduced cardiovascular mortality (6% versus 10%; P < 0.03)but not the cumulative incidence of stroke (9% versus 11%; P< 0.2) (7). Further studies are needed to directly comparethe effects of drugs inhibiting the renin angiotensin systemwith CCB on cerebrovascular events in diabetes mellitus.
Table 2. Adjusted relative risks and 95% CI for death from any cause and for the cumulative prevalence of myocardial infarction in the selected studies, which describe a comparison between inhibitors of the renin angiotensin system and dihydropyridinic CCB in type 2 diabetic patients with arterial hypertension
Calcium Channel Blockers and Renal Protection in Diabetes Mellitus
The ACE inhibitors were not advised when they were first introducedin the therapy of arterial hypertension in patients with abnormalitiesof albumin excretion. This contraindication was based on theassumption that this category of drugs (at that time, captopril)did worsen proteinuria. On the other hand, first Taguma et al.(24) and then Lewis et al. (13) upended the indication of captopril(and more generally speaking of ACE inhibitors) in type 1 diabetesmellitus with proteinuria (13). In fact, Lewis et al.demonstratedthat ACE inhibitors significantly delay the onset of clinicallysound renal outcomes, such as dialysis, renal transplantation,death, and doubling of baseline serum creatinine in about 200type 1 diabetic patients with overt proteinuria compared witha matched group on conventional antihypertensive therapy (13).Interestingly enough, captopril did also decrease the overallmortality as compared with conventional treatment (13), whichencompassed -blockers, diuretics clonidine, -doxazosin, andother compounds, except CCB (13). This latter feature of thetrial has been a recurring theme in the discussion on the first-choicedrug in the treatment of diabetic nephropathy, as a direct comparisonbetween ACE inhibitors and CCB had never been tested until recently.In the last 2 to 3 yr, this item has been properly investigatedin type 2 diabetes mellitus, both in patients with overt andpatients with incipient nephropathy. The aim of the presentparagraph will be to summarize the most prominent results ofsuch trials from the point of view of renal outcomes, as wedid in the previous paragraph from the point of view of cardiovascularoutcomes.
One of those newly published trials provides outcome data inhypertensive patients with type 2 diabetes and overt nephropathywho were treated with ARB (Irbesartan Diabetes Nephropathy Trial[IDNT]) in comparison with amlodipine (9). The primary end pointswith regard to renal outcome in the IDNT study were the occurrencerate of end-stage renal diseases (ESRD) and the percentage ofpatients who showed a doubling of serum creatinine baselinelevels during a 3 to 4 yr follow-up period. The rate of occurrenceof ESRD was lower in the irbesartan than in the amlodipine group,but this difference did not reach a statistically significantdegree (adjusted relative risk, 0.76; 95% CI, 0.57 to 1.02;P < 0.06). On the contrary, the patients who had a doublingof baseline serum creatinine were significantly lower in theirbesartan than in the amlodipine group (adjusted relative risk,0.61; 95% CI, 0.48 to 0.79; P < 0.001). The results of thistrial support the growing conviction that renin angiotensininhibition gives better renoprotection and has disease-retardingeffects independent of BP reduction particularly, but not only,in type 2 diabetic patients with hypertension and renal diseases.An important feature in this latter study is that CCB were usedas comparators of ARB. A possible bias of the IDNT study isthat an ACE inhibitor was not used as comparator. The authorsof the IDNT trial (9) defend themselves by saying that the NationalInstitutes of Health and the American Diabetic Association hadnot granted them support for such comparison. However, withouta direct comparison between ACE inhibitors and ARB, an assessmentof their relative capacity to delay or prevent the progressionof renal damage cannot be made. Table 3 also shows the mainfeatures of four other studies (9,15,25,26,27), which were selectedfrom the available literature because they show a direct comparisonbetween the effects of ACE inhibitors and CCB on renal outcomeduring a follow-up period of at least 3 yr, except in the reportof Chan et al. (25), where the follow-up period was 1 yr. Nodifference was observed in all these reports between ACE inhibitorsand CCB as regards the rate of change from baseline of creatinineclearance or GFR as assessed using more sophisticated markersof glomerular function. Of note may be the observation of Chanet al. (25), who showed that creatinine clearance fell similarlyin both groups while plasma creatinine concentration was increasedby 20% in the enalapril group versus 8% in the nifedipine group(P < 0.001). On the other hand, it has to be pointed outthat the rate of excretion of albumin was more markedly reducedin the majority of the above-mentioned trials by ACE inhibitorsand ARB than by CCB. These results might be explained as follows.First, by causing vasodilation of afferent renal arterioles,CCB of the dihydropyridinic type increase intraglomerular pressureand therefore promote proteinuria. There is good evidence thatan increasing degree of proteinuria reflects increasing renaldamage. Second, the dihydropyridinic CCB might gear up the sympatheticactivity, which is usually already altered in patients withevidence of advanced renal damage. On the contrary, the ACEinhibitors, by promoting dilation of both the afferent and efferentrenal arterioles, could be expected to reduce intraglomerularpressure and hence to lessen the rate of excretion of albumin.ACE inhibitors are also known to blunt the sympathetic activity.The clinical and physiologic characteristics of dihydropyridinicCCB may not apply to the non-dihydropyridinic CCB, verapamiland diltiazem, which reduce rather than increase plasma catecholamineconcentrations, are not as vigorous in afferent vasodilation,and have been effective in small clinical trials in proteinurictype 2 diabetic patients (26).
Table 3. Main characteristics at entry and differences with regard to the primary end point of the selected studies, which describe a comparison between inhibitors of the renin angiotensin system and dihydropyridinic CCB on renal outcome in type 2 diabetic patients with arterial hypertensiona
Recent findings have profoundly changed the understanding ofthe pathogenesis of altered albumin filtration at glomerularlevel and of the formation of lesions in the vascular bed. Withregard to the factors determining the abnormalities of microalbuminuriaand macroalbuminuria in mammals, altered molecular structureof several components of slit diaphragms and podocytes has beenobserved. Recent advances in research proposed a completelynew definition of glomerular function (glomerular permselectivityhypothesis). More particularly, glomerular permselectivity encompassestwo molecular filters in series according to this new definition:glomerular basement membrane is the coarse filter restrictinglarge molecules, and slit diaphragm is the fine filter withthe size selectivity only permeable to molecules smaller thanalbumin. The molecular characteristics of the two filters aredescribed in detail in Figure 1. The latter studies emphasizethe role of nephrin, a key component of the slit diaphragm,as well as the podocytes and slit diaphragm–associatedintracellular proteins, CD2-associated proteins, podocin, and-actin-4, as central size-selective filtration barriers (28).In summary, these studies, mainly based on findings in few rarefamilial diseases, have demonstrated a crucial role for podocytesand slit diaphragm in glomerular filtration function. Nephrinpodocin and CD2—associated protein appear to be majorphysiologic structural components of slit diaphragm; its abnormalfunction or absence leads to the loss of the slit diaphragmfilter and massive proteinuria (28). This information was accomplishedin Finnish congenital nephrotic syndrome, in minimal-changenephrotic syndrome, in the steroid-resistant congenital nephroticsyndrome, in membranous nephropathy, and in one variant of focalsegmental glomerulosclerosis. Preliminary studies suggest thatimpaired expression of nephrin plays a role in the pathogenesisof proteinuria in streptozotocin diabetic rats (29). AngiotensinII causes excessive generation of reactive oxygen species inthe vessel wall in patients with hypertension (Figure 2). Thesemetabolic intracellular disorders are markedly accelerated byhyperglycemia (30). Enhanced patterns of reactive oxygen speciesmay lead to albuminuria by damaging slit diaphragm components(31). This view may explain a slightly better outcome of ARBand ACE inhibitors in diabetes mellitus as far as albumin excretionrate is concerned in comparison with other drugs. On the otherhand, the overproduction of reactive oxygen compounds does occurin diabetes mellitus in the overall vascular bed and may explainthe close relationship of microalbuminuria with early and rapidlyprogressive vascular damage in diabetes mellitus. However, ithas to be pointed out that the mechanical stress secondary toarterial hypertension, particularly to systolic hypertension,is also a potent factor in the stimulation of overproductionof superoxide compounds independently from angiotensin II circulatingconcentrations (Figure 2). It is thus conceivable that monotherapyof arterial hypertension, based on ACE inhibitors and/or ARBmay not lead to the correction of superoxide overproduction,if adequate patterns of systolic BP levels are not accomplished.
Figure 1. Schematic drawing of a podocyte attached to the lamina rara externa of the glomerular basement membrane. The slit diaphragms insert laterally into the podocyte cell membrane. Three membrane domains may be identified: in the apical cell membrane above the slit diaphragm (the portion where the podocalyxin is located), in the membrane to which the slit diaphragm is closely connected (the portion where nephrin is located), and in the membrane of the cell base of the foot process (the portion where podoplanin is located). The simplified graph describes the molecules that have been so far identified.
Figure 2. The role of angiotensin II and mechanical stress in the generation of reactive oxygen species in the vessel wall in type 2 diabetic patients with hypertension. Hyperglycemia amplifies the rate of generation of both above-described stimuli.
The results of the studies mentioned in the preceding paragraphssuggest that the strategies to reduce the risk of cardiovascularand renal complications in diabetes mellitus require an appropriatetreatment of hypertension. Drugs that inhibit the renin angiotensinsystem have been effective in the prevention of cardiac andrenal complications. However, hypertension, particularly systolichypertension, is inadequately controlled by monotherapy in mosttype 2 diabetic patients. Long-acting CCB appears to be an appropriatecandidate for second-line therapy to lower systolic BP levelsbelow 130 mmHg as indicated by the American Diabetes Associationguidelines (32) for the treatment of hypertension in diabetesmellitus, a target that is rarely accomplished even in experimentaltrials.
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Abstract
Introduction
-blockers. However one should raise the question of the real meaning of BP control in diabetes mellitus. Indeed the results of several recent large trials showed that the patterns of BP control accomplished, using multiple antihypertensive therapies, are far higher than those indicated above. 
-doxazosin, and other compounds, except CCB (13). This latter feature of the trial has been a recurring theme in the discussion on the first-choice drug in the treatment of diabetic nephropathy, as a direct comparison between ACE inhibitors and CCB had never been tested until recently. In the last 2 to 3 yr, this item has been properly investigated in type 2 diabetes mellitus, both in patients with overt and patients with incipient nephropathy. The aim of the present paragraph will be to summarize the most prominent results of such trials from the point of view of renal outcomes, as we did in the previous paragraph from the point of view of cardiovascular outcomes. 
