Role Of Combination Therapy

It has been proposed that the combination of two or more antihypertensive agents may be beneficial in the treatment of hypertension in the diabetic patient with or without evidence of renal involvement. The various combinations have been reviewed recently [57].

Brown et al postulated in 1993, that the combination of a calcium antagonist with a converting enzyme inhibitor should result in a greater reduction in urinary protein excretion and slow progression of nephropathy, as assessed morphologically [58]. Bakris et al have compared the renal hemodynamic and antiproteinuric effects of a calcium antagonist, verapamil, and an ACEI, lisinopril, alone and in combination in three groups of DM2 subjects with documented nephrotic range proteinuria, hypertension, and renal insufficiency [23]. Patients treated with the combination of a calcium antagonist and an ACEI manifested the greatest reduction in albuminuria. In addition, the decline in GFR was the lowest in that group. Similar findings are suggested by another study performed in microalbuminuric subjects using the combination of verapamil and cilazapril [59]. Sano et al have shown that the addition of enalapril to nifedipine conferred an additional effect in decreasing albuminuria in a group of microalbuminuric DM2 subjects [32]. Bakris et al have suggested that the combination of verapamil and trandolapril, administered in a fixed dose combination, is more effective at reducing proteinuria than either drug alone, despite similar effects on blood pressure [14, 60]. Fogari et al have also shown that ACEI (benazepril) plus CCB (amlodipine) tends to be more effective than benazepril alone in reducing albuminuria in microalbuminuric, hypertensive DM2 patients [61]. Shigihara et al also compared the effects of the combination of different ACEI drugs and CCB (amlodipine) and found that in DM2 the combination resulted in a greater decrease in diastolic blood pressure and in a greater reduction in UAE [62]. In a study comparing the use of a combination of verapamil and trandolapril to a combination of enalapril and a thiazide diuretic,

Fernandez et al were able to show a similar decrease in blood pressure and albuminuria, whereas metabolic control was better in the CCB-ACEI group [63]. In a recent study, designed to study the effects of an ACEI-CCB (benazapril-amlodopine) combination on lipid subfractions, Bakris et al showed that this combination had the greatest effect on systolic blood pressure, while the effect on albuminuria was similar to that in patients receiving only an ACE-I [64]. Fogari et al also showed that the ACEI-CCB (fosinopril-amlodipine) combination had a greater effect on blood pressure and albuminuria than either of the drugs alone [44]. In summary these studies show that the addition of either a non-dihydropyrdine CCB or dihydropyridine CCB to an ACEI or ARB result in a substantial improvement in control of hypertension with a concomitant reduction in albuminuria. Rachmani et al have explored the combination of cilazapril and doxazosin and shown this regimen to be effective at reducing blood pressure and albuminuria [30].

Mogensen et al showed in a relatively short-term study that 3 months of dual blockade of the RAS with a combination of ACEI (lisinopril) and ARB (candesartan) was superior to each of the individual agents in reducing blood pressure and superior to candesartan in reducing albuminuria [65]. In an acute study, in which DM1 and DM2 patients, who received their regular ACEI treatment for one week, followed by the addition of losartan for another week, Hebert et al were able to show that the combination of ACEI and ARB produced a more complete blockade of the RAS as shown by a sharp rise in serum renin [66]. Kuriyama et al added candesartan to a group of diabetic patients with overt nephropathy, who had previously received either temocapril or amlodipine for a period of 12 weeks [67]. These subjects were followed for an additional 12 weeks. The combination ARB-CCB reduced albuminuria significantly more than CCB alone, but the greatest decrease was achieved with the combination of ARB-ACEI. Rossing et al performed a crossover study in 18 DM2 hypertensive subjects with overt albuminuria, where the patients received candesartan or placebo in addition to regular treatment [68]. All patients were receiving ACEI and most were receiving a diuretic and CCB. Addition of the ARB resulted in a 10 mmHg drop in the 24 hour systolic blood pressure and 25% reduction in albuminuria. This was accompanied by a 5 ml/min decrease in GFR. In another randomized crossover study, where candesartan was added to patients with chronic renal disease and proteinuria who were receiving an ACEI, there was no change in albuminuria in the diabetic patients despite a decrease in blood pressure [69]. These studies show that the combination of ACEI-ARB has a superior effect on blood pressure control than either agent as monotherapy alone or in another combination. The effect of the combination on albuminuria is not yet fully clarified and requires more long-term studies.

The above findings with combination therapy provide an exciting approach for optimizing antihypertensive therapy in diabetic patients with renal disease. Indeed, the recent criteria for blood pressure control in diabetes as proposed by JNC-VI [70] and WHO-ISH [71, 72] will require the use of multiple antihypertensive agents. This has also been stressed in recent review articles [73, 74].

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Responses

  • bruno
    Can give dihydropyridine and nondihydropyrdine together?
    8 years ago

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