Long-Term Dual Blockade With Candesartan and Lisinopril in Hypertensive Patients With Diabetes

Abstract

OBJECTIVE -To assess and compare the long-term effects of the combination of candesartan and lisinopril with high-dose lisinopril on systolic blood pressure in patients with hypertension and diabetes.RESEARCH DESIGN AND METHODS -This was a prospective, randomized, parallel-group, double-blind, double-dummy study with a 12-month follow-up. Drug therapy was either lisinopril 40 mg once daily or dual-blockade treatment with candesartan 16 mg once daily and lisinopril 20 mg once daily. The study comprised 75 type 1 and type 2 diabetic patients aged 35-74 years. The main outcome measures were seated and 24-h ambulatory systolic blood pressure.RESULTS -Reduction in systolic blood pressure (24-h systolic blood pressure) reduction was obtained in both treatment arms (mean reduction at final follow-up: dual blockade 6 mmHg vs. lisinopril 2 mmHg), but no significant difference was found between dual-blockade and lisinopril 40 mg once daily (P ϭ 0.10). Both treatments were generally well tolerated, and similar low rates of side effects were found in the two groups.CONCLUSIONS -There was no statistically significant difference between lisinopril 40 mg once daily and lisinopril 20 mg in combination with candesartan 16 mg once daily in reducing systolic blood pressure in hypertensive patients with diabetes. Diabetes Care 28:273-277, 2005D ual blockade of the renin-angiotensin system was opted for based on the principle of obtaining the broadest and most efficient blockade of the effects of angiotensin II by using the combination of an ACE inhibitor and an angiotensin II receptor blocker (AIIA).By combining two different pharmacological principles and inhibiting both the ACE and the angiotensin II type 1 receptor, it seems possible to arrive at a treatment regimen that inhibits both the production and the action of angiotensin II and serves as an efficient antihypertensive therapy. The Candesartan and Lisinopril Microalbuminuria (CALM) study was among the first to show an additional effect from dual blockade on blood pressure in a population of type 2 diabetic patients with microalbuminuria over a 12-week follow-up period (1). Following the CALM study, several small-scale studies indicated that using dual blockade in treating type 1 and type 2 diabetic patients might produce additional clinical effects on both blood pressure and albumin excretion (2-4). Moreover, one large-scale study in nondiabetic patients with nephropathy has also shown that dual-blockade treatment has an effect in the long term (5).However, several important clinical questions remain unresolved: 1) What are the clinical effects of dual blockade compared with an efficient dosage titration of an ACE inhibitor? 2) Does the effect of dual blockade persist over a longer period of time? 3) What are the long-term safety and tolerability characteristics of the two treatment regimes?Thus, the primary objective of the CALM II study was to compare over a 12-month period the results of adding either candesartan cilexetil 16 mg or lisinopril 20 mg to concomitant antihy...

Effects of Monotherapy of Temocapril or Candesartan with Dose Increments or Combination Therapy with Both Drugs on the Suppression of Diabetic Nephropathy

“…In the design of these studies, an ARB was added to the maximum dose of an ACEI, or high doses of an ACEI and an ARB were combined without dose adjustment. On the other hand, the Candesartan and Lisinopril Microalbuminuria (CALM) II study showed that 40 mg/day of lisinopril and the combination of 20 mg lisinopril and 16 mg candesartan caused similar reductions in both BP and ACR (9). In contrast, Fujisawa et al reported that in patients with diabetic nephropathy who had been treated with an ACEI or ARB, halving the dose of the RAS inhibitor and combining it with a half dose of an other RAS inhibitor resulted in a significant reduction in ACR as compared with the value before combination (23).…”

“…It has also been reported that very high doses of ARB exert better antialbuminuric effects than the more commonly used doses (7). Moreover, recent studies indicate that dual blockade of the RAS with an ACEI and an ARB is superior to either drug alone in reducing proteinuria in diabetic patients (8)(9)(10)(11). However, only a few studies have examined which of the two dosing regimens-monotherapy featuring dose increments or combination therapy-is more effective (12).…”

Evidence for renoprotection by blockade of the renin–angiotensin–aldosterone system in hypertension and diabetes

“…34,40,[46][47][48][56][57][58][59] Clinical trials, grouped by the degree of albuminuria, demonstrating the beneficial effects of RAAS inhibition on renal end points in patients with diabetes mellitus are summarized in Table 2. 34,40,42,48,49,[57][58][59][60][61][62][63][64][65][66][67][68][69][70][71] Normoalbuminuria The Bergamo Nephrologic Diabetes Complications Trial (BENEDICT) is the only primary prevention study to date to demonstrate that the development of microalbuminuria can be prevented by the use of an ACE inhibitor alone or in combination with a CCB in hypertensive normoalbuminuric patients with type II diabetes. 59 …”

“…65 In the 12-month Candesartan and Lisinopril Microalbuminuria (CALM) II trial, however, no significant differences in systolic BP or albumin:creatinine ratio were seen when combination therapy of ACE inhibitor and ARB was compared with higher doses of the ACE inhibitor. 66 Another recent study followed 28 subjects with type I diabetes who had a BP p140/80 mm Hg with residual albuminuria (albumin:creatinine ratio 410 mg/mmol) while receiving the maximal recommended renal dose of lisinopril. 69 Candesartan or amlodipine was added to lisinopril for 24 weeks.…”

Study of antihypertensive effect of ramipril alone and in combination with telmisartan

“…30 In patients having hypertension with diabetes, there was no significant difference in SBP reduction found between lisinopril 40 mg once daily and lisinopril 20 mg in combination with candesartan 16 mg once daily. 31 In this study, significant difference in SBP reduction between ramipril+telmisartan combination and ramipril alone was seen during 4 to 12 weeks. No significant difference in the SBP reduction between two groups was seen at the end of the study.…”