Emerging drug combinations to optimize renovascular protection and blood pressure goals

Figures & data

Table 1 Percentage of patients who attain blood pressure (BP) goals according to cardiovascular risk and clinical profile

Hypertensive population attended daily by primary care physicians
Clinical condition	Low risk	Medium risk	High risk	Diabetes	Metabolic syndrome	Cardiovascular disease	Cardiac disease
BP control rates	37.5%	30.2%	15.4%	6.3%	17.2%	25.3%	27.4%

Note: Data from the PRESCOT (Prevención Cardiovascular en España en Atención Primaria: Intervención Sobre el Colesterol en Hipertensión) study (adapted from Barrios³²).

Table 2 Relevant studies that have studied the effects of renin-angiotensin system inhibition on renal outcomes

Clinical setting	Study	Population	Commentary
Prevention of microalbuminuria in patients with hypertension and type 2 diabetes	BENEDICT^Citation41	Subjects with type 2 diabetes and hypertension but with normoalbuminuria	The use of trandolapril plus verapamil (5.7%) and trandolapril alone (6.0%) decreased the incidence of microalbuminuria to a similar extent The effect of verapamil alone (11.9%) was similar to that of placebo (10.0%)
	ROADMAP^Citation42	Patients with type 2 diabetes and normoalbuminuria	Microalbuminuria developed in 8.2% of the patients in the olmesartan group and 9.8% in the placebo group Time to the onset of microalbuminuria was increased by 23% with olmesartan (HR, 0.77; P = 0.01)
Reduction of overt diabetic nephropathy	HOPE^Citation43	Patients of HOPE with diabetes	Ramipril reduced the risk of overt nephropathy by 24% (P = 0.027) when compared with placebo
	IRMA2^Citation44	Patients with type 2 diabetes and microalbuminuria	Irbesartan was shown to be renoprotective independently of its BP-lowering effect
	RENAAL^Citation45	Patients with type 2 diabetes and nephropathy	The composite primary end point of doubling of serum creatinine concentration, end-stage renal disease, or death was reduced with losartan when compared with placebo (risk reduction, 16%; P = 0.02)
	IDNT^Citation46	Hypertensive patients with type 2 nephropathy diabetes	Irbesartan reduced the risk of the primary end point (doubling of serum creatinine concentration, end-stage renal disease, or death) by 20% and 23%, compared with placebo and amlodipine, respectively
	ORIENT^Citation47	Type 2 diabetic patients with overt nephropathy	Olmesartan did not improve renal outcome on top of ACE inhibitors
	AVOID^Citation40	Hypertensive patients with type 2 diabetic nephropathy	Despite a small, not statistically significant difference in BP between groups, aliskiren reduced the mean urinary albumin-to-creatinine ratio by 20% (P < 0.001)
Nondiabetic renal disease	ROAD^Citation51	Patients with nondiabetic chronic renal insufficiency	Optimal antiproteinuric dosages of benazepril and losartan, at comparable BP control, achieved a greater reduction in both proteinuria and the rate of decline in renal function than with their conventional dosages

Abbreviations: ACE, angiotensin-converting enzyme; AVOID, Aliskiren in the Evaluation of Proteinuria in Diabetes; BENEDICT, Bergamo Nephrologic Diabetes Complications Trial; BP, blood pressure; HOPE, Heart Outcomes and Prevention Evaluation; HR, hazard ratio; IDNT, Irbesartan in Diabetic Nephropathy Trial; IRMA2, Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria; ORIENT, Olmesartan Reducing Incidence of End Stage Renal Disease in Diabetic Nephropathy Trial; RENAAL, Reduction of Endpoints in Non-Insulin-Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan; ROAD, Renoprotection of Optimal Antiproteinuric Doses; ROADMAP, Randomized Olmesartan and Diabetes Microalbuminuria Prevention.

Table 3 Relevant studies of the effects of combining diuretics or calcium channel blockers with renin-angiotensin system inhibitors on renal outcomes

Clinical setting	Study	Population	Commentary
Diuretics	PREMIER^Citation60	Patients with type 2 diabetes, albuminuria, and hypertension	The combination of perindopril and indapamide, when compared with enalapril, resulted in a greater, statistically significant fall in both BP (Δsystolic BP −3.0 mmHg, P = 0.012; Δdiastolic BP −1.5 mmHg, P = 0.019) and albumin excretion rate (−42% vs −27%)
	ADVANCE^Citation61	Patients with type 2 diabetes	Those patients assigned to active treatment (perindoprilindapamide) were associated with a significant reduction (21%) in all renal events (P < 0.0001), with a trend in the reduction in new or worsening nephropathy (P = 0.055) and a significant reduction in the development of microalbuminuria (relative risk reduction, 21%; P < 0.0001)
Calcium channel blockers	AMANDHA^Citation66	Type 2 diabetic patients with hypertension and microalbuminuria uncontrolled with renin-angiotensin system blockers	Although manidipine and amlodipine decreased BP values to a similar extent, urinary albumin excretion was more greatly reduced with manidipine than with amlodipine (65.5% vs 20%, respectively, P < 0.01 at 6 months; 62.7% vs 16.6%, respectively, P < 0.01 at the end of the extension phase of 18 months)
	CARTER^Citation70	Hypertensive patients with kidney disease	After 1 year of treatment, despite a similar BP reduction, the urinary protein-to-creatinine ratio significantly decreased in the cilnidipine group compared with the amlodipine group
	DIAL^Citation75	Hypertensive patients with type 2 diabetes	After 9–12 months of follow-up, both lercanidipine and ramipril treatments resulted in a significant reduction in albumin excretion rate without a statistically significant difference between the two treatments
	ACCOMPLISH^Citation78	Patients with hypertension and at high risk for cardiovascular events	2.0% of the benazepril plus amlodipine group vs 3.7% of patients treated with the benazepril plus hydrochlorothiazide showed chronic kidney disease progression (HR, 0.52; P < 0.0001)

Abbreviations: ACCOMPLISH, Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension; ADVANCE, Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified-Release Controlled Evaluation; AMANDHA, Efficacy and Tolerance Assessment of Manidipine in Type 2 Diabetic Patients with Hypertension and Microalbuminuria Uncontrolled with Renin-Angiotensin System Blockers; BP, blood pressure; CARTER, Cilnidipine versus Amlodipine Randomised Trial for Evaluation in Renal Desease; DIAL, Diabete, Ipertensione, Albuminuria, Lercanidipina; HR, hazard ratio; PREMIER, Preterax in Albuminuria Regression; vs, versus.

BarriosVEscobarCCalderónABlood pressure and lipid goal attainment in the hypertensive population in the primary care setting in SpainJ Clin Hypertens (Greenwich)20079532432917485967

 PubMedGoogle Scholar

RuggenentiPFassiAIlievaAPPreventing microalbuminuria in type 2 diabetesN Engl J Med2004351191941195115516697

 PubMed Web of Science ®Google Scholar

HallerHItoSIzzoJLJrOlmesartan for the delay or prevention of microalbuminuria in type 2 diabetesN Engl J Med20113641090791721388309

 PubMed Web of Science ®Google Scholar

Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudyHeart Outcomes Prevention Evaluation Study InvestigatorsLancet2000355920025325910675071

 PubMed Web of Science ®Google Scholar

ParvingHHLehnertHBröchner-MortensenJThe effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetesN Engl J Med20013451287087811565519

 PubMed Web of Science ®Google Scholar

BrennerBMCooperMEde ZeeuwDEffects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathyN Engl J Med20013451286186911565518

 PubMed Web of Science ®Google Scholar

LewisEJHunsickerLGClarkeWRRenoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetesN Engl J Med20013451285186011565517

 PubMed Web of Science ®Google Scholar

ImaiEChanJCItoSEffects of olmesartan on renal and cardiovascular outcomes in type 2 diabetes with overt nephropathy: a multicentre, randomised, placebo-controlled studyDiabetologia201154122978298621993710

 PubMed Web of Science ®Google Scholar

ParvingHHPerssonFLewisJBLewisEJHollenbergNKAVOID Study InvestigatorsAliskiren combined with losartan in type 2 diabetes and nephropathyN Engl J Med2008358232433244618525041

 PubMed Web of Science ®Google Scholar

HouFFXieDZhangXRenoprotection of Optimal Antiproteinuric Doses (ROAD) study: a randomized controlled study of benazepril and losartan in chronic renal insufficiencyJ Am Soc Nephrol20071861889189817494885

 PubMed Web of Science ®Google Scholar

MogensenCEVibertiGHalimiSEffect of low-dose perindopril/indapamide on albuminuria in diabetes: preterax in albuminuria regression: PREMIERHypertension20034151063107112654706

 PubMed Web of Science ®Google Scholar

PatelAADVANCE Collaborative GroupMacMahonSEffects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trialLancet2007370959082984017765963

 PubMed Web of Science ®Google Scholar

Martinez-MartinFJSaiz-SatjesMAdd-on manidipine versus amlodipine in diabetic patients with hypertension and microalbuminuria: the AMANDHA studyExpert Rev Cardiovasc Ther20086101347135519018688

 PubMedGoogle Scholar

FujitaTAndoKNishimuraHAntiproteinuric effect of the calcium channel blocker cilnidipine added to renin-angiotensin inhibition in hypertensive patients with chronic renal diseaseKidney Int200772121543154917943080

 PubMed Web of Science ®Google Scholar

Dalla VestraMPozzaGMoscaAEffect of lercanidipine compared with ramipril on albumin excretion rate in hypertensive type 2 diabetic patients with microalbuminuria: DIAL study (diabete ipertensione, albuminuria, lercanidipina)Diabetes Nutr Metab200417525926616295047

 PubMedGoogle Scholar

BakrisGLSarafidisPAWeirMRRenal outcomes with different fixed-dose combination therapies in patients with hypertension at high risk for cardiovascular events (ACCOMPLISH): a prespecified secondary analysis of a randomised controlled trialLancet201037597211173118120170948

 PubMed Web of Science ®Google Scholar