indapamide--perindopril-drug-combination and Diabetic-Nephropathies

Most recent meta-analyses of morbidity-mortality risk hazards brought about by the presence of diabetes as compared with non-diabetics underline the dominant risk of renal disease and cardiovascular outcomes and the relevance of blood glucose, blood pressure (BP) and cholesterol levels. The translation of this reality into therapeutic guidelines always requires interventional evidence. Evidence for combined approaches in controlling for BP and blood glucose was provided by Action in Diabetes and Vascular disease: PreterAx and DiamicroN-MR Controlled Evaluation (ADVANCE), conducted in over 11 000 subjects from 20 countries. Reduction in systolic BP by 7.1 mm Hg, in diastolic BP by 2.9 mm Hg and in glycated haemoglobin A1c by 0.61% points in the combined routine BP lowering and intensive blood glucose-control group after an average 4.3 years of follow-up resulted in a relative risk reduction of 28% in renal events, 24% in cardiovascular death and 18% in all-cause mortality. While other major intervention trials performed in similar populations with analogous goals did not achieve the same level of positive therapeutic evidence and even pointed to some risk of intensified treatment of type 2 diabetes, all three major studies [Action to Control Cardiovascular Risk in Diabetes (ACCORD), Veterans Affairs Diabetes Trial (VADT) and ADVANCE] showed significant reduction in renal events, the major risk in type 2 diabetes. The divergence for other outcomes underlines the importance of considering specific therapeutic approaches for glucose control and prudent targets for BP. The current target values for glycated haemoglobin of 6.5-7% and for BP of 130/80 mmHg appear safe and beneficial. The potential long-term benefit, particularly that of initial tight blood glucose control, suggested by recent post-trial evidence is currently being evaluated in the ADVANCE-ON study.

Topics: Antihypertensive Agents; Biomarkers; Blood Glucose; Blood Pressure; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Drug Combinations; Glycated Hemoglobin; Humans; Hypertension; Hypoglycemic Agents; Incidence; Indapamide; Kidney Failure, Chronic; Multicenter Studies as Topic; Perindopril; Randomized Controlled Trials as Topic; Risk Factors

Type 2 diabetes mellitus (T2DM) is often accompanied by high blood pressure (BP) and the clustering of several cardiovascular risk factors, and is the most frequent cause of end-stage renal disease. The stages of development of overt nephropathy in T2DM patients range from an initial alteration in renal function with an increased GFR, followed by the development of microalbuminuria and macroalbuminuria or proteinuria, featuring an established diabetic nephropathy, which eventually progresses to end-stage renal disease. Early intervention is needed to prevent the development of diabetic nephropathy and requires effective control of the different risk factors, and in particular high BP. In the initial stages of the disease, strict BP control is crucial to prevent the development of initial renal and vascular damage. Adequate BP control is particularly difficult in T2DM patients and in most cases requires the use of combination therapy. Preterax, a fixed-dose combination of perindopril 2 mg and indapamide 0.625 mg, allows BP to be significantly reduced compared with conventional strategies; this combination can be uptitrated to BiPreterax when further BP control is needed. In the PREMIER study performed in T2DM over 12 months, the perindopril/indapamide combination brought about, in addition to excellent BP control, a significant reduction in urinary albumin excretion, compared with monotherapy with enalapril. In more advanced degrees of renal damage, higher doses of the fixed combination have to be considered. The pharmacological basis of the renoprotective effect of perindopril/indapamide is the demonstration that this combination prevented nephropathy as well as proteinuria in obese Zucker rats, independently of BP control. Strict BP control from the initial stages of nephropathy together with inhibition of the renin-angiotensin system is mandatory to prevent albuminuria. The fixed combination of perindopril/indapamide can greatly help clinicians in achieving the above goals, using Preterax in the early and BiPreterax in the late stages of nephropathy.

Topics: Albuminuria; Antihypertensive Agents; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Combinations; Humans; Hypertension; Indapamide; Perindopril

Discontinuation of angiotensin-converting enzyme (ACE) inhibitor is recommended if patients experience ≥30% acute increase in serum creatinine after starting this therapy. However, the long-term effects of its continuation or discontinuation on major clinical outcomes after increases in serum creatinine are unclear. In the ADVANCE trial (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation), 11 140 diabetes mellitus patients were randomly assigned to perindopril-indapamide or placebo after a 6-week active run-in period. The current study included 11 066 participants with 2 serum creatinine measurements recorded before and during the active run-in period (3 weeks apart). Acute increase in creatinine was determined using these 2 measurements and classified into 4 groups: increases in serum creatinine of <10%, 10% to 19%, 20% to 29%, and ≥30%. The primary study outcome was the composite of major macrovascular events, new or worsening nephropathy, and all-cause mortality. An acute increase in serum creatinine was associated with an elevated risk of the primary outcome ( P for trend <0.001). The hazard ratios were 1.11 (95% CI, 0.97-1.28) for those with an increase of 10% to 19%, 1.34 (1.07-1.66) for 20% to 29%, and 1.44 (1.15-1.81) for ≥30%, compared with <10%. However, there was no evidence of heterogeneity in the benefit of randomized treatment effects on the outcome across subgroups defined by acute serum creatinine increase ( P for heterogeneity=0.94). Acute increases in serum creatinine after starting perindopril-indapamide were associated with greater risks of subsequent major clinical outcomes. However, the continuation of angiotensin-converting enzyme inhibitor-based therapy reduced the long-term risk of major clinical outcomes, irrespective of acute increase in creatinine. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT00145925.

Topics: Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Cardiovascular Diseases; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Combinations; Drug Monitoring; Female; Humans; Indapamide; Male; Medication Therapy Management; Middle Aged; Perindopril; Risk Assessment; Treatment Outcome; Withholding Treatment

ADVANCE was planned to investigate the effects of routine blood pressure lowering with the fixed combination perindopril-indapamide on major vascular events in people with type 2 diabetes, irrespective of initial blood pressures or the use of other blood pressure-lowering drugs, including angiotensin-converting enzyme inhibitors.. A total of 11140 individuals with type 2 diabetes were randomly assigned to fixed combination perindopril-indapamide or matching placebo, after a 6-week run-in period. The primary outcomes were composites of major macrovascular and major microvascular events, analysed jointly and separately, by intention to treat.. Active treatment reduced blood pressure by 5.6/2.2 mmHg compared with placebo and the relative risks of all deaths, cardiovascular deaths and major vascular events, by 14% (P = 0.025), 18% (P = 0.027) and 9% (P = 0.041), respectively. There were also reductions in total coronary events (14%; P = 0.02) and total renal events (21%; P < 0.0001). Study treatment was well tolerated, with 73% and 74% of participants who received active treatment and placebo, respectively, still adherent to randomized therapy after an average of 4.3 years of follow-up.. Routine treatment with the fixed combination perindopril-indapamide, on top of all concomitant protective therapies, was well tolerated and reduced the risks of death and vascular disease irrespective of the initial level of blood pressure. The results suggest that for every 79 patients so treated, one death would be averted over 5 years.

Topics: Aged; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Combinations; Female; Follow-Up Studies; Humans; Hypertension, Renal; Indapamide; Male; Middle Aged; Perindopril; Placebos; Treatment Outcome