Combined Angiotensin Inhibition for the Treatment of Diabetic Nephropathy

Abstract

Combination therapy with angiotensin-converting-enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) decreases proteinuria; however, its safety and effect on the progression of kidney disease are uncertain. Methods We provided losartan (at a dose of 100 mg per day) to patients with type 2 diabetes, a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 300, and an estimated glomerular filtration rate (GFR) of 30.0 to 89.9 ml per minute per 1.73 m(2) of body-surface area and then randomly assigned them to receive lisinopril (at a dose of 10 to 40 mg per day) or placebo. The primary end point was the first occurrence of a change in the estimated GFR (a decline of ≥ 30 ml per minute per 1.73 m(2) if the initial estimated GFR was ≥ 60 ml per minute per 1.73 m(2) or a decline of ≥ 50% if the initial estimated GFR was <60 ml per minute per 1.73 m(2)), end-stage renal disease (ESRD), or death. The secondary renal end point was the first occurrence of a decline in the estimated GFR or ESRD. Safety outcomes included mortality, hyperkalemia, and acute kidney injury. Results The study was stopped early owing to safety concerns. Among 1448 randomly assigned patients with a median follow-up of 2.2 years, there were 152 primary end-point events in the monotherapy group and 132 in the combination-therapy group (hazard ratio with combination therapy, 0.88; 95% confidence interval [CI], 0.70 to 1.12; P=0.30). A trend toward a benefit from combination therapy with respect to the secondary end point (hazard ratio, 0.78; 95% CI, 0.58 to 1.05; P=0.10) decreased with time (P=0.02 for nonproportionality). There was no benefit with respect to mortality (hazard ratio for death, 1.04; 95% CI, 0.73 to 1.49; P=0.75) or cardiovascular events. Combination therapy increased the risk of hyperkalemia (6.3 events per 100 person-years, vs. 2.6 events per 100 person-years with monotherapy; P<0.001) and acute kidney injury (12.2 vs. 6.7 events per 100 person-years, P<0.001). Conclusions Combination therapy with an ACE inhibitor and an ARB was associated with an increased risk of adverse events among patients with diabetic nephropathy. (Funded by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development; VA NEPHRON-D ClinicalTrials.gov number, NCT00555217.).

Characterisation of glomerular haemodynamic responses to SGLT2 inhibition in patients with type 1 diabetes and renal hyperfiltration

“…On the other hand, whether such a combination may reduce intraglomerular pressure to an extent that could increase the risk for acute kidney injury events needs to be elucidated. In light of findings from the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET), Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints (ALTITUDE) and Veterans Affairs Nephropathy in Diabetes trial (VA-NEPHRON-D), which use strategies of dual RAAS blockade [8][9][10], this is an important consideration that requires further human physiological investigation and surveillance in ongoing clinical trials. Finally, our observations may have particular implications for primary renal preventive strategies in patients with type 1 diabetes, since RAAS blockade monotherapy is ineffective in normotensive, normoalbuminuric patients with preserved renal function.…”

Blood pressure level and risk of major cardiovascular events and all-cause of mortality in patients with type 2 diabetes and renal impairment: an observational study from the Swedish National Diabetes Register

“…Similar results were later found in the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE) and the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trials: findings showed no benefit with respect to mortality or CVEs and that intensive treatment with dual reninangiotensin-aldosterone system (RAAS) blockade even may even be harmful. The effects of BP lowering and/or RAAS blockade are therefore still under debate [27,28].…”

50 years forward: mechanisms of hyperglycaemia-driven diabetic complications

“…Further investigation is underway to determine a possible role in prevention of diabetic nephropathy and cardiovascular disease CCR2; C-C chemokine receptor 2; CTGF, connective tissue growth factor; JAK, Janus kinase; MCP1, monocyte chemoattractant protein 1; NEP, neutral endopeptidase; Nrf2, nuclear factor (erythroid-derived 2)-like 2; SGLT2, sodium-glucose co-transporter 2; STAT, signal transducers and activators of transcription inhibitor and ARB therapy and with the addition of renin inhibitors or mineralocorticoid receptor antagonists to ACE inhibitors or ARBs (for example, see [17]). Recent research has uncovered new dimensions of the RAAS, including pathways that produce vasoactive angiotensins other than angiotensin II and perhaps an important role for the type 2 angiotensin receptor subtype in the transduction of signals leading to diabetic complications [10].…”