Dual inhibition of the renin–angiotensin system in high-risk diabetes and risk for stroke and other outcomes: results of the ONTARGET trial

Background: A recent study suggested that addition of a direct renin inhibitor to either an angiotension-converting enzyme (ACE) inhibitor (ACEi) or an angiotensin receptor blocker (ARB) may increase stroke risk in people with diabetes and renal disease. Methods: We examined the effects of addition of an ACE inhibitor (ramipril) to an ARB (telmisartan) for a mean follow-up of 56 months in people with diabetes [n = 9628, mean age 66 years, baseline blood pressure 144/82 mmHg, BMI 29 kg/m2, estimated glomerular filtration rate (eGFR) 73 ml/min, and urine albumin 11 mg/mmol] who participated in the ONTARGET trial, divided by those with (n = 3163) and without (n = 6465) nephropathy. We compared participants on monotherapy with either ramipril or telmisartan with those on dual therapy. Results: SBP decreased more with dual over monotherapy (−7.1 vs. −5.3 mmHg, P < 0.0001) and the same number of strokes occurred (1.19 vs. 1.22 per 100 patient-years; hazard ratio 0.99, 95% confidence interval 0.82–1.20). Stroke rate was higher in participants with than those without diabetic nephropathy (1.5 vs. 1.0 per 100 patient-years), but effects of dual-therapy vs. monotherapy were not different in either subgroup (1.59 vs. 1.55 and 1.01 vs. 1.08 per 100 patient-years; P value for interaction = 0.60). Other cardiovascular and kidney outcomes (dialysis or doubling of serum creatinine) did not differ between dual-therapy and monotherapy in subgroups, but adverse events, namely acute dialysis, hyperkalemia and hypotension, tended to be more frequent with dual therapy, Conclusion: A combination of ACEi and ARB does not increase strokes or alter other major cardiovascular or renal events in patients with diabetes, irrespective of the presence of nephropathy.