Question Over Role of RAS Blockers for Hypertension in Diabetes

Miriam E Tucker

February 26, 2016

Diabetes is not a "compelling indication" for the use of renin-angiotensin system (RAS) blockers in patients with hypertension who don't have kidney disease, a new systemic review and meta-analysis suggests.

The findings were published online February 11 in the BMJ by Sripal Bangalore, MD, director of research at the cardiac catheterization laboratory and associate professor of medicine at New York University School of Medicine, New York, and colleagues.

In their analysis of randomized controlled trials involving 25,414 patients, for a total of 95,910 patient-years of follow-up, Dr Bangalore and his team found no significant differences between RAS blockers — comprising ACE inhibitors and angiotensin-receptor blockers (ARBs) — and other antihypertensive agents in terms of the risks of death, cardiovascular death, myocardial infarction, angina pectoris, stroke, heart failure, revascularization, or the "hard" end point of end-stage renal disease in diabetes patients with hypertension, most of whom did not have kidney disease at baseline.

"When something becomes a compelling indication, it means you really have to do this. But we know that some patients don't tolerate certain medications, and in some systems it's possible that some medications are cheaper than others. It's always better to have options," Dr Bangalore told Medscape Medical News.

He acknowledged that RAS blockers are usually well-tolerated and that all the antihypertensive classes are available in generic form, so cost shouldn't be a major issue. However, he said, the key point is, "You don't have to flog patients, saying you need to be on this medication because you have diabetes.…If there's a side effect and the patient can't tolerate it, this gives me [another]…option."

But in an accompanying editorial, Sumit R Majumdar, MD, professor of medicine at the University of Alberta, Edmonton, said that the findings may not mean much for busy clinicians taking care of these types of patients.

"First, many patients with diabetes already have other compelling indications for RAS blockers. Second, because most people with diabetes need at least two or three agents for good blood-pressure control, it probably does not matter which agent is started first — any of the commonly used regimens will do."

Conflicting Opinions on Whether to Use RAS Blockers First

Current guidelines differ on this issue. The American Diabetes Association (ADA), the American Society of Hypertension/International Society of Hypertension, and the National Kidney Foundation–Kidney Disease Outcomes Quality Initiative all advise RAS blockers as first-line antihypertensives in all patients with diabetes.

On the other hand, the European Society of Cardiology/European Society of Hypertension and the Eighth Joint National Committee (JNC8) on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recommend any class of antihypertensive agents in people with diabetes, with a preference for RAS blockers only in the presence of proteinuria or microalbuminuria.

Asked to comment on the paper, ADA chief scientific and medical officer Robert E Ratner, MD, said that the organization would not be changing its recommendation based on this paper. First of all, he said, "Meta-analyses very seldom tell you anything beyond the individual papers.…I prefer to look at the original data and make judgments based on those."

Beyond that, Dr. Ratner said, the choice of end points for the analysis doesn't reflect the outcomes that matter most to people with diabetes.

"Why do we treat hypertension in people with diabetes? The single primary reason is to decrease the progression of renal insufficiency. What we know is that ACE inhibitors and ARBs clearly have a beneficial effect on the progression of albuminuria and on the doubling of serum creatinine….Stopping the progression of kidney disease really makes a huge difference."

What's more, he added, "it's hard to get definitive data on hard outcomes that take 40 years [to occur]."

Dr Majumdar agrees. "The main limitation of the new work relates to renal end points. Bangalore and colleagues conclude that RAS blockers convey no advantage for the uncommon but easy-to-count outcome of end-stage renal disease. The authors discount 'doubling of serum creatinine' as a soft end point, although it is widely accepted as a robust surrogate measure."

Dr Ratner also pointed out that the alternative agents all have downsides, including increased glucose levels and hypokalemia with thiazide diuretics and inferior heart-failure outcomes with calcium-channel blockers.

In fact, Dr. Ratner added, the ADA recommendation does allow for choice and gave the recommendation of RAS inhibitors as first line only a "C" rating for evidence precisely because it mostly comes from those "soft" interim outcomes.

"I can't argue that choice isn't better or that in the absence of any evidence of kidney disease anything to lower blood pressure isn't beneficial. But I find it difficult to identify a reason not to use the ACE inhibitors and ARBs in people with diabetes who have any evidence of kidney disease and can tolerate them."

In Selected Trials, No Differences in Hard Outcomes

In Dr Bangalore's meta-analysis, the mean follow-up time was 3.8 years. Fifteen trials compared RAS blockers with a calcium-channel blocker, three with a thiazide diuretic, and two with a beta-blocker. In 14 trials the RAS blockers were ACE inhibitors and in six they were ARBs.

All but two of the trials enrolled people with both diabetes and hypertension, but just three included patients with microalbuminuria or proteinuria.

Of note, the investigators had excluded trials that enrolled patients with heart failure, given the known efficacy of RAS blockers in that group, and studies that compared RAS blockers with placebo, since antihypertensive treatment is the current standard of care.

Compared with other antihypertensive agents, RAS blockers were associated with a similar risk of all-cause death (13 studies; relative risk [RR], 0.99), cardiovascular death (10 studies; RR, 1.02), myocardial infarction (nine studies; RR, 0.87), angina pectoris (four studies; RR, 0.80), stroke (13 studies; RR, 1.04), heart failure (eight studies; RR, 0.90), and revascularization (four studies; RR, 0.97).

The combined outcome of major adverse cardiovascular events did not differ between the two groups [RAS blockers vs other antihypertensives; RR, 0.97], nor did the incidence of end-stage renal disease (three studies; RR, 0.99) or drug withdrawal owing to adverse effects (five studies; RR, 0.89).

There were also few differences in outcomes in comparisons of RAS blockers with each of the other individual antihypertensive classes, except that RAS blockers were associated with a significant reduction in heart failure compared with calcium-channel blockers (RR, 0.78).

Only three studies compared RAS blockers with diuretics and only two with beta-blockers, so the confidence intervals for both of these comparisons were wide, the authors note.

And although the numbers were small, there was also no difference in the outcomes for patients who had nephropathy at baseline (P > .05).

Beyond Blood-Pressure Lowering?

There was, and still is, debate as to whether the renoprotective effect of RAS blockers extends beyond their blood-pressure–lowering capacity.

As Dr Majumdar explains, " 'Lumpers' conclude that the benefits of RAS blockers are attributable entirely to blood-pressure lowering, whereas 'splitters' suggest additional vascular protective benefits. 'Splitters' acknowledge but often discount the extra 3 to 5 mm Hg of systolic pressure reduction reported in RAS-blocker study arms, even though this is a clinically worthwhile reduction."

Maybe we should also spend less time and fewer resources being distracted by which specific drug to use first and just get on with treating these high-risk patients.

Dr Bangalore said he essentially agrees that for patients with kidney disease — with or without diabetes — RAS blockers are likely the best choice. However, he noted, that's based on older studies comparing RAS blockade with placebo, not with other agents. However, "at least there are some data to suggest that using these in patients with kidney problems might be a good option."

But Dr Ratner countered there are several head-to-head trials showing benefit of RAS blockers over the other agents.

These include: the Fosinopril Versus Amlodipine Cardiovascular Events Randomized Trial (FACET) in patients with hypertension and type 2 diabetes (Diabetes Care. 1998;21:597-603); the Irbesartan Diabetic Nephropathy Trial of patients with type 2 diabetes and overt nephropathy (Ann Intern Med. 2003;138:542-549); and the Losartan Intervention For Endpoint reduction in hypertension study (LIFE; Lancet. 2002;359:995-1003).

No benefit was seen with RAS blockers in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT; Arch Intern Med. 2005;165:1401-1409), however, but that was "a very poorly done study," Dr Ratner said.

In the end, Dr Majumdar comments, the choice of specific antihypertensive agent may not really matter as much as other measures.

"Given the abysmal rates of blood-pressure control in this high-risk population…we collectively need to spend more time and resources figuring out how best to consistently and persistently lower blood pressure using systems approaches, new technologies, allied health professionals, and various patient education and engagement strategies."

He continued, "Given all of the synthesized evidence already available, maybe we should also spend less time and fewer resources being distracted by which specific drug to use first and just get on with treating these high-risk patients."

Dr Bangalore receives honoraria from Abbott, Boehringer Ingelheim, Daiichi Sankyo, Merck, Gilead, and Pfizer; disclosures for the coauthors are listed in the article. Dr Majumdar and Dr Ratner have no relevant financial relationships.

BMJ. Published online February 11, 2016. Article, Editorial


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