ACE-inhibitors/ARBs in diabetics: Evidence doesn’t support the CDA guidelines

As part of my work on a provincial committee, the issue came up recently regarding a quality metric evaluating proportion of all diabetic patients aged >55  who are being prescribed an ACE-inhibitor or ARB. When it was pointed out that the evidence supporting this specific metric is weak, the response was that this recommendation is part of the Canadian Diabetes Association Clinical Practice Guidelines, and that for a committee to go against an established guideline would be difficult.

The full CDA Clinical Practice Guidelines were last updated in 2013 (partial updates in 2015, February 2016, and November 2016), including the section specific to vascular protection in people with diabetes. Here is the recommendation around ACE-inhibitors/ARBs:


The efficacy for ACE-inhibitor/ARB use in established macrovascular disease was established back in 2000 with the HOPE trial. No argument there. Same with patients with diabetes and kidney disease (including microalbuminuria) from the RENAAL trial showing losartan improved proteinuria and renal outcomes.

I want to focus on the first half of point #2, where they recommend ACE-inhibitors for all patients 55 or older “with an additional risk factor”. From the HOPE definition, these risk factors would include hypertension, cigarette smoking, elevated total cholesterol levels, low HDL levels, or microalbuminuria.

Should ACE-inhibitors be the preferred treatment for hypertensive diabetics without cardiovascular or kidney disease? Not quite. The 2017 CHEP Guidelines reviewed the evidence and found that thiazide/thiazide-like diuretics and dihydropyridine CCBs would also be appropriate choices in this population (Section XII, Point #3). American guidelines from JNC 8 came to a similar conclusion (Recommendation #6). Here’s a systematic review from the BMJ from 2016 on the topic.

The most relevant question to me is, should patients with diabetes with no history of cardiovascular disease, no history of hypertension, and no end-organ damage, be prescribed an ACE-inhibitor? Simply on the basis of having hyperlipidemia or cigarette smoking?

The HOPE study population was a mix of patients with established cardiovascular disease and those who where 55 or older with one of the above mentioned risk factors. While a benefit was found to ACE-inhibition in the study population as a whole, here were the confidence intervals for those with and without cardiovascular disease:


As you can see, it is very difficult to make any conclusions about the “no cardiovascular disease” group. Point estimate around 0.8, but very wide confidence intervals. One could argue that the point estimate could be hypothesis-generating, but certainly no more than that in terms of guiding whether these patients should be all prescribed ACE-inhibitor/ARB therapy.

The guidelines also cite a “recent meta-analysis indicates that ACE inhibitors and ARBs reduce CVD events in normotensive individuals with and without diabetes” and “accordingly, the use of ACE inhibitors or ARBs for vascular protection with persons with diabetes ≥55 years or with any evidence of organ damage is recommended, even in the absence of hypertension”.

But hold on a second. What did this meta-analysis show? Or should I ask, what studies did this meta-analysis look at? 13 studies in total: 3 studies including only those with heart failure (SOLVD, SAVE, and TRACE), the RENAAL trial (patients with nephropathy), PROGRESS (patients with stroke or TIA), CAMELOT (those with angiographically documented CAD and elevated DBP), EUROPA (stable CAD patients), DIABHYCAR (patients with microalbuminuria), DREAM (dysglycemia, no frank diabetes), TRANSCEND (established atherosclerotic disease or end-organ damage), PROFESS (history of ischemic stroke), ACTIVE-I (history of atrial fibrillation), and the above-mentioned HOPE trial.

So the only study in this meta-analysis that included the patients from our relevant clinical question (diabetes with only hyperlipidemia or smoking as a risk factor) is the HOPE trial, which we already showed we cannot look to for a definite answer on this. None of the other trials cited by the CDA Guidelines looked at ACE-inhibitor/ARB use in our subset of patients.

Why is this relevant? In my practice alone, of 220 patients with diabetes, I have 40 patients who either smoker or have hyperlipidemia, and who have no history of cardiovascular disease, no microalbuminuria, and are not on an ACE-inhibitor/ARB for hypertension. The current guidelines suggest that all 40 of these patients should be on treatment, despite the evidence not supporting this claim. This is not a minor clinical issue. And to compound this problem, we have provincial and local organizations uneasy about contradicting these guidelines, and feeding data to physicians with the intent of altering prescribing rates.

I would suggest that the Canadian Diabetes Association Clinical Practice Guidelines Expert Committee re-evaluate their stance on the issue of ACE-inhibitor/ARB use in patients 55 and older with one additional risk factor (without macrovascular disease or end-organ damage) given the paucity of evidence supporting their current recommendation.

2 thoughts on “ACE-inhibitors/ARBs in diabetics: Evidence doesn’t support the CDA guidelines

  1. Russell Jockvim

    With due respect I disagree. Dr Elia is cherry-picking the data to make his point. I think he’s throwing out the baby with the bath water. In the data table he displayed from the HOPE trial, the benefit of ACEi treatment is statistically significantly evident for “diabetes”, “male sex”, “no hypertension”, “no coronary artery disease”, “no myocardial infarction”, “no peripheral vascular disease”, “no cerebrovascular disease”, and “no Microalbuminuria”. Dr Elia makes his point looking at the only category on the plot that doesn’t have statistical significance, which means the null hypothesis cannot be rejected for that category. To suggest that somehow this table fails to provide evidence of benefit is simply mis-reading or mis-representing the data. It is clear from HOPE and other primary prevention studies in diabetics (ADVANCE comes to mind) that ACEi therapy overall will save lives, prevent events, and has a NNT to be economical within the population. Perhaps the 40 patients mentioned from Dr Elia’s practice would benefit from seeing the data table to be fully informed rather than arbitrarily disqualifying them from protection?


    1. supermarioelia Post author

      Hi Russell, thanks for the comments.

      A few things to clarify. There was no cherry-picking of the data from the HOPE trial. The cohorts you describe that saw benefit all include patients with existing cardiovascular disease which raises the risk of the overall cohort. For example, the “no peripheral vascular disease” cohort of 5246 patients includes 4111 patients with other cardiovascular disease, who have a much different level of risk than the other 1135 patients in that cohort with no cardiovascular disease at all. It’s comparing apples and oranges to guide management. The only cohort that looks specifically at the low-risk group, “no cardiovascular risk” didn’t conclusively show benefit. All of the other cohorts are contaminated with many patients who have had cardiovascular disease.

      As for the ADVANCE trial, we have the same issue. The baseline BP in ADVANCE was 145/80, and 75% of patients were on anti-hypertensives prior to the trial. Again, this is a higher risk cohort than diabetics with NO cardiovascular disease, NO hypertension, and NO chronic kidney disease. ACE or ARB treatment reduces cardiovascular outcomes in high-risk patients, certainly, but that is not my argument. There is a complete absence of evidence to support ACE or ARB treatment in the lower-risk diabetic cohort that I have described.



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