ACE inhibitors reduce CV morbidity and mortality in diabetics

Cheng J, Zhang W, Zhang X et al.
JAMA Intern Med. 2014 Mar 31

Background

Diabetes mellitus (DM) is a strong independent risk factor for cardiovascular disease (CVD), and associated with macrovascular complications. The renin-angiotensin-aldosterone system (RAAS) is an important regulator of CV and renal function [1,2]. Suppression of RAAS activity has been found to reduce CV mortality and all-cause mortality [3-6].
The cardioprotective effects of RAAS-blockade have, however, recently been questioned. The Non–Insulin-Dependent Diabetes, Hypertension, Microalbuminuria or Proteinuria, Cardiovascular Events, and Ramipril (DIABHYCAR) study [7] found that angiotensin-converting enzyme inhibitors (ACEI) had no effects on CV events in patients with type 2 DM (T2DM) and albuminuria, and in another study a higher rate of fatal CV events was observed with olmesartan in T2DM patients (ROADMAP study [8]).
The American Diabetes Association recommends that patients with DM and hypertension be treated with a therapeutic regimen that should include an ACEI or an angiotensin II receptor blocker (ARB) [9]. Both types of drugs inhibit angiotensin II, but via a different mechanism of action.
A recent meta-analysis demonstrated that ACEIs and ARBs differently affected all-cause mortality in patients with hypertension. This difference may also be relevant in the treatment of DM. This meta-analysis evaluated the effect of ACEIs and ARBs separately vs. placebo or other medications, on all-cause mortality, CV death, and CV events in patients with DM.
35 trials, enrolling 56444 patients, were included in this analysis, 23 of which evaluated ACEIs and 13 compared ARBs with control therapy.

Main results

• In 20 prospective trials, ACEIs were associated with a statistically significant 13% reduction in all-cause mortality as compared with control therapy (RR: 0.87, 95%CI: 0.78-0.98, P=0.02). There was no difference between comparisons with placebo or active treatment.
• Based on 13 studies of 23 RCTs, a significant 17% reduction of CV deaths was seen with ACEIs as compared with control therapy (RR: 0.83, 95%CI: 0.70-0.99, P=0.04). There was no interaction with comparison with placebo or active treatment.
• No significant decrease in all-cause mortality was seen with ARBs as compared with control therapy, based on 11 studies (RR: 0.94, 95%CI: 0.82-1.08, P=0.39). No difference was seen with respect to type of control treatment.
• With respect to CV mortality, no difference was seen between ARB treatment and control therapy (RR: 1.21,95CI: 081-1.80, P=0.35), without an interaction for type of control treatment. Heterogeneity across trials was significant, which disappeared when 2 trials involving olmesartan were excluded. When comparing only olmesartan with control therapy, a significant increase in the risk of CV death was seen (2 trials, 5024 patients, RR: 4.10, 95%CI: 1.68-9.98, P=0.002).
• Major CV events were significantly reduced with ACEI (RR: 0.86, 95%CI: 0.77-0.95). ACEI therapy also reduced the risk of myocardial infarction (RR: 0.79, 95%CI: 0.65-0.95, P=0.01) and heart failure (RR: 0.81, 95%CI: 0.71-0.93, P=0.002), but not stroke (RR: 0.95, 95%CI: 0.86-1.04, P=0.28).
• ARBs did not give a significant decrease in the risk of major CV events (RR: 0.94, 95%CI: 0.85-1.01, P=0.07). There were no significant effects of ARBs on myocardial infarction (RR: 0.89, 95%CI: 0.74-1.07, P=0.22) or stroke (RR: 1.00, 95%CI: 0.89-1.12, P=0.94). Risk of heart failure was reduced with ARBs (RR: 0.70, 95%CI: 0.59-0.82, P<0.01).

Conclusion

This meta-analysis of RCTs shows that ACEIs and ARBs differentially affect the risk of all-cause mortality, CV deaths and CV events in patients with diabetes. ACEIs reduce the risk of mortality, myocardial infarction and heart failure, while ARBs does not affect risk of mortality and major CV events. ARB therapy did reduce the risk of heart failure. No effect on stroke was seen with either treatment. Based on these data, ACEIs should be considered first-line treatment in patients with diabetes mellitus, to reduce mortality and morbidity.

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References

1. Ferrario CM, Strawn WB. Role of the renin-angiotensin-aldosterone system and proinflammatory mediators in cardiovascular disease. Am J Cardiol. 2006;98(1):121-128.
2. Ruster C,Wolf G. Renin-angiotensin-aldosterone system and progression of renal disease. J AmSoc Nephrol. 2006;17(11):2985-2991.
3. Strippoli GF, CraigM, Deeks JJ, et al. Effects of angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists on mortality and renal outcomes in diabetic nephropathy: systematic review. BMJ. 2004;329(7470):828. doi:10.1136 /bmj.38237.585000.7C.
4. Ruggenenti P, Perna A, Remuzzi G; Gruppo Italiano di Studi Epidemiologici in Nefrologia. ACE inhibitors to prevent end-stage renal disease: when to start and why possibly never to stop: a post hoc analysis of the REIN trial results: Ramipril Efficacy in Nephropathy. J AmSoc Nephrol. 2001;12(12):2832- 2837.
5. Matchar DB, McCrory DC, Orlando LA, et al. Systematic review: comparative effectiveness of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers for treating essential hypertension. Ann Intern Med. 2008;148(1):16-29.
6. Lewis EJ, Hunsicker LG, ClarkeWR, et al; Collaborative Study Group. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345(12):851-860.
7. Remuzzi G, MaciaM, Ruggenenti P. Prevention and treatment of diabetic renal disease in type 2 diabetes: the BENEDICT study. J AmSoc Nephrol. 2006;17(4)(suppl 2):S90-S97.
8. Marre M, Lievre M, Chatellier G, et al.; DIABHYCAR Study Investigators. Effects of low dose ramipril on cardiovascular and renal outcomes in patients with type 2 diabetes and raised excretion of urinary albumin: randomised, double blind, placebo controlled trial (the DIABHYCAR study). BMJ. 2004;328(7438): 495-502.
9. Haller H, Ito S, Izzo JL Jr, et al; ROADMAP Trial Investigators. Olmesartan for the delay or prevention ofmicroalbuminuria in type 2 diabetes. N Engl J Med. 2011;364(10):907-917.
10. American Diabetes Association. Executive summary: standards of medical care in diabetes—2012. Diabetes Care. 2012;35(suppl 1):S4-S10.