Current issues of ACP Journal Club are published in Annals of Internal Medicine


Therapeutics

Review: ACE inhibitors and angiotensin-receptor blockers reduce diabetes in hypertension and other CV risk factors

PDF

ACP J Club. 2007 Jan-Feb;146:11. doi:10.7326/ACPJC-2007-146-1-011

Related Content in this Issue
• Companion Abstract and Commentary: Ramipril did not reduce incident diabetes in patients with impaired glycemic control


Clinical Impact Ratings

GIM/FP/GP: 6 stars

Endocrinology: 6 stars


Source Citation

McCall KL, Craddock D, Edwards K. Effect of angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers on the rate of new-onset diabetes mellitus: a review and pooled analysis. Pharmacotherapy. 2006;26:1297-306. [PubMed ID: 16945052]


Abstract

Question

In patients with hypertension or other cardiovascular risk factors, can angiotensin-converting enzyme (ACE) inhibitors or angiotensin II type 1 receptor blockers (ARBs) reduce new-onset diabetes mellitus?

Methods

Data sources: MEDLINE (January 1966 to October 2005).

Study selection and assessment: Randomized controlled trials (RCTs) that compared ACE inhibitors or ARBs as the primary intervention with a control group that did not receive an ACE inhibitor or ARB and reported the rate of new-onset diabetes. 13 RCTs (n = 67 271; age range 22 to 89 y; mean follow-up 4 y, range 1 to 6 y) met the selection criteria.

Outcomes: New-onset diabetes.

Main results

Meta-analyses showed that patients receiving ACE inhibitors or ARBs had lower incidences of diabetes than those receiving a control medication (β-blocker or thiazide, atenolol or hydrochlorothiazide, dihydropyridine calcium-channel blockers, amlodipine, chlorthalidone, or placebo) (Table).

Conclusion

Angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers reduce new-onset diabetes mellitus in patients with hypertension or other cardiovascular risk factors.

Source of funding: Not stated.

For correspondence: Dr. K.L. McCall, Texas Tech University Health Sciences Center, Amarillo, TX, USA. E-mail ken.mccall@ttuhs.edu.


Table. Prevention of new-onset diabetes with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II type 1 receptor blockers (ARBs) vs control in patients with hypertension or other cardiovascular risk factors at mean 4 years*

Number of trials (n) Comparisons Weighted event rates RRR (95% CI) NNT (CI)
13 (67 271) ACE inhibitor or ARB vs control† 7.2% vs 9.0% 20% (16 to 24) 56 (47 to 70)
6 (20 891) ACE inhibitor or ARB vs placebo 6.1% vs 7.9% 23% (15 to 31) 55 (41 to 85)
6 (32 429) ACE inhibitor or ARB vs-β blocker or thiazide 6.0% vs 7.8% 23% (17 to 29) 56 (45 to 76)
3 (17 384) ACE inhibitor or ARB vs dihydropyridine CCB 10% vs 13% 18% (11 to 24) 45 (34 to 73)

*CCB = calcium-channel blocker. Other bbreviations defined in Glossary; weighted event rates, RRR, NNT, and CI calculated from control event rates and relative risks in article.
†Control = β-blocker or thiazide, atenolol or hydrochlorothiazide, dihydropyridine CCB, amlodipine, chlorthalidone, or placebo.


Commentary

Difficulties in implementing intensive lifestyle changes have fueled enthusiasm for pharmacologic interventions to prevent diabetes. ACE inhibitors and ARBs have small beneficial effects on glucose metabolism, presumably by inhibiting the renin–angiotensin system. The DREAM trial by Bosch and colleagues and the review by McCall and colleagues present apparently contradictory inferences. The systematic review and meta-analysis of 13 RCTs of ACE inhibitors and ARBs in patients with hypertension or CV disease showed a significant reduction in the incidence of diabetes (as a secondary or post hoc outcome in each trial). The methodologically rigorous DREAM trial investigated the prevention of diabetes and showed that taking ramipril for 3 years did not reduce the incidence of diabetes in patients with impaired fasting glucose or impaired glucose tolerance. However, patients taking ramipril showed an increased regression to normoglycemia. Why do these results differ, and which should clinicians trust more: a large RCT (n > 5000) or a meta-analysis based on large trials (n > 67 000)?

The meta-analysis by McCall and colleagues showed a 20% relative risk reduction (95% CI 16 to 24) in the incidence of diabetes, similar to previous meta-analyses of 10 (1) and 12 (2) RCTs. Some methodological issues merit attention. First and foremost, reporting bias may affect these reviews. Bias occurs when the likelihood of publication of research depends on the direction of the results (i.e., when secondary or exploratory analyses of RCTs conducted with a different primary purpose do not get published because they failed to show a significant effect of these medications on the incidence of diabetes). If the reviewers did not contact authors of all ACE inhibitor and ARB trials for data on the effect of ACE inhibitor and ARBs on the incidence of diabetes, then reporting bias may affect their reviews. For example, these reviews did not include the ACE inhibitor trials AIRE (3) and TRACE (4), which did not report diabetes as an outcome. Therefore, because of reporting bias, systematic reviews of published analyses may overestimate the true effect of the interventions. Other shortcomings of this review include no analyses of the methodological quality of individual included studies, no assessment of heterogeneity between studies, and no description of pooling procedures.

The DREAM trial yielded results that were less sanguine but not entirely incompatible with the results of the systematic review. The duration of follow-up was brief (curves for the incidence of diabetes in each group began to separate as the trial drew to a close) and the resulting CI was wide, meaning that the results did not exclude the possibility of some benefit of ramipril in preventing diabetes.

Ultimately, is delaying the diagnosis of diabetes desirable enough to begin prescribing a medication to patients at risk, or should clinicians demand evidence that earlier introduction (i.e., before the diagnosis) is indeed associated with improved health outcomes, especially for CV events? In the DREAM trial, CV events were not significantly reduced when ACE inhibitors were given to patients at very low risk for these events.

Except in rare cases where patients with diabetes develop hypoglycemia when they start using ACE inhibitors, it remains doubtful whether ACE inhibitors or ARBs significantly improve glucose metabolism. While improvement in glucose tolerance may be an added benefit for patients who take ACE inhibitors for other indications, especially hypertension, these drugs cannot be recommended solely with the intention of preventing type 2 diabetes. 2 large RCTs with ARBs are currently underway, which may shed more light on this issue (5, 6).

Gunjan Y. Gandhi, MD, MSc
William L. Isley, MD
Mayo Clinic College of Medicine
Rochester, Minnesota, USA


References

1. Scheen AJ. Renin-angiotensin system inhibition prevents type 2 diabetes mellitus. Part 1. A meta-analysis of randomised clinical trials. Diabetes Metab. 2004;30:487-96. [PubMed ID: 15671918]

2. Abuissa H, Jones PG, Marso SP, O’Keefe JH Jr. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers for prevention of type 2 diabetes: a meta-analysis of randomized clinical trials. J Am Coll Cardiol. 2005;46:821-6. [PubMed ID: 16139131]

3. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet. 1993;342:821-8. [PubMed ID: 8104270]

4. Køber L, Torp-Pedersen C, Carlsen JE, et al. A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 1995;333:1670-6. [PubMed ID: 7477219]

5. The NAVIGATOR Trial Steering Committee. Nateglinide and valsartan in impaired glucose tolerance outcomes research: rationale and design of the NAVIGATOR trial. Diabetes. 2002;51(Suppl 2): A116.

6. Teo K, Yusuf S, Sleight P, et al. Rationale, design, and baseline characteristics of 2 large, simple, randomized trials evaluating telmisartan, ramipril, and their combination in high-risk patients: the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial/Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (ONTARGET/TRANSCEND) trials. Am Heart J. 2004;148:52-61. [PubMed ID: 15215792]