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ACE inhibitor use was associated with severe hypoglycemia in patients with diabetes mellitus

ACP J Club. 1998 Mar-April; 128:50. doi:10.7326/ACPJC-1998-128-2-050

Source Citation

Morris AD, Boyle DI, McMahon AD, et al., and the DARTS/MEMO Collaboration. ACE inhibitor use is associated with hospitalization for severe hypoglycemia in patients with diabetes. Diabetes Care. 1997 Sep; 20:1363-7.



To examine whether an association exists between the use of angiotensin-converting enzyme (ACE) inhibitors and hospitalization for severe hypoglycemia in patients with diabetes mellitus.


Nested case-control study using the Diabetes Audit and Research in Tayside, Scotland (DARTS), database, a registry of all persons with diabetes in Tayside.


Community-based study in Scotland.


6649 patients with diabetes who used insulin or oral antidiabetic drugs were identified using the DARTS database. 64 patients (median age 60 y, 61% men) who were hospitalized with severe hypoglycemia were studied as case-patients. Exclusion criteria were a hospital stay within 1 month of admission for hypoglycemia or abuse of antidiabetic drugs. Each patient was matched for sex and age with up to 7 control-patients. The control group consisted of 440 persons from the community.

Assessment of risk factors

Previous exposure to ACE inhibitors, β-blockers, and calcium antagonists; dose, strength, and type of diabetes treatment; hemoglobin A1clevel; serum creatinine level; place of diabetes care; cardiovascular drug use; loop diuretic use (as a marker of heart failure); and duration of diabetes.

Main outcome measure

Association between hospital admission for severe hypoglycemia and use of ACE inhibitors.

Main results

Use of ACE inhibitors was reported by 7 patients (11%) who were hospitalized for hypoglycemia and by 19 control-patients (4%) (P = 0.023); the unadjusted odds ratio (OR) for hospitalization for hypoglycemia was 3.2 (95% CI 1.2 to 8.3). Use of β-blockers (OR 0.9, CI 0.3 to 3.3) and calcium antagonists (OR 1.7, CI 0.2 to 2.1) did not contribute to an increased risk for hospitalization. When the OR was adjusted for type of diabetes treatment, place of diabetes care, diuretic use, and duration of diabetes, the risk for hospitalization of patients using ACE inhibitors remained (OR 4.3, CI 1.2 to 16.0). Hypoglycemic patients were more likely than control-patients to have been insulin users, to have received hospital-based diabetes care or loop diuretics, and to have had a longer duration of diabetes.


Patients with diabetes who used angiotensin-converting enzyme inhibitors had an increased risk for hospitalization resulting from severe hypoglycemia.

Sources of funding: Scottish Home and Health Department; Wellcome Trust; Robertson Trust; U.K. Medicines Control Agency.

For article reprint: Dr. A.D. Morris, University Department of Medicine, Ninewells Hospital and Medical School, Dundee DD1 9SY, Scotland, UK. E-mail: amorris@clinpharm.


ACE inhibitors have quickly emerged as the antihypertensive drug of choice for patients with diabetes because of their protective effects on the kidneys. Given the current understanding of the mechanism of action of ACE inhibitors, most clinicians would not immediately think that this class of drug causes hypoglycemia. However, Morris and colleagues have added another study to 12 years of literature suggesting just that. First, ACE inhibitors were shown to improve glucose tolerance, leading to a reduction in insulin requirements or discontinuation of oral hypoglycemic therapy. Next, a few case reports of hypoglycemia attributed to ACE inhibitors appeared. 2 of 3 studies using the euglycemic hyperinsulinemic clamp technique confirmed improved insulin sensitivity in patients receiving ACE inhibitors. Then, a controversial case-control study suggested that ACE inhibitor use was a risk factor for severe hypoglycemia.

Morris and colleagues have attempted to control for confounding by taking into account risk factors, such as the use of β-blockers, elevated creatinine levels, cardiac disease (imperfectly represented by use of cardiovascular drugs), duration of diabetes, and other indications, and still found an association between ACE inhibitor use and hypoglycemia that resulted in hospitalization. The study did not address milder hypoglycemia, and given the increased number of comorbid conditions of the patients who were hospitalized for hypoglycemia, one wonders whether these conditions contributed to the decision to hospitalize. One hopes that some of the side effect data from randomized trials of ACE inhibitors could be analyzed for an association with milder hypoglycemia.

With the growing use of ACE inhibitors for patients with diabetes, clinicians need to be aware that ACE inhibitors may exacerbate hypoglycemia in patients with a history of the disorder and increase the risk for hypoglycemia in patients with excellent glycemic control. However, because most patients with diabetes have fair to poor glycemic control, the addition of an ACE inhibitor may help achieve improved control.

Jacqueline A. Pugh, MD
University of TexasSan Antonio, Texas, USA