ACE Inhibitors Improve
Survival in Type 2 Diabetes
May 27, 2004

Angiotensin-converting enzyme (ACE) inhibitors significantly reduce all-cause mortality in patients with type 2 diabetes who do not have a history of cardiovascular disease, according to the results of a cohort study published in the June issue of Diabetes Care.

"ACE inhibitor therapy is widely used in lower-risk patients with type 2 diabetes to reduce mortality, despite limited evidence to support this clinical strategy," write Dean T. Eurich, BSP, MSC, from the Institute of Health Economics in Edmonton, Alberta, Canada, and colleagues.

Using the Saskatchewan health databases, the investigators identified 12,272 new users of oral hypoglycemic agents during the period from 1991 to 1996. After exclusion of 3,202 subjects with previous cardiovascular disease, 1,187 "new users" of ACE inhibitors remained, as did 4,989 control subjects not receiving ACE inhibitors throughout the follow-up period.

Subjects were followed up prospectively for an average duration of 5.3 ± 2.1 years until death or the end of 1999. Mean duration of ACE inhibitor therapy was 3.6 ± 1.8 years. Compared with the control cohort, the ACE inhibitor cohort had significantly fewer deaths (102 [8.6%] vs. 853 [17.1%]; adjusted hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.40 - 0.61; P < .001). Mortality from cardiovascular causes was also reduced in the ACE inhibitor group (40 [3.4%] vs. 261 [5.2%]; adjusted HR, 0.63; 95% CI, 0.44 - 0.90; P = .01).

Study limitations include those inherent in administrative data, including inability to verify medication adherence.

"Our study suggests that ACE inhibitors can be used by many newly treated patients with type 2 diabetes and that this practice may be associated with reduced mortality," the authors write. "As it is unlikely that a randomized controlled trial of ACE inhibitor versus placebo therapy in patients with diabetes will ever be undertaken, our observational data may provide the best available evidence that many patients with diabetes will derive substantial mortality benefits from the routine use of ACE inhibitors."

The Alberta Heritage Foundation for Medical Research, the Institute of Health Economics, and the Alliance for Canadian Health Outcomes in Diabetes helped support this study.

Diabetes Care. 2004;27:1330-1334

Clinical Context

ACE inhibitors are widely used for patients with diabetes given their renoprotective effects in this group. These agents have also been shown to promote better cardiovascular outcomes among diabetic patients. In a subgroup analysis of diabetic subjects from the Heart Outcomes Prevention Evaluation (HOPE) study published in the Jan. 22, 2000, issue of The Lancet, ramipril was found to reduce the risk of myocardial infarction by 22% and stroke by 33% when compared with placebo. Researchers also found that ramipril significantly improved rates of revascularization and overt nephropathy.

In the HOPE trial, ramipril was generally more efficacious in diabetic patients with a greater disease burden (eg, those with preexisting cardiovascular disease or microalbuminuria) than those with less vascular complications of diabetes. In fact, ramipril was not superior to placebo in the combined primary outcome of myocardial infarction, stroke, or cardiovascular death when evaluating the subgroup of diabetic patients without a history of cardiovascular disease.

The authors of the current study performed a retrospective analysis to determine the benefits of ACE inhibitors among patients receiving initial treatment for type 2 diabetes and no history of recent cardiovascular disease.

Study Highlights

  • The authors performed a retrospective analysis of beneficiaries of the Saskatchewan Health Insurance Plan between 1991 and 1996. This plan covers the drug benefits for more than 90% of the population of Saskatchewan. All subjects were at least 30 years old with at least one year of continuous coverage in the health plan and were prescribed either a sulfonylurea or metformin for the first time during the study period.
  • Patients were excluded from analysis if they had a history of a cardiovascular event within the previous 3 years, if they were prescribed common cardiac agents, such as nitrates or loop diuretics, or if they had begun ACE inhibitors prior to receiving diabetes medications.
  • Subjects were divided into a group of 4,989 patients who had not received ACE inhibitors and 1,187 who had received at least 1 year of ACE inhibitor therapy following their prescription for diabetes medicine.
  • The primary study outcome was all-cause and cardiovascular-related mortality. The authors performed regression analyses using a multivariate model accounting for possible confounding factors, including a Chronic Disease Score designed to estimate the burden of concomitant comorbidities in each patient.
  • The mean age of subjects was 60.7 years, and 56.4% of patients were men. The mean follow-up period was 5.3 years, and the mean duration of ACE inhibitor treatment was 3.6 years.
  • The ACE inhibitor group was younger, contained fewer men, had a longer mean follow-up period, and had a greater number of comorbid conditions than the control group. Use of medications such as other antihypertensive agents, lipid-lowering drugs, and antiplatelet therapy were more common in the ACE inhibitor group compared with the control group, but insulin treatment was similar between the two groups.
  • 17.1% of the control group died during the follow-up period compared with 8.6% of the ACE inhibitor group (HR = 0.43). 5.2% of subjects in the control group died secondary to cardiovascular causes compared with 3.4% of the ACE inhibitor group (HR = 0.54). These data suggest that 12 patients with newly treated type 2 diabetes would need to receive ACE inhibitors for nearly 4 years to prevent one additional death among the group.
  • After adjusting for age, sex, Chronic Disease Score, and drug therapies known to affect cardiovascular outcomes the HRs were 0.49 for all-cause mortality and 0.63 for cardiovascular-related mortality, both favoring the ACE inhibitor group.
  • The survival curves between the two groups demonstrate that ACE inhibitors had an immediate impact on mortality, and the curves of the control and ACE inhibitor groups diverged to a greater degree with time.

Pearls for Practice

  • Previous research has demonstrated that ACE inhibitors improve cardiovascular and renal outcomes in a generalized cohort of patients with type 2 diabetes.
  • Recent data show that ACE inhibitors reduce all-cause and cardiovascular mortality in newly treated patients with type 2 diabetes.