Intensive therapy to lower HbA1c, BP, and cholesterol failed to reduce mortality

The trial included 2,542 patients ages 45 to 69 years who had type 2 diabetes with an HbA1c of 6.9% or higher and hypertension, dyslipidemia, or both, recruited at 81 sites in Japan.


Lower targets for HbA1c, blood pressure (BP), and LDL cholesterol did not significantly lower mortality or a composite cardiovascular outcome in a recent trial of Japanese patients with type 2 diabetes, while post hoc analysis suggested a potential benefit of the intensive intervention for prevention of cerebrovascular events.

The trial included 2,542 patients ages 45 to 69 years who had type 2 diabetes with an HbA1c of 6.9% or higher and hypertension, dyslipidemia, or both, recruited at 81 sites in Japan. Patients were enrolled between June 2006 and March 2009 and were randomly assigned to either conventional or intensive therapy. Conventional therapy targets were as follows: HbA1c below 6.9%, BP below 130/80 mm Hg, and LDL cholesterol below 120 mg/dL (3.10 mmol/L) or below 100 mg/dL (2.59 mmol/L) in patients with a history of coronary artery disease. The intensive therapy targets were HbA1c below 6.2%, BP below 120/75 mm Hg, and LDL cholesterol below 80 mg/dL (2.07 mmol/L) or 70 mg/dL (1.81 mmol/L) in patients with a history of coronary artery disease. Median follow-up was 8.5 years, and two patients in the intensive group were excluded after randomization due to ineligibility.

The study received funding from a number of pharmaceutical manufacturers and was published online Oct. 24 by The Lancet Diabetes & Endocrinology.

The intensive therapy group had significantly lower mean concentrations on all the targets than the conventional group: HbA1c, 6.8% versus 7.2%; systolic BP, 123 mm Hg versus 129 mm Hg; diastolic BP, 71 mm Hg versus 74 mm Hg; and LDL cholesterol, 85 mg/dL (2.20 mmol/L) versus 104 mg/dL (2.69 mmol/L) (P<0.0001 for all comparisons). The study's primary outcome was a composite of myocardial infarction, stroke, revascularization, and all-cause mortality. It occurred in fewer intensive therapy patients (109 vs. 133), but the difference was not significant (hazard ratio [HR], 0.81; 95% CI, 0.63 to 1.04; P=0.094). In a post hoc breakdown of the composite, a significantly lower rate of cerebrovascular events was found in the intensive therapy group (HR, 0.42; 95% CI, 0.24 to 0.74; P=0.002). Rates of nonsevere hypoglycemia and edema were higher in the intensive group (41% vs. 22% and 15% vs. 10%, respectively), but other major adverse events did not differ.

“Our results do not fully support the efficacy of further intensified multifactorial intervention compared with current standard care for the prevention of a composite of coronary events, cerebrovascular events, and all-cause mortality,” the study authors concluded. However, they noted that the findings do suggest a potential reduction in cerebrovascular events from such an intervention. The lack of overall difference may be due to the relatively small differences in HbA1c, BP, and LDL cholesterol between groups, with the conventional group achieving good control and the intensive group not meeting the assigned targets. Event and mortality rates were also lower than expected, the authors said. They noted that the generalizability of the study may be limited by the participating institutions having a diabetes care clinic with diabetes specialists and educators but that nonspecialists could potentially apply the results using a treatment algorithm.

An accompanying comment said that the study demonstrated “feasibility of using conventional therapies to treat low-risk middle-aged patients with type 2 diabetes to new targets of cardiometabolic risk factors safely and effectively.” In addition to reducing cerebrovascular events by 58%, the intensive arm was associated with a 32% reduced risk of renal events, the comment author noted. The cost-effectiveness of the intervention will need to be studied, and more data are needed to determine treatment targets in younger patients with type 2 diabetes, the comment said.