ORLANDO (EGMN) – Intensive glycemic control did not reduce the risk for developing advanced measures of microvascular outcomes, although it did delay the onset of albuminuria and some measures of eye complications and neuropathy among patients with longstanding type 2 diabetes at high cardiovascular risk.

The mixed results, from a subanalysis of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, suggest that the microvascular benefits of intensive therapy should be weighed against the increase in total disease-related mortality, increased weight gain, and high risk for severe hypoglycemia that emerged with the main findings of the trial 2 years ago, Dr. Faramarz Ismail-Beigi said on June 29 at the annual scientific sessions of the American Diabetes Association.

“Caution should be exercised in pursuit of a strategy of intensive glycemic control for prevention of microvascular complications in patients with established type 2 diabetes and characteristics similar to those in the ACCORD trial,” Dr. Ismail-Beigi of Case Western Reserve University, Cleveland, said. The findings were released simultaneously online in the Lancet (doi:10.1016/S0140-6736(10)60576-4).

The ACCORD trial randomized 10,251 adults with type 2 diabetes to either intensive glycemic control with a target hemoglobin A_1c of less than 6.0%, or standard therapy aiming for HbA_1c values of 7.0%-7.9%. The intensive arm was stopped early in February 2008 – after a median follow-up of 3.7 years—because of a 22% higher all-cause mortality in the intensive group. They were then transitioned to standard therapy for the rest of the trial, which also included blood pressure and lipid control arms (N. Engl. J. Med. 2008;358:2545-59).

At the time of that transition and at study end, the two groups did not differ in the prespecified primary composite outcome of advanced nephropathy and diabetic eye complications (development of renal failure or retinal photocoagulation or vitrectomy to treat retinopathy), nor in a second composite end point that added a peripheral neuropathy outcome (score of greater than 2.0 on the Michigan neuropathy screening instrument or the first composite outcome). At the end of the study, 10.9% of the intensive group and 11.5% of the standard treatment group met the first composite end point, and 38.2% and 40.0%, respectively, met the second.

However, microvascular renal outcomes based on urinary measures were significantly reduced in the intensive glycemic therapy group. Intensive glycemia therapy led to a 21% reduction in the development of microalbuminuria at the time of transition. This effect was attenuated to 15% at study end, but remained statistically significant, Dr. Ismail-Beigi reported.

For diabetes-related eye events, three-line worsening of visual acuity was more common in the standard group than in the intensive group at both transition and study end (20.7% vs. 19.1%). Cataract extraction was also significantly reduced, by 21%, in the intensive group, compared with standard group at study end. Other diabetes-related eye outcomes did not differ between the two groups, he said.

Peripheral neuropathy (MNSI greater than 2.0) was less common in the intensive group than in the standard group at study end (55.6% vs. 58.6%). Loss of ankle jerk reflex and light touch (10-g monofilament) perception were both rarer in the intensive vs. standard therapy groups at study end, but loss of vibratory sensation did not differ between the two groups.

In an accompanying editorial in the Lancet, Dr. Ronald Klein pointed out that the American Diabetes Association’s recommendation of a hemoglobin value of less than 7.0% was based on the findings of the United Kingdom Prospective Diabetes Study (UKPDS), which showed that intensive glycemic therapy in newly diagnosed type 2 diabetes patients didreduce the risk for the same composite microvascular endpoints as the ones used in ACCORD (Lancet 1998;352:837-53).

However, the follow-up period of ACCORD was much shorter than that of the UKPDS, in which it took about 10 years to show efficacy of intensive glycemic control for the same advanced end points, noted Dr. Klein, of the department of ophthalmology and visual sciences at the University of Wisconsin, Madison.

“I do not believe the ACCORD experience will (or should) cause clinicians to doubt the importance of glycemic control in preventing microvascular complications of diabetes ... might be that the regimen used in ACCORD was perhaps more aggressive than is prudent in patients with type 2 diabetes at high risk for cardiovascular disease. However ... it is important that ACCORD’s findings not be misinterpreted as a justification for a return to poor glycemic control that was common before UKPDS was reported,” Dr. Klein concluded.

The ACCORD trial was funded by the U.S. National Heart Lung and Blood Institute, with contributions of medications, equipment, or supplies from several manufacturers. Dr. Ismail-Beigi has received travel support from NHLBI and did not disclose any other relationships. However, several coauthors declared financial relationships with many manufacturers of diabetes-related products. Dr. Klein has worked as a consultant for AstraZeneca, Eli Lilly, GlaxoSmithKline, Takeda, Pfizer, and Novartis.

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