Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial

Abstract

Design ACCORD is a parallel group, randomized trial designed to investigate whether intensive glycemic therapy with a target HbA1c of <6.0% versus standard therapy with a target of 7.0 to 7.9% reduces cardiovascular disease (CVD) morbidity, mortality, and microvascular complications in participants with type 2 diabetes. Methods Volunteers with established type 2 diabetes, HbA1c levels ≥ 7.5% and CVD or two or more CVD risk factors were recruited at 77 clinical sites across the U.S. and Canada. Instructional materials, behavioral counseling, glucose-lowering medications and self-monitoring supplies were provided by the study. Therapeutic regimens were individualized on the basis of randomized assignment and response to therapy. This investigation examines the effect of treatment to glycemic goals on occurrence of microvascular diabetes complications. Prespecified composite outcomes were: 1) dialysis or renal transplantation, or serum creatinine >291.7 micromol/L, or retinal photocoagulation or vitrectomy, and 2) these plus peripheral neuropathy. Thirteen prespecified secondary measures of kidney, eye, and peripheral nerve function were also evaluated. Randomization was performed at clinical sites using a central randomization routine available on the study website. Both investigators and participants were unmasked to treatment arm assignment. Results A total of 10,251 participants were randomized (5,128 intensive and 5,123 standard) between January, 2001 and October, 2005. This analysis includes 10,234 patients (5,107 intensive and 5,108 standard). Intensive therapy was stopped before study end due to increased mortality, and patients were transitioned to standard therapy. Outcomes are reported at transition and at study end. At transition, the first composite outcome occurred in 443/5107 and 444/5108 participants in the intensive and standard arms, respectively (p= 0.99), and the second outcome in 1591/5107 and 1659/5108 participants in intensive and standard arms (p=0.20). Results were similar at study end. Secondary measures at study end favoring intensive therapy (p<0.05) included development of macroalbuminuria, cataract extraction, visual acuity, a score of >2.0 on the Michigan Neuropathy Screening Instrument, loss of ankle jerk and light touch. Conclusions Intensive glycemic treatment did not reduce the risk of advanced measures of microvascular outcomes, but delayed the onset of macroalbuminuria and some measures of eye complications and neuropathy. These benefits must be weighed against the increase in total and CVD-related mortality, increased weight gain, and higher risk for severe hypoglycemia.

Diabetes and obesity are the main metabolic drivers of peripheral neuropathy

“…The neuropathy definition was based on standardized examination and questionnaires, but not on a neurologist's history and examination or confirmatory measures (nerve conduction studies or skin biopsies). On the other hand, the MNSI questionnaire and examination are validated measures of neuropathy and have been used successfully in both type 1 and type 2 diabetic cohorts 28, 38, 39, 40. While the MNSI instruments have not been validated in Asian populations, the prevalence of neuropathy was comparable to a previous large Chinese cohort study using a different neuropathy definition 24.…”

Effects of glucose-lowering agents on vascular outcomes in type 2 diabetes: A critical reappraisal

“…Seven secondary measures at study end favoured intensive therapy with significant differences versus standard therapy [65]. In a systematic review focusing on the role of intensive glucose control in development of renal end points in T2DM patients, intensive glucose control reduces the risk for microalbuminuria and macroalbuminuria, but evidence is lacking that intensive glycaemic control reduces the risk for significant clinical renal outcomes, such as doubling of the serum creatinine level, ESRD, or death from renal disease during the years of follow-up of the trials [63].…”

Therapeutic Modalities in Diabetic Nephropathy: Standard and Emerging Approaches

“…Likewise, the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial, showed significantly lower rates of albuminuria (but not of more advanced nephropathy) in the intensive glycemic therapy group. 24 Contrary, the VADT (Veterans Affair Diabetic Trial) 25 did not show improvements in either nephropathy or retinopathy with intensive glycemic control. The lack of benefit in VADT may be explained by the longer duration of diabetes and the short follow-up time.…”