Diabetes is emerging as a leading cause of morbidity and mortality. The total number of people in the world with diabetes is projected to rise from 171 million in 2000 to 366 million in 2030.1 The quality of life in diabetic subjects is often worsened by the presence of microvascular complications such as neuropathy, nephropathy, retinopathy, and cataracts.2 Analysis of available epidemiological evidence suggests that hyperglycemia is an important contributor to development and progression of microvascular complications in type 2 diabetes.3
In an analysis of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, Ismail-Beigi and colleagues investigated whether reduction of blood glucose concentration decreases the rate of microvascular complications in people with type 2 diabetes. They compared two groups of patients, intensive and standard.4 Intensive treatment targeted a HbA1c concentration of less than 6% and standard treatment targeted HbA1c of 7.0–7.9%. The investigators determined two prespecified composite outcomes, the first combined advanced kidney and eye disease and the second included advanced kidney disease, eye disease, and peripheral neuropathy. Several sub-outcomes were measured for nephropathy, diabetic eye complications, and neuropathy. Additionally, the authors predefined the primary microvascular outcome as the first composite endpoint (development of renal failure, or retinal photocoagulation or vitrectomy to treat diabetic retinopathy), which is characterized as advanced microvascular disease. A total of 10,251 participants were assigned to therapy. The intensive therapy arm was stopped before the end of the study due to higher mortality in that group. However, intensive therapy subjects were transitioned to standard therapy to continue the study.
Upon discontinuation of the intensive therapy arm outcomes were assessed at both transition and study end to evaluate the results. The primary composite outcome of advanced nephropathy and diabetic eye complications did not differ between the two arms at transition (HR 1.00 (0.88–1.14) P=0.9969) or study end (HR 0.95 (0.85–1.07) P=0.4226). The secondary composite endpoint which included peripheral neuropathy did not differ at transition (0.96 (0.89–1.02) P=0.1948) or study end (HR 0.95 (0.89–1.01) P=0.1172). The intensive therapy group had a significantly higher BMI at both transition and at study end (P <0.0001). For nephropathy related events, the sub-outcomes of microalbuminuria and macroalbuminuria favored intensive control, P=0.0012 and P=0.0003 respectively. However, the number of patients with end stage renal disease was alike in both groups at study completion (P=0.7126). For diabetic related eye events, the sub-outcomes of three-line worsening of visual acuity favored the intensive group at transition, P=0·0163, and at the conclusion of the study, P=0·0467. Additionally, the incidence of cataract surgery favored the intensive therapy group at end of study, P= 0.0265. The sub-outcomes of neuropathy (MNSI score >2), loss of ankle jerk, and loss of sensation to light touch all favored the intensive group at end of study, P= 0.0265, P= 0.005, P= 0.0043 respectively. Sub-outcomes of photocoagulation or vitrectomy, severe loss of vision, and loss of vibratory sensation were not statistically significant between the two groups at study end, P= 0.9, P= 0.5, P=0.29 respectively.
Ismail-Beigi and colleagues conclude that targeting a HbA1c of 6.0% or less with the methods used for the ACCORD cohort is not recommended on the basis of the microvascular benefits associated with the intensive glycemia therapy, as the observed benefits associated with intensive glycemic management should be weighed against the higher total mortality, cardiovascular related mortality, weight gain, and severe hypoglycemia in patients at high risk of cardiovascular disease. Additionally, they state caution should be exercised in the pursuit of ...