VANCOUVER – Intensive glucose control needs to begin early in the course of kidney disease to have its greatest renal protective effect in patients with type 2 diabetes, suggests a study reported at the World Diabetes Congress.

The conclusions are based on long-term follow-up of patients with type 2 diabetes and high vascular risk who were treated on an international randomized trial for about 5 years with either intensive or standard glucose control.

Results for the 8,494 patients at a median total follow-up of nearly a decade showed that patients with lesser stages of chronic kidney disease (CKD) at the start of the study benefited more from intensive over standard glucose control in reducing the risk of onset of dialysis or renal transplantation, reported Dr. Sophia Zoungas.

Reassuringly, intensive glucose lowering was not associated with an increase in the risk of death or cardiovascular death, regardless of patients’ CKD stage at baseline. And the higher relative risk of severe hypoglycemia with the intensive strategy was likewise similar across baseline CKD stages.

“We think that the commencement of intensive glucose control is particularly important early in the disease process, and hopefully we can get in before the development of significant kidney disease,” said Dr. Zoungas, an endocrinologist with the Monash University School of Public Health and Preventive Medicine in Clayton, Australia.

“The lesser benefit in those with moderately reduced kidney function (CKD stage 3 or greater) may indicate that the glucose-independent mechanisms of renal progression may predominate in the later stages of the disease,” she speculated.

These new data are helpful for real-world clinical care, according to session co-moderator Dr. David A. D’Alessio, a professor of medicine and director of the division of endocrinology, metabolism, and nutrition at Duke University, Durham, N.C.

“I think this study was really important. It shows the strength of doing a good trial and then not stopping at 5 years, but continuing to collect data,” he said in an interview. “These studies end up being really useful to practitioners because we oftentimes see patients whom we’ve followed for up to 10 years.”

The patients studied had participated in the ADVANCE trial (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation), which tested both intensive glucose control and blood pressure–lowering therapy. After the 5-year trial, patients returned to their usual practitioners’ care but had continued collection of data. The ADVANCE post-trial observational study (ADVANCE-ON) analyses were conducted after a median total follow-up of 9.9 years. Main findings were previously published (N Engl J Med. 2014;371:1392-406).

The greater reduction in hemoglobin A1c levels seen with intensive glucose control versus standard control on the trial was lost after the trial ended, Dr. Zoungas noted. “So if there was any effect in ADVANCE-ON, it would be attributable to the difference achieved during the in-trial period,” she said.

Compared with peers in the standard control group, patients in the intensive control group had a reduction in the risk of end-stage kidney disease during the entire follow-up (hazard ratio, 0.54) similar to that seen while they were on the trial (hazard ratio, 0.35).

In subgroup analyses, the lower the baseline stage of CKD, the greater the edge of intensive glucose control over standard glucose control for reducing the risk of end-stage kidney disease. The hazard ratio was 0.16 for patients with no CKD at baseline, 0.34 for those with stage 1 or 2, and 0.89 for patients with stage 3 or higher (P = .04). The number needed to treat for 5 years to prevent one case of end-stage kidney disease during the entire follow-up was 259, 109, and 393, respectively.

“What’s interesting to note here is that during the overall 9.9 years of follow-up, we have smaller numbers needed to treat for those with no evidence of CKD or early-stage CKD,” Dr. Zoungas said.

The investigators explored treatment impact on all-cause mortality and cardiovascular mortality according to baseline CKD stage, prompted by findings from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial showing increased risks of these outcomes in patients with mild to moderate CKD at baseline who received intensive glucose control (Kidney Int. 2015;87:649-59).

ADVANCE-ON results, in contrast, showed no significant elevation in risk with intensive control, either while patients were on the trial or for the total 9.9 years of follow-up even in those at the more advanced stages of CKD, Dr. Zoungas said.

The relative risk of severe hypoglycemia was similarly elevated with intensive control, compared with standard control across CKD subgroups, although the absolute risk was higher for those with stage 3 or higher disease.

Dr. Zoungas disclosed that she receives honoraria from Servier for speaking about ADVANCE and ADVANCE-ON at scientific meetings, and that she is on the speakers bureau and advisory boards for and receives travel support from Merck Sharp & Dohme and AstraZeneca/Bristol-Myers Squibb. The study was funded in part by Servier.

Early-stage kidney disease benefits most from intensive glucose control