Intensive Glucose Control in Patients with Type 2 Diabetes - 15-Year Follow-up

Abstract

Background: We previously reported that a median of 5.6 years of intensive as compared with standard glucose lowering in 1791 military veterans with type 2 diabetes resulted in a risk of major cardiovascular events that was significantly lower (by 17%) after a total of 10 years of combined intervention and observational follow-up. We now report the full 15-year follow-up.

Methods: We observationally followed enrolled participants (complete cohort) after the conclusion of the original clinical trial by using central databases to identify cardiovascular events, hospitalizations, and deaths. Participants were asked whether they would be willing to provide additional data by means of surveys and chart reviews (survey cohort). The prespecified primary outcome was a composite of major cardiovascular events, including nonfatal myocardial infarction, nonfatal stroke, new or worsening congestive heart failure, amputation for ischemic gangrene, and death from cardiovascular causes. Death from any cause was a prespecified secondary outcome.

Results: There were 1655 participants in the complete cohort and 1391 in the survey cohort. During the trial (which originally enrolled 1791 participants), the separation of the glycated hemoglobin curves between the intensive-therapy group (892 participants) and the standard-therapy group (899 participants) averaged 1.5 percentage points, and this difference declined to 0.2 to 0.3 percentage points by 3 years after the trial ended. Over a period of 15 years of follow-up (active treatment plus post-trial observation), the risks of major cardiovascular events or death were not lower in the intensive-therapy group than in the standard-therapy group (hazard ratio for primary outcome, 0.91; 95% confidence interval [CI], 0.78 to 1.06; P = 0.23; hazard ratio for death, 1.02; 95% CI, 0.88 to 1.18). The risk of major cardiovascular disease outcomes was reduced, however, during an extended interval of separation of the glycated hemoglobin curves (hazard ratio, 0.83; 95% CI, 0.70 to 0.99), but this benefit did not continue after equalization of the glycated hemoglobin levels (hazard ratio, 1.26; 95% CI, 0.90 to 1.75).

Conclusions: Participants with type 2 diabetes who had been randomly assigned to intensive glucose control for 5.6 years had a lower risk of cardiovascular events than those who received standard therapy only during the prolonged period in which the glycated hemoglobin curves were separated. There was no evidence of a legacy effect or a mortality benefit with intensive glucose control. (Funded by the VA Cooperative Studies Program; VADT ClinicalTrials.gov number, NCT00032487.).

Figure 1.. Median Glycated Hemoglobin Levels According to Year since Start of the Trial, Starting at Year 3.

Year 3 was a point at which all the participants had been enrolled and had been receiving treatment per protocol for at least 3 months. The I bars (slightly offset for better visibility) represent interquartile ranges. The dotted line represents the end of the interventional component of the trial and the beginning of the follow-up period. To convert values for glycated hemoglobin to millimoles per mole, multiply by 10.93 and then subtract 23.50.

Figure 2.. Kaplan–Meier Curves for the Primary and Secondary Outcomes during the Trial and Follow-up Period.

The primary outcome was a major cardiovascular event (a composite of myocardial infarction, stroke, new or worsening congestive heart failure, amputation for ischemic gangrene, or death from cardiovascular causes). Secondary outcomes were any major diabetes event (primary composite outcome plus nontraumatic amputation or end-stage renal disease, defined as an estimated glomerular filtration rate [GFR] of <15 during the original trial period or as an estimated GFR of <15 or dialysis or kidney transplantation during the follow-up study), death from cardiovascular causes, and death from any cause.