In total, 10
251 individuals were enrolled in the ACCORD trial (5128 in the intensive arm and 5123 in the standard arm), 460 of whom had died and were included in the dataset assessed when the intensive glycaemia protocol was stopped early in January 2008.6
The crude, annualised mortality rate was 1.14% a year in the standard glycaemia control arm and 1.42% a year in the intensive glycaemia control arm. Of the deceased participants, 451 had completed a scheduled follow-up visit to ascertain if they had experienced an episode of severe hypoglycaemia before death. More participants in the intensive arm than the standard arm experienced an episode of HA (816 (15.9%) v
256 (5.0%)) or HMA (528 (10.3%) v
175 (3.4%)). A total of 703 participants experienced an HMA at some point in the study. An additional 369 individuals reported at least one event requiring assistance of another person but did not report an event requiring medical assistance.
The proportion of participants who died stratified by the number of previous hypoglycaemic events and by glycaemia intervention treatment arm is shown in table 1. Among the 451 individuals who died, 377 had no history of HA and 400 had no history of HMA. On the other hand, 74 of those who died had experienced at least one HA and 51 at least one HMA. Overall in the ACCORD study, mortality rates in participants who experienced at least one HA, or the more restrictive HMA, were higher than in participants with no history of HA or HMA (74/1072 (6.9%) v 377/9122 (4.1%) and 51/703 (7.3%) v 400/9491 (4.2%), respectively; see table 1), with the highest rate seen in those participants with three events or more (HM: 13/172 (7.6%), HMA: 9/59 (15.3%)).
Table 1 Mortality, proportion deceased, and episodes of hypoglycaemia among all participants and by study arm
When analyses stratified by study arm were performed, the findings were similar in the standard arm and the intensive arm. Cox regression analyses of time between entry into the study and death identified a significant interaction between the number of HMA episodes and the glycaemia control arm (P=0.0494). This interaction indicated that the risk of death in participants with no history of HMA events was greater in those in the intensive arm than in those in the standard arm (HR 1.25, 95% CI 1.03 to 1.52). However, the mortality risk was lower in the intensive arm than in the standard arm among participants with one, two, or three or more HMA events (HR 0.63, 95% CI 0.31 to 1.28; HR 0.30, 95% CI 0.06 to 1.51; and HR 0.45, 95% CI 0.11 to 1.81, respectively; table 1). The interaction between the number of HA episodes and the glycaemia control arm was also not significant (P=0.2264).
On the basis of the information in table 1, the proportion of deaths during follow-up that could be attributable to HA events was 5.9% (95% CI 2.8 to 12.2) in the intensive arm and 5.1% (95% CI 1.6 to 15.2) in the standard arm. The proportion of deaths that could be attributable to HMA events (the aetiological fraction) in the intensive treatment arm was estimated to be 3.4% (95% CI 0.9 to 12.3), whereas this value was 5.4% (95% CI 2.6 to 12.3) in the standard treatment arm.
Table 2 shows the crude, annualised mortality rates, total number of deaths per person years of follow-up, and hazard ratios within glycaemia treatment arm by history of symptomatic, severe hypoglycaemia. When using previous hypoglycaemia as a “yes” or “no” indicator rather than a count of previous events (as reported earlier), there was a significant interaction between history of HMA and the glycaemia intervention arm (P=0.009), indicating that the glycaemic control treatment had a different effect according to whether or not the patient had a history of HMA.
Table 2 Crude, annualised mortality rates and hazard ratios within treatment groups by occurrence of hypoglycaemia
The annual mortality rate among participants who had never experienced an HMA was higher among participants in the intensive arm than in those in the standard arm (1.3% a year v 1.0% a year; HR 1.25, 95% CI 1.03 to 1.52). When mortality among participants who had experienced an HMA event was compared, however, the annual mortality rate was lower in the intensive arm than in the standard arm (2.8% a year v 4.9% a year; HR 0.55, 95% CI 0.31 to 0.99), indicating a lower relative risk of death among those in the intensive arm who had experienced hypoglycaemia than in those in the standard arm who had experienced hypoglycaemia. A similar trend was seen when the intensive and standard arms were compared among participants who had an HA (HR 0.74, 95% CI 0.45 to 1.23).
We next analysed information from the logs of finger stick blood glucose measurements collected in the seven days before each four month visit. We found that there were more incidences where blood glucose was less than 3.9 mmol/l in the intensive treatment group than in the standard treatment group (intensive 1.21±SD1.84 and standard 0.32±SD0.91; P<0.001). There was no significant relation between self reported low blood glucose concentration and risk of death, except among those participants who reported a history of HMA. Within this subgroup, the association between self reported low blood glucose concentration and risk of death was characterised by a lower risk of death in participants who reported a larger number of blood glucose measurements below 3.9 mmol/l (HR 0.68, 95% CI 0.36 to 1.24). In participants with no history of HMA, however, there was no relation between self reported blood glucose concentration and risk of death (HR 0.97, 95% CI 0.85 to 0.96; P against history of HMA=0.0497). The relation between the risk of death and finger stick blood glucose concentration of less than 3.9 mmol/l did not differ according to glycaemia control arm (P=0.2828).
Hypoglycaemia was judged to be involved in 431 of 451 deaths where enough information was available to make this decision. Overall, hypoglycaemia was not judged to have had a role in 389 (90.3%) of the 431 deaths with sufficient information to adjudicate for hypoglycaemia. In 38 (8.8%) of the deaths, hypoglycaemia was deemed to have had a possible role, whereas it was felt to have a probable role in three (0.7%) deaths. Hypoglycaemia was felt to have had a definite role in the death of one participant in the intensive treatment arm. These numbers did not vary much by study arm, with hypoglycaemia thought to possibly be involved in 25 (10.2%) deaths and probably be involved in one (0.41%) death in the intensive arm, whereas 13 (7.0%) and two (1.1%) of the deaths in participants in the standard arm were adjudicated as possibly related to hypoglycaemia and probably involved, respectively.
The time between the last reported episode of HA and death was also examined. Overall, of the 74 participants who reported any HA during the study and died, six (8.1%) died within 30 days of the event. A similar proportion of participants in the intensive treatment arm (n=3 (5.7%)) and in the standard arm (n=3 (14.3%)) died within 30 days of their last reported HA episode.