| |
Intensive Blood Glucose Control Has Positive Outcomes in ADVANCE Study
|
| |
| |
The results show that lowering blood pressure and intensive glucose control are additive in reducing the risk of cardiovascular mortality and all-cause mortality in type 2 diabetes.....There has been great interest in ADVANCE following surprising results from the ACCORD (Action to Control Cardiovascular Risk in Diabetes) study which was terminated prematurely earlier this year due to a 22% increase in all cause mortality in patients whose blood glucose was aggressively controlled using regimens which included thiazolidinediones.....the drug strategy used in ACCORD may have been too aggressive for frail elderly patients......over-intensive efforts to achieve 'near-normal' glucose control in ACCORD may have increased risk of mortality in 'vulnerable' patients. "The intensity of glucose control must be adapted to the circumstances of the individual. Hypoglycaemia and abnormalities of the diabetic heart may combine to increase susceptibility to fatal heart attack."
ADVANCE helps clarify ACCORD mortality mystery but questions remain
11 September 2008 www.pharmatimes.com
The latest findings from the ADVANCE (Action in Diabetes and Vascular Disease) study have been presented at this week's meeting of the European Association for the Study of Diabetes congress held in Rome.
The results show that lowering blood pressure and intensive glucose control are additive in reducing the risk of cardiovascular mortality and all-cause mortality in type 2 diabetes.
In the study - the largest-ever performed in patients with type 2 diabetes - combining intensive blood sugar control based on gliclazide modified release (Diamicron MR, Servier) with intensive blood pressure lowering based on a fixed combination of perindopril and indapamide (Preterax, Servier) reduced the risk of death from heart disease by nearly one-quarter (24%) and risk of kidney complications by one-third (33%) in patients with type 2 diabetes. The benefits of tight blood glucose control and blood pressure lowering were both independent and fully additive.
There has been great interest in ADVANCE following surprising results from the ACCORD (Action to Control Cardiovascular Risk in Diabetes) study which was terminated prematurely earlier this year due to a 22% increase in all cause mortality in patients whose blood glucose was aggressively controlled using regimens which included thiazolidinediones.
At an EASD press conference, results from ADVANCE, ACCORD and a third trial VADT (Veterans Affairs Diabetes Trial), were discussed by three leading diabetes researchers: John Chalmers of The George Institute for International Health, Sydney, Australia and head of ADVANCE; David Matthews (Oxford Centre for Diabetes, Endocrinology and Metabolism) and Cliff Bailey, Head of Diabetes Research and Professor of Clinical Science at Aston University in Birmingham.
They addressed the question of why there was no increase in all cause mortality in ADVANCE, despite blood glucose (HBa1c) being lowered to around the same level as that achieved in the intensive arm of ACCORD.
They broadly agreed that the drug strategy used in ACCORD may have been too aggressive for frail elderly patients. Two speakers also stated that although specific effects of drugs used in ACCORD could not be blamed for the excess mortality observed, neither could such effects be ruled out.
Professor Bailey drew attention to the increased number of hypoglycaemic episodes observed in ACCORD, compared with ADVANCE and speculated that these may be linked to the increased mortality observed in ACCORD.
He said that over-intensive efforts to achieve 'near-normal' glucose control in ACCORD may have increased risk of mortality in 'vulnerable' patients. "The intensity of glucose control must be adapted to the circumstances of the individual. Hypoglycaemia and abnormalities of the diabetic heart may combine to increase susceptibility to fatal heart attack."
He added that existing treatment guidelines remained appropriate, but they need to be applied flexibly to fit the circumstances of the individual patient.
Prof Chalmers said that ADVANCE had used a more gradual approach and fewer drugs to get patients to target HbA1c levels than the regimens used in ACCORD. Prof Matthews agreed that the strategy used in ACCORD had been too aggressive and that the gradual approach to glucose control used in ADVANCE made more sense biologically.
He added that although results from the two trials could not be used directly to compare the drugs employed in each, some drugs used in ACCORD may have had a downside: "We don't yet know," he said. The new ADVANCE findings will be published early next year. By Ian Mason in Rome
- Meantime, an editorial in this week's New England Journal of Medicine calls for tighter control of new diabetes therapies, following cardiovascular safety fears.
Allison Goldfine says that the US Food and Drug Administration's Endocrinologic and Metabolic Drugs Advisory Committee has discussed a new two-step process for evaluating the cardiovascular safety of new diabetes agents. It would consist of a randomised cardiovascular-event-driven trial, before approval with a longer, larger post-approval trial to establish the safety margin more clearly.
Dr Goldfine adds that the FDA could require manufacturers to submit a design for a cardiovascular-safety trial and ongoing progress reports to obtain and maintain a drug's approved status; failure to achieve milestones might lead to restrictions or withdrawal of approval.
Intensive Blood Glucose Control and Vascular Outcomes in Patients with Type 2 Diabetes -
The ADVANCE Collaborative Group
NEJM June 2008
ABSTRACT
Background In patients with type 2 diabetes, the effects of intensive glucose control on vascular outcomes remain uncertain.
Methods We randomly assigned 11,140 patients with type 2 diabetes to undergo either standard glucose control or intensive glucose control, defined as the use of gliclazide (modified release) plus other drugs as required to achieve a glycated hemoglobin value of 6.5% or less. Primary end points were composites of major macrovascular events (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) and major microvascular events (new or worsening nephropathy or retinopathy), assessed both jointly and separately.
Results After a median of 5 years of follow-up, the mean glycated hemoglobin level was lower in the intensive-control group (6.5%) than in the standard-control group (7.3%). Intensive control reduced the incidence of combined major macrovascular and microvascular events (18.1%, vs. 20.0% with standard control; hazard ratio, 0.90; 95% confidence interval [CI], 0.82 to 0.98; P=0.01), as well as that of major microvascular events (9.4% vs. 10.9%; hazard ratio, 0.86; 95% CI, 0.77 to 0.97; P=0.01), primarily because of a reduction in the incidence of nephropathy (4.1% vs. 5.2%; hazard ratio, 0.79; 95% CI, 0.66 to 0.93; P=0.006), with no significant effect on retinopathy (P=0.50). There were no significant effects of the type of glucose control on major macrovascular events (hazard ratio with intensive control, 0.94; 95% CI, 0.84 to 1.06; P=0.32), death from cardiovascular causes (hazard ratio with intensive control, 0.88; 95% CI, 0.74 to 1.04; P=0.12), or death from any cause (hazard ratio with intensive control, 0.93; 95% CI, 0.83 to 1.06; P=0.28). Severe hypoglycemia, although uncommon, was more common in the intensive-control group (2.7%, vs. 1.5% in the standard-control group; hazard ratio, 1.86; 95% CI, 1.42 to 2.40; P<0.001).
Conclusions A strategy of intensive glucose control, involving gliclazide (modified release) and other drugs as required, that lowered the glycated hemoglobin value to 6.5% yielded a 10% relative reduction in the combined outcome of major macrovascular and microvascular events, primarily as a consequence of a 21% relative reduction in nephropathy.
The prevalence of diabetes is increasing worldwide, and most people with diabetes will die or be disabled as a consequence of vascular complications.1,2 Prospective studies have shown continuous associations of blood glucose and glycated hemoglobin levels with the risks of major vascular events.3,4 However, previous randomized trials evaluating the effects of glycemic control in patients with diabetes have provided inconsistent evidence of effects on vascular disease.5,6,7,8,9,10,11 Nevertheless, current guidelines recommend a target glycated hemoglobin level of 7.0% or less for most patients with diabetes.12,13,14
The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial was designed to assess the effects on major vascular outcomes of lowering the glycated hemoglobin value to a target of 6.5% or less in a broad cross-section of patients with type 2 diabetes. The part of the study that evaluated the lowering of blood pressure with the use of perindopril and indapamide, completed in June 2007, showed a reduction in the risks of major vascular events and death, regardless of the initial blood pressure.15 Here we report the main results from the comparison of the blood-glucose-lowering strategies, completed in January 2008, which evaluated an intensive glucose-control strategy based on gliclazide (modified release) and other drugs as required to achieve the target glycated hemoglobin level.
Discussion
In the ADVANCE trial, an intensive glucose-control strategy involving gliclazide (modified release), and other drugs as required, lowered the average glycated hemoglobin value to 6.5% in a broad range of patients with type 2 diabetes and reduced the incidence of the combined primary outcome of major macrovascular or microvascular events. The main contributor to the 10% relative reduction in the primary outcome found with intensive control as compared with standard control was a 21% relative reduction in the risk of new or worsening nephropathy. There was no evidence of a reduction in macrovascular events. Intensive glucose control was associated with an increased risk of severe hypoglycemia and an increased rate of hospitalization, as compared with standard control. There was no evidence that the effects of intensive glucose control were dependent on the baseline glycated hemoglobin or blood glucose level, age, sex, or presence or absence of a history of vascular disease.
There were no significant differences between the two study groups in the rate of death from any cause or death from cardiovascular causes. These findings contrast with the reported excess mortality that led to premature termination of the intensive glucose-control strategy in another large, randomized trial involving patients with type 2 diabetes (Action to Control Cardiovascular Risk in Diabetes [ACCORD]; ClinicalTrials.gov number, NCT00000620 [ClinicalTrials.gov] ), in which similar levels of glucose control were achieved with the intensive-control strategy.20,21 Mechanisms speculated to underlie the excess mortality found with intensive glucose control in the ACCORD trial include the initial level of glycated hemoglobin, the degree and pace of glucose lowering, and the treatments used to achieve such lowering.20,22 In the ADVANCE trial, no subgroup of participants was identified to have evidence of an adverse effect of intensive glucose lowering on major vascular outcomes, including the subgroup with an initial median glycated hemoglobin value similar to that in the ACCORD study population.21
Intensive glucose control in the ADVANCE trial resulted in a reduction by one fifth in the development of new or worsening nephropathy and a more modest, though significant, reduction in that of new-onset microalbuminuria. In the U.K. Prospective Diabetes Study (UKPDS), the largest previously reported randomized trial of glycemic control in patients with type 2 diabetes, tighter glucose control did not reduce the incidence of major renal outcomes, although there was some evidence of a reduction in the development of microalbuminuria and overt proteinuria with a prolonged follow-up period.6 The clear reduction in nephropathy demonstrated in the ADVANCE trial is important, because indexes of renal impairment are strongly associated with the future risk of major vascular events, end-stage renal disease, and death in patients with diabetes.23,24
There is no evidence that intensive glucose control in the ADVANCE trial led to reduced new or worsening retinopathy, including retinal photocoagulation. The lower rate of retinal photocoagulation in the ADVANCE trial than in previous studies of diabetes7,25 was also reported in another recent trial.26 This low event rate limited the power of the study to detect any moderate effects of the intervention on microvascular eye disease. However, more evidence about the retinovascular effects of intensive glucose control will be provided by the ADVANCE retinal imaging substudy.27
The ADVANCE trial did not show a significant effect of intensive glucose control on the risk of major macrovascular events. Although the results may indicate that lowering blood glucose levels to an average glycated hemoglobin level of 6.5% with the treatments used does not reduce the risk of macrovascular events, the results do not preclude a benefit of the size predicted by the achieved difference between the intensive-control group and the standard-control group in glycated hemoglobin levels. From observational data describing the association between glycated hemoglobin and cardiovascular events and a meta-analysis of previous randomized trials of glycemic control,4,10 a 0.7% reduction in the glycated hemoglobin value might be expected to produce a reduction in the rate of macrovascular events by approximately one sixth. The confidence intervals for the estimate of the effect of treatment on macrovascular events in the ADVANCE trial are consistent with such a reduction, but the ADVANCE trial did not have adequate statistical power to detect such an effect reliably. The annual rate of macrovascular events (2.2%) was lower than the anticipated rate of 3.0% based on previous studies of patients with type 2 diabetes,7,25 possibly as a consequence of the greater use of statins, blood-pressure-lowering drugs, and antiplatelet agents. Future combined analyses of the ADVANCE trial, the ACCORD trial, and other studies should provide further insight into the effects of intensive glucose control on macrovascular events.21,28
In the part of the ADVANCE trial evaluating the lowering of blood pressure,15 a reduction of 5.6 mm Hg in the systolic blood pressure among patients randomly assigned to receive perindopril and indapamide, as compared with those assigned to receive placebo, resulted in a relative risk reduction of 9% for the primary combined outcome. Thus, the expected relative risk reduction associated with a 1.6 mm Hg reduction in systolic blood pressure would be less than 3%. This suggests that the lower blood pressure among patients undergoing intensive glucose control probably explains some, but no more than one quarter to one third, of the 10% reduction seen with intensive glucose control as compared with standard control. The explanation for the reduction in blood pressure in the intensive-control group is unclear. The difference in blood pressure so soon after randomization may indicate an early effect of the study treatment regimen.29,30,31 However, it is also possible that the difference reflects nonspecific effects associated with more frequent contact with health care providers.
As expected, there was a significantly higher incidence of hypoglycemia in the intensive-control group (three additional severe events for every 1000 patients treated for 1 year), although the overall risk of this complication was low. Almost half of all patients undergoing intensive control remained free from any hypoglycemia (severe or minor) during the follow-up period. The proportion of patients with at least one severe hypoglycemic episode each year was about one quarter that observed in the UKPDS,6 despite the lower glycated hemoglobin levels among the ADVANCE participants.
In the ADVANCE trial, an intensive glucose-control strategy involving gliclazide (modified release) and other glucose-lowering drugs as required reduced the glycated hemoglobin level to an average of 6.5%. There was no evidence that this treatment strategy increased mortality.20,21 Intensive glucose control significantly reduced the primary composite outcome of major macrovascular or microvascular events, mainly as a consequence of a reduction in nephropathy. There was no separately significant reduction in major macrovascular events, although a modest benefit could not be ruled out. However, it is clear that the prevention of macrovascular complications of diabetes requires a multifactorial approach32 addressing all major modifiable risk factors, including blood pressure33 and blood lipids.34 The main benefit conferred by the ADVANCE treatment regimen was a one-fifth reduction in renal complications, indicating that intensive control of glucose has an important role in the prevention of microvascular complications of type 2 diabetes.
Supported by grants from Servier (the major financial sponsor) and the National Health and Medical Research Council of Australia (211086 and 358395). Servier manufactures gliclazide (modified release) and the fixed combination of perindopril and indapamide.
Methods
The ADVANCE trial is a factorial randomized, controlled trial conducted at 215 collaborating centers in 20 countries from Asia, Australasia, Europe, and North America (see the Supplementary Appendix, available with the full text of this article at www.nejm.org). Approval to conduct the trial was obtained from the ethics committee of each study center, and all participants provided written informed consent. Detailed study methods have been published previously.16
The ADVANCE trial was an investigator-initiated trial that was designed, conducted, analyzed, and had data interpreted independently of both sponsors. Study data were collected and retained by the investigators and were not made available to the study sponsors. The writing committee and the management committee, whose membership did not include any sponsor representatives, had final responsibility for the manuscript preparation and the decision to submit for publication. The first five authors vouch for the validity and completeness of the reported data.
Participants
Eligibility criteria, as detailed previously,16 were a diagnosis of type 2 diabetes mellitus at 30 years of age or older, an age of at least 55 years at the time of study entry, and a history of major macrovascular or microvascular disease or at least one other risk factor for vascular disease. There were no inclusion or exclusion criteria related to glycated hemoglobin. Exclusion criteria included a definite indication for, or contraindication to, any of the study treatments or a definite indication for long-term insulin therapy at the time of study entry.
Study Treatment
Potentially eligible participants entered a 6-week run-in period, during which they continued their usual methods of glucose control and received a fixed combination of perindopril and indapamide. Those who tolerated and were compliant with the treatment during the run-in period were randomly assigned, according to a factorial design, to receive continued therapy with either perindopril and indapamide or matching placebo and to undergo either a strategy of intensive blood glucose control (target glycated hemoglobin value, 6.5%) or a strategy of standard glucose control (with target glycated hemoglobin levels defined on the basis of local guidelines). Central, computer-based randomization was stratified according to several factors,16 including study center and presence or absence of a history of major vascular disease.
Patients who were randomly assigned to undergo intensive glucose control were given gliclazide (modified release, 30 to 120 mg daily) and were required to discontinue any other sulfonylurea. Although the timing, selection, and doses of all other treatments were at the discretion of the treating physician, a treatment protocol was suggested (see the Supplementary Appendix). On the basis of the glycated hemoglobin level at each visit, this protocol initially advised increasing the dose of gliclazide (modified release), with the sequential addition or increase in dose of metformin, thiazolidinediones, acarbose, or insulin (advising the initial use of basal insulin, with the addition of short-acting insulin at meals for patients in whom the target glycated hemoglobin level was not achieved, despite acceptable fasting blood glucose levels). Patients in the standard-control group who were using gliclazide (modified release) when they entered the study were required to substitute this drug with another sulfonylurea, if continued therapy was required.
Follow-up Schedule
Patients in the intensive-control group were seen at week 2 after randomization; then at months 1, 2, 3, 4, and 6; and every 3 months thereafter. These patients were also encouraged to attend other, unscheduled visits to improve the monitoring and intensification of glucose control. Participants assigned to undergo standard control were seen at 3, 4, and 6 months after randomization and every 6 months thereafter. At study visits common to both groups, information was collected on blood glucose, glycated hemoglobin, blood pressure, and lipids, as well as adherence to, and tolerability of, study treatments and occurrence of study outcomes. At the 2-year, 4-year, and final visits, the ratio of urinary albumin to creatinine was measured and a retinal examination, the Mini-Mental State Examination, and quality-of-life assessment were also performed. At study visits for patients in the intensive-control group only, the information collected was limited to blood glucose, glycated hemoglobin, and glucose-lowering treatments.
Laboratory Measurements
All measurements were performed in local laboratories, and each glycated hemoglobin measurement was standardized (see the Supplementary Appendix).17 Blood glucose measurements were performed on samples of venous or capillary blood, depending on local practice.
End Points
The primary study outcomes were a composite of macrovascular events and a composite of microvascular events, considered both jointly and separately. Macrovascular events were defined as death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Microvascular events were defined as new or worsening nephropathy (i.e., development of macroalbuminuria, defined as a urinary albumin:creatinine ratio of more than 300 μg of albumin per milligram of creatinine [33.9 mg per millimole], or doubling of the serum creatinine level to at least 200 μmol per liter [2.26 mg per deciliter], the need for renal-replacement therapy, or death due to renal disease) or retinopathy (i.e., development of proliferative retinopathy, macular edema or diabetes-related blindness or the use of retinal photocoagulation therapy).
Prespecified secondary outcomes were death from any cause, death from cardiovascular causes, major coronary events (death due to coronary heart disease [including sudden death] or nonfatal myocardial infarction), total coronary events (major coronary events, silent myocardial infarction, coronary revascularization, or hospital admission for unstable angina), major cerebrovascular events (death due to cerebrovascular disease or nonfatal stroke), total cerebrovascular events (major cerebrovascular events, transient ischemic attack, or subarachnoid hemorrhage), heart failure (death due to heart failure, hospitalization for heart failure, or worsening New York Heart Association class), peripheral vascular events, all cardiovascular events, new or worsening nephropathy, new or worsening retinopathy, development of microalbuminuria (urinary albumin:creatinine ratio, 30 to 300 μg per milligram [0.34 to 33.9 mg per millimole]), visual deterioration, new or worsening neuropathy, decline in cognitive function (reduction in the Mini-Mental State Examination score by at least 3 points, as compared with the baseline score), dementia (satisfying the criteria in the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition), and hospitalization for 24 hours or more. Hypoglycemia was defined as a blood glucose level of less than 2.8 mmol per liter (50 mg per deciliter) or the presence of typical symptoms and signs of hypoglycemia without other apparent cause. Patients with transient dysfunction of the central nervous system who were unable to treat themselves (requiring help from another person) were considered to have severe hypoglycemia.
An independent End Point Adjudication Committee, unaware of the group assignments, reviewed source documentation for all suspected primary end points and deaths. An independent data and safety monitoring committee reviewed the unblinded data at regular intervals.
Statistical Analysis
The ADVANCE trial was originally designed to have a statistical power of 90% to detect a relative risk reduction of 16% or more for intensive control, as compared with standard control, for each of the primary outcomes, with the use of a two-tailed test with an alpha level of 5%. After a mean of approximately 3 years of follow-up, it became apparent that the event rates (in the two groups combined) were lower than expected. Thus, in a manner blinded to any results of the effects of intervention, two changes were made to the protocol to increase the power of the study: joint (as well as separate) analysis of the primary outcomes was prespecified, and the period of treatment and follow-up was extended by 12 months for the part of the study that evaluated the lowering of blood pressure and by 18 months for the part that evaluated the control of blood glucose.
All analyses were conducted according to the intention-to-treat principle. Effects of treatment on study end points were estimated with the use of unadjusted Cox proportional-hazard models, involving survival time to the first relevant end point in any individual patient. Data for patients were censored at their date of death, date of last visit (for those still alive at the end of the follow-up period), or date when last known to be alive (for those with unknown vital status). Differences in continuous variables between the two study groups during the follow-up period were estimated with the use of linear mixed models. The numbers needed to treat were calculated as reciprocals of the absolute differences in risk with their normally approximated 95% confidence intervals.18 All P values were two-sided, and P values less than 0.05 were considered to indicate statistical significance. No adjustment for multiple statistical testing was made.19
The homogeneity of treatment effects across subgroups (none of which were prespecified) was tested by adding interaction terms to the relevant Cox models. Interaction between the blood-pressure intervention and the blood-glucose intervention in the ADVANCE trial was assessed with the use of the database locked at the end of the period of follow-up for the blood-pressure-lowering part of the study (average duration of follow-up, 4.3 years). All analyses were performed with the use of SAS software, version 9.1 (SAS Institute).
Results
Enrollment and Baseline Characteristics of Participants
Between June 2001 and March 2003, a total of 12,877 potentially eligible participants were registered, 1737 (13.5%) were withdrawn during the run-in period, and 11,140 (86.5%) underwent randomization (Figure 1). The median duration of follow-up was 5.0 years. The two groups had similar characteristics at baseline (Table 1, and Table 1 in the Supplementary Appendix). The mean baseline glycated hemoglobin was 7.5%, and the mean fasting blood glucose level was 8.5 mmol per liter (153 mg per deciliter). At baseline, 91% of patients were receiving oral hypoglycemic agents.
Effects on Glycated Hemoglobin and Fasting Blood Glucose
At the end of the follow-up period, the mean glycated hemoglobin values were 6.5% in the intensive-control group and 7.3% in the standard-control group. During the follow-up period, the time-weighted average glycated hemoglobin level was reduced by 0.67 percentage point and the fasting blood glucose level by 1.2 mmol per liter (21.9 mg per deciliter) among patients undergoing intensive control as compared with those undergoing standard control (Figure 2).
Effects on Other Risk Factors
Table 1 describes the levels of other risk factors among study participants. At the end of the follow-up period, the mean systolic blood pressure was lower in the intensive-control group than in the standard-control group (135.5 vs. 137.9 mm Hg; average difference, 1.6 mm Hg; P<0.001) (Table 1). This difference was apparent at the first common post-randomization visit (at 3 months) and all subsequent common visits (Fig. 1 in the Supplementary Appendix). The mean body weight during the follow-up period was 0.7 kg greater in the intensive-control group than in the standard-control group (P<0.001).
Use of Glucose-Lowering Therapy and Other Treatments
On average, each patient in the intensive-control group attended 31 study visits, as compared with 11 for each patient in the standard-control group, over the course of the trial period. During the follow-up period, the use of most classes of oral hypoglycemic drug and of insulin had increased to a greater degree in the intensive-control group than in the standard-control group (Table 1, and Table 1 in the Supplementary Appendix). In the intensive-control group, 90% of patients attending the final visit were still receiving gliclazide (modified release), 70.4% of whom were taking 120 mg of the drug daily. Insulin was prescribed for 40.5% and 24.1% of patients in the intensive-control group and the standard-control group, respectively, by the end of the follow-up period. At the final visit, 16.8% of patients undergoing intensive glucose control and 10.9% of those undergoing standard glucose control were receiving thiazolidinediones. The use of blood-pressure-lowering, lipid-modifying, and antiplatelet treatments was similar between the two groups during the follow-up period.
Effects on Primary Outcomes
A total of 2125 participants had a major macrovascular or microvascular event: 18.1% in the intensive-control group and 20.0% in the standard-control group (hazard ratio, 0.90; 95% confidence interval (CI), 0.82 to 0.98; P=0.01) (Figure 3). Thus, it was estimated that such an event would be averted during a 5-year period in 1 of every 52 participants (95% CI, 30 to 213) undergoing intensive control. As compared with standard control, intensive control resulted in a significant reduction in the incidence of major microvascular events (hazard ratio, 0.86; 95% CI, 0.77 to 0.97; P=0.01) but not in the incidence of major macrovascular events (hazard ratio, 0.94; 95% CI, 0.84 to 1.06; P=0.32). There was no evidence of an interaction between the blood-pressure intervention and the blood-glucose intervention in the ADVANCE trial for the primary outcomes (P>0.50 for all comparisons).
Effects on Death and Other Secondary Outcomes
A total of 1031 participants died: 8.9% in the intensive-control group and 9.6% in the standard-control group (hazard ratio, 0.93; 95% CI, 0.83 to 1.06; P=0.28) (Figure 3). As compared with standard control, intensive control was associated with a significant reduction in renal events, including new or worsening nephropathy (hazard ratio, 0.79; 95% CI, 0.66 to 0.93; P=0.006) and new-onset microalbuminuria (hazard ratio, 0.91; 95% CI, 0.85 to 0.98; P=0.02) (Figure 4). The component of new or worsening nephropathy most clearly reduced through intensive glucose control was the development of macroalbuminuria (2.9%, vs. 4.1% with standard control; hazard ratio, 0.70; 95% CI, 0.57 to 0.85; P<0.001), with a trend toward a reduction in the need for renal-replacement therapy or death from renal causes (0.4% vs. 0.6%; hazard ratio, 0.64; 95% CI, 0.38 to 1.08; P=0.09) but no effect on the doubling of serum creatinine level (1.2% vs. 1.1%; hazard ratio, 1.15; 95% CI, 0.82 to 1.63; P=0.42). More patients undergoing intensive control were hospitalized for any cause (44.9%, vs. 42.8% of those in the standard-control group; hazard ratio, 1.07; 95% CI, 1.01 to 1.13; P=0.03), with some of the excess of hospitalizations due to severe hypoglycemia (1.1% vs. 0.7%; odds ratio, 1.52; 95% CI, 1.01 to 2.28; P=0.04). There were no significant differences between the two groups for any of the other prespecified secondary outcomes (Figure 4).
Effects on Hypoglycemia
Severe hypoglycemia occurred more frequently in the intensive-control group than in the standard-control group: 150 patients (2.7%) undergoing intensive control had at least one severe hypoglycemic episode, as compared with 81 patients (1.5%) undergoing standard control (hazard ratio, 1.86; 95% CI, 1.42 to 2.40; P<0.001). These included one fatal episode in the standard-control group and one episode resulting in permanent disability in each group. On average, the rate of severe hypoglycemic events was 0.7 event per 100 patients per year in the intensive-control group and 0.4 event per 100 patients per year in the standard-control group. Minor hypoglycemia also occurred more frequently in patients undergoing intensive control (120 events per 100 patients per year, vs. 90 with standard control). Approximately 47% of patients in the intensive-control group and 62% of those in the standard-control group remained free of any hypoglycemic event during the follow-up period.
Effects in Subgroups of Patients
The effects of intensive control on major vascular events were consistent across participant subgroups, as defined by a range of baseline characteristics (P for heterogeneity, ≥0.10 for all comparisons) (Figure 5).
|
|
| |
| |
|
|
|
