Diabetes is defined by its association with hyperglycemia-specific microvascular complications;
however, it also imparts a two- to fourfold risk of cardiovascular disease (CVD).
Although microvascular complications can lead to significant morbidity and premature
mortality, by far the greatest cause of death in people with diabetes is CVD.
Results from randomized controlled trials have demonstrated conclusively that the
risk of microvascular complications can be reduced by intensive glycemic control in
patients with type 1 (1,2) and type 2 diabetes (3–5). In the Diabetes Control and
Complications Trial (DCCT), there was an ∼60% reduction in development or progression
of diabetic retinopathy, nephropathy, and neuropathy between the intensively treated
group (goal A1C <6.05%, mean achieved A1C ∼7%) and the standard group (A1C ∼9%) over
an average of 6.5 years. The relationship between glucose control (as reflected by
the mean on-study A1C value) and risk of complications was log-linear and extended
down to the normal A1C range (<6%) with no threshold noted.
In the UK Prospective Diabetes Study (UKPDS), participants newly diagnosed with type
2 diabetes were followed for 10 years, and intensive control (median A1C 7.0%) was
found to reduce the overall microvascular complication rate by 25% compared with conventional
treatment (median A1C 7.9%). Here, too, secondary analyses showed a continuous relationship
between the risk of microvascular complications and glycemia extending into the normal
range of A1C, with no glycemic threshold.
On the basis of these two large controlled trials, along with smaller studies and
numerous epidemiologic reports, the consistent findings related to microvascular risk
reduction with intensive glycemic control have led the American Diabetes Association
(ADA) to recommend an A1C goal of <7% for most adults with diabetes (6), recognizing
that more or less stringent goals may be appropriate for certain patients. Whereas
many epidemiologic studies and meta-analyses (7,8) have clearly shown a direct relationship
between A1C and CVD, the potential of intensive glycemic control to reduce CVD events
has been less clearly defined. In the DCCT, there was a trend toward lower risk of
CVD events with intensive control (risk reduction 41% [95% CI 10–68]), but the number
of events was small. However, 9-year post-DCCT follow-up of the cohort has shown that
participants previously randomized to the intensive arm had a 42% reduction (P = 0.02)
in CVD outcomes and a 57% reduction (P = 0.02) in the risk of nonfatal myocardial
infarction (MI), stroke, or CVD death compared with those previously in the standard
arm (9).
The UKPDS of type 2 diabetes observed a 16% reduction in cardiovascular complications
(combined fatal or nonfatal MI and sudden death) in the intensive glycemic control
arm, although this difference was not statistically significant (P = 0.052), and there
was no suggestion of benefit on other CVD outcomes such as stroke. However, in an
epidemiologic analysis of the study cohort, a continuous association was observed
such that for every percentage point of lower median on-study A1C (e.g., 8–7%) there
was a statistically significant 18% reduction in CVD events, again with no glycemic
threshold.
Because of ongoing uncertainty regarding whether intensive glycemic control can reduce
the increased risk of CVD in people with type 2 diabetes, several large long-term
trials were launched in the past decade to compare the effects of intensive versus
standard glycemic control on CVD outcomes in relatively high-risk participants with
established type 2 diabetes. In 2008, two of these trials, Action in Diabetes and
Vascular Disease—Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE)
and the Veterans Affairs Diabetes Trial (VADT), were completed and showed no significant
reduction in cardiovascular outcomes with intensive glycemic control. A third trial,
Action to Control Cardiovascular Risk in Diabetes (ACCORD), terminated its glycemic
control study early due to the finding of increased mortality in participants randomized
to a strategy of very intensive glycemic control with a target A1C of <6%. The findings
of these three major trials led the ADA, with representatives of the American Heart
Association (AHA) and the American College of Cardiology (ACC), to reexamine the recommendations
for glycemic targets in patients with diabetes, the majority of whom have type 2 diabetes.
What did the ACCORD, ADVANCE, and VA Diabetes trials show?
Table 1 provides a summary of baseline characteristics, glycemic treatment strategies
and goals, concomitant risk factor control, achieved glycemic control, and primary
results of each of the three studies. The ACCORD study randomized 10,251 participants
with either history of a CVD event (aged 40–79 years) or significant CVD risk (aged
55–79 years with anatomical CVD, albuminuria, left ventricular hypertrophy, or at
least two other CVD risk factors) to a strategy of intensive glycemic control (target
A1C <6.0%) or standard glycemic control (target A1C 7.0–7.9%). Investigators used
multiple glycemic medications in both arms. ACCORD participants were on average 62
years of age and had a mean duration of diabetes of 10 years, with 35% already treated
with insulin at baseline. From a baseline median A1C of 8.1%, the intensive arm reached
a median A1C of 6.4% within 12 months of randomization, while the standard group reached
a median A1C of 7.5%. Other risk factors were treated aggressively and equally in
both groups. The intensive glycemic control group had more use of insulin in combination
with multiple oral agents, significantly more weight gain, and more episodes of severe
hypoglycemia than the standard group.
In February 2008, the glycemic control study of ACCORD was halted (embedded blood
pressure and lipid studies are ongoing) on the recommendation of the study's data
safety monitoring board due to the finding of an increased rate of mortality in the
intensive arm compared with the standard arm (1.41 vs. 1.14% per year; 257 vs. 203
deaths over a mean 3.5 years of follow-up; hazard ratio [HR] 1.22 [95% CI 1.01–1.46]);
there was a similar increase in cardiovascular deaths. The primary outcome of ACCORD
(MI, stroke, or cardiovascular death) was reduced in the intensive glycemic control
group due to a reduction in nonfatal MI, although this finding was not statistically
significant when the study was terminated (0.90 [0.78–1.04], P = 0.16).
Exploratory analyses of the mortality findings of ACCORD (evaluating variables including
weight gain, use of any specific drug or drug combination, and hypoglycemia) were
unable to identify an explanation for the excess mortality in the intensive arm (10).
In both study arms, participants with severe hypoglycemia had higher mortality than
those without severe hypoglycemia. However, there was a complex interaction between
hypoglycemia, study arm, and mortality: Among participants with at least one episode
of severe hypoglycemia, mortality was higher in those in the standard treatment arm,
while among participants with no history of severe hypoglycemia, mortality was higher
in those in the intensive treatment arm. Other prespecified subset analyses showed
that participants with no previous CVD event and those who had a baseline A1C <8%
had a statistically significant reduction in the primary CVD outcome.
The ADVANCE study randomized 11,140 participants at sites in Europe, Australia/New
Zealand, Canada, and Asia to a strategy of intensive glycemic control (with primary
therapy being the sulfonylurea gliclizide and additional medications as needed to
achieve a target A1C of ≤6.5%) or to standard therapy (in which any medication but
gliclizide could be used, with the glycemic target set according to “local guidelines”).
ADVANCE participants (required to be at least 55 years of age with either known vascular
disease or at least one other vascular risk factor) were slightly older and of a high
CVD risk similar to that in ACCORD participants. However, they had an average duration
of diabetes 2 years shorter, lower baseline A1C (median 7.2%), and almost no use of
insulin at enrollment. The median A1C levels achieved in the intensive and standard
arms were 6.3 and 7.0%, respectively, and maximal separation between the arms took
several years to achieve. Use of other drugs that favorably impact CVD risk (aspirin,
statins, ACE inhibitors) was lower in ADVANCE than in ACCORD or VADT.
The primary outcome of ADVANCE was a combination of microvascular events (nephropathy
and retinopathy) and major adverse cardiovascular events (MI, stroke, and cardiovascular
death). Intensive glycemic control significantly reduced the primary end point (HR
0.90 [95% CI 0.82–0.98], P = 0.01), although this was due to a significant reduction
in the microvascular outcome (0.86 [0.77–0.97], P = 0.01), primarily development of
macroalbuminuria, with no significant reduction in the macrovascular outcome (0.94
[0.84–1.06], P = 0.32). There was no increase in overall or cardiovascular mortality
in the intensive compared with the standard glycemic control arms (11).
VADT randomized 1,791 participants with type 2 diabetes uncontrolled on insulin or
maximal-dose oral agents (median entry A1C 9.4%) to a strategy of intensive glycemic
control (goal A1C <6.0%) or standard glycemic control, with a planned A1C separation
of at least 1.5%. Medication treatment algorithms were used to achieve the specified
glycemic goals, with a goal of using similar medications in both groups. Median A1C
levels of 6.9 and 8.5% were achieved in the intensive and standard arms, respectively,
within the first year of the study. Other CVD risk factors were treated aggressively
and equally in both groups, with the trial achieving excellent blood pressure control,
high levels of aspirin and statin usage, and a high degree of smoking cessation (12).
The primary outcome of VADT was a composite of CVD events (MI, stroke, cardiovascular
death, revascularization, hospitalization for heart failure, and amputation for ischemia).
During a median 5.6-year follow-up period, the cumulative incidence of the primary
outcome was not significantly lower in the intensive arm (HR 0.88 [95% CI 0.74–1.05],
P = 0.12). There were more CVD deaths in the intensive arm than in the standard arm
(38 vs. 29, sudden deaths 11 vs. 4), but the difference was not statistically significant.
Post hoc subgroup analyses suggested that duration of diabetes interacted with randomization
such that participants with duration of diabetes less than about 12 years appeared
to have a CVD benefit of intensive glycemic control, while those with longer duration
of disease before study entry had a neutral or even adverse effect of intensive glycemic
control. Other exploratory analyses suggested that severe hypoglycemia within the
past 90 days was a strong predictor of the primary outcome and of CVD mortality, with
an association of severe hypoglycemia with all-cause mortality apparent only for participants
in the standard arm. An embedded ancillary study within the main VADT showed that
baseline coronary or aortic calcium scores predicted future CVD events and that intensive
glycemic control significantly reduced the primary CVD end point in those with low
baseline coronary artery calcium scores but not in those with high baseline scores.
2. What are potential explanations for the increased CVD deaths with intensive glycemic
control in ACCORD?
Numerous post hoc analyses have been unable to prove or disprove causes; in fact,
the design of the study renders such “proof” elusive. Randomization to the intensive
arm was associated with or led to many downstream effects, such as higher rates of
severe hypoglycemia; more frequent use of insulin, thiazolidinediones, other drugs,
and drug combinations; and greater weight gain. Such factors may be associated statistically
with the higher mortality rate in the intensive arm but may not be causative. It is
biologically plausible that severe hypoglycemia could increase the risk of cardiovascular
death in participants with high underlying CVD risk. This might be further confounded
by the development of hypoglycemia unawareness, particularly in patients with coexisting
cardiovascular autonomic neuropathy (a strong risk factor for sudden death). Death
from a hypoglycemic event may be mistakenly ascribed to coronary artery disease, since
there may not have been a blood glucose measurement and since there are no anatomical
features of hypoglycemia detected postmortem. Other plausible mechanisms for the increase
in mortality in ACCORD include weight gain, unmeasured drug effects or interactions,
or the “intensity” of the ACCORD intervention (use of multiple oral glucose-lowering
drugs along with multiple doses of insulin, frequent therapy adjustments to push A1C
and self-monitored blood glucose to very low targets, and an intense effort to rapidly
reduce A1C by ∼2% in participants entering the trial with advanced diabetes and multiple
comorbidities).
Since the ADVANCE trial did not show any increase in mortality in the intensive glycemic
control arm, examining the differences between ADVANCE and ACCORD supports additional
hypotheses. ADVANCE participants on average appeared to have earlier or less advanced
diabetes, with shorter duration by 2–3 years and lower A1C at entry despite very little
use of insulin at baseline. A1C was also lowered, even more gradually, in the ADVANCE
trial, and there was no significant weight gain with intensive glycemic therapy. Although
severe hypoglycemia was defined somewhat differently in the three trials, it appears
that this occurred in fewer than 3% of intensively treated ADVANCE participants for
the entire study duration (median 5 years) compared with ∼16% of intensively treated
subjects in ACCORD and 21% in VADT.
It is likely that the increase in mortality in ACCORD was related to the overall treatment
strategies for intensifying glycemic control in the study population—not the achieved
A1C per se. The ADVANCE study achieved a median A1C in its intensive arm similar to
that in the ACCORD study, with no increased mortality hazard. Thus, the ACCORD mortality
findings do not imply that patients with type 2 diabetes who can easily achieve or
maintain low A1C levels with lifestyle modifications with or without pharmacotherapy
are at risk and need to “raise” their A1C.
3. Why did none of the trials show a significant benefit of intensive glycemic control
on CVD in type 2 diabetes—in contrast to many epidemiologic studies and the DCCT follow-up
study?
Although randomized controlled trials often confirm hypotheses grounded in observational
evidence or physiologic studies of surrogate end points, this is certainly not the
first time that such trials have failed to do so. The results of ACCORD, ADVANCE,
and VADT highlight the critical need for randomized controlled trials with meaningful
clinical outcomes, such as in these trials, to help answer major clinical questions.
In the three glucose-lowering trials, other CVD risk factors were treated to a moderate
or high degree, and likely due to this, all had lower rates of CVD in the standard
arm than originally predicted. The evidence for CVD prevention by statin therapy,
blood pressure treatment, aspirin therapy in high-risk participants, and other interventions
is robust. In type 2 diabetes, where other CVD risk factors are highly prevalent,
the additive benefits of intensive glycemic control might be difficult to demonstrate
except in even larger or longer trials. It is likely that a real benefit of glucose
lowering on CVD in type 2 diabetes, even if it could be proven, is modest compared
with and incremental to treatment of other CVD risk factors.
Additionally, the three trials compared treatments to A1C levels in the “flatter”
part of the observational glycemia-CVD risk curves (median A1C 6.4–6.9% in the intensive
arms compared with 7.0–8.4% in the standard arms). Their results should not be extrapolated
to imply that there would be no cardiovascular benefit of glucose lowering from very
poor control (e.g., A1C >9%) to good control (e.g., A1C <7%).
All three trials were carried out in participants with established diabetes (mean
duration 8–11 years) and either known CVD or multiple risk factors, suggesting the
presence of established atherosclerosis. Subset analyses of the three trials suggested
a significant benefit of intensive glycemic control on CVD in participants with shorter
duration of diabetes, lower A1C at entry, and/or or absence of known CVD. The finding
of the DCCT follow-up study, that intensive glycemic control initiated in relatively
young participants free of CVD risk factors was associated with a 57% reduction in
major CVD outcomes, supports the above hypothesis. Of note, the benefit on CVD in
the DCCT-EDIC (Epidemiology of Diabetes Interventions and Complications) required
9 years of follow-up beyond the end of the DCCT to become statistically significant.
A recent report (13) of 10 years of follow-up of the UKPDS cohort describes, for the
participants originally randomized to intensive glycemic control compared with those
randomized to conventional glycemic control, long-term reductions in MI (15% with
sulfonylurea or insulin as initial pharmacotherapy and 33% with metformin as initial
pharmacotherapy, both statistically significant) and in all-cause mortality (13 and
27%, respectively, both statistically significant). These findings support the hypothesis
that glycemic control early in the course of type 2 diabetes may have CVD benefit.
As is the case with microvascular complications, it may be that glycemic control plays
a greater role before macrovascular disease is well developed and a minimal or no
role when it is advanced.
People with type 1 diabetes, in whom insulin resistance does not predominate, tend
to have lower rates of coexisting obesity, hypertension, and dyslipidemia than those
with type 2 diabetes and yet are also at high lifetime risk of CVD (14). It is possible
that CVD is more strongly glycemia mediated in type 1 diabetes and that intervening
on glycemia would ameliorate CVD to a greater extent in type 1 than in type 2 diabetes.
Finally, the inability of ACCORD, ADVANCE, and VADT to demonstrate significant reduction
of CVD with intensive glycemic control could also suggest that current strategies
for treating hyperglycemia in patients with more advanced type 2 diabetes may have
counter-balancing consequences for CVD (such as hypoglycemia, weight gain, or other
metabolic changes). Results of long-term CVD outcome trials utilizing specific antihyperglycemic
drugs, intensive lifestyle therapy (such as the Look AHEAD [Action for Health in Diabetes]
study), bariatric surgery, or other emerging therapies may shed light on this issue.
4. What are the implications of these findings for clinical care?
The benefits of intensive glycemic control on microvascular and neuropathic complications
are well established for both type 1 and type 2 diabetes. The ADVANCE trial has added
to that evidence base by demonstrating a significant reduction in the risk of new
or worsening albuminuria when median A1C was lowered to 6.3% compared with standard
glycemic control achieving an A1C of 7.0%. The lack of significant reduction in CVD
events with intensive glycemic control in ACCORD, ADVANCE, and VADT should not lead
clinicians to abandon the general target of an A1C <7.0% and thereby discount the
benefit of good control on serious and debilitating microvascular complications.
The ADA's Standards of Medical Care in Diabetes (6) and the AHA and ADA's scientific
statement on prevention (15) advocate controlling nonglycemic risk factors (through
blood pressure control, lipid lowering with statin therapy, aspirin therapy, and lifestyle
modifications) as the primary strategies for reducing the burden of CVD in people
with diabetes. The lower-than-predicted CVD rates in ACCORD, ADVANCE, and VADT, as
well as the recent long-term follow-up of the Steno-2 multiple risk factor intervention
(16), provide strong confirmation of the concept that comprehensive care for diabetes
involves treatment of all vascular risk factors—not just hyperglycemia.
The evidence for a cardiovascular benefit of intensive glycemic control remains strongest
for those with type 1 diabetes. However, subset analyses of ACCORD, ADVANCE, and VADT
suggest the hypothesis that patients with shorter duration of type 2 diabetes and
without established atherosclerosis might reap cardiovascular benefit from intensive
glycemic control. Conversely, it is possible that potential risks of intensive glycemic
control may outweigh its benefits in other patients, such as those with a very long
duration of diabetes, known history of severe hypoglycemia, advanced atherosclerosis,
and advanced age/frailty. Certainly, providers should be vigilant in preventing severe
hypoglycemia in patients with advanced disease and should not aggressively attempt
to achieve near-normal A1C levels in patients in whom such a target cannot be reasonably
easily and safely achieved.
The evidence obtained from ACCORD, ADVANCE, and VADT does not suggest the need for
major changes in glycemic control targets but, rather, additional clarification of
the language that has consistently stressed individualization:
Microvascular disease: Lowering A1C to below or around 7% has been shown to reduce
microvascular and neuropathic complications of type 1 and type 2 diabetes. Therefore,
the A1C goal for nonpregnant adults in general is <7%. ADA, A-level recommendation;
ACC/AHA, class I recommendation (level of evidence A).
Macrovascular disease: In type 1 and type 2 diabetes, randomized controlled trials
of intensive versus standard glycemic control have not shown a significant reduction
in CVD outcomes during the randomized portion of the trials. However, long-term follow-up
of the DCCT and UKPDS cohorts suggests that treatment to A1C targets below or around
7% in the years soon after the diagnosis of diabetes is associated with long-term
reduction in risk of macrovascular disease. Until more evidence becomes available,
the general goal of <7% appears reasonable. ADA, B-level recommendation; ACC/AHA,
class IIb recommendation (level of evidence A).
For some patients, individualized glycemic targets other than the above general goal
may be appropriate:
Subgroup analyses of clinical trials such as the DCCT and UKPDS and the microvascular
evidence from the ADVANCE trial suggest a small but incremental benefit in microvascular
outcomes with A1C values closer to normal. Therefore, for selected individual patients,
providers might reasonably suggest even lower A1C goals than the general goal of <7%
if this can be achieved without significant hypoglycemia or other adverse effects
of treatment. Such patients might include those with short duration of diabetes, long
life expectancy, and no significant cardiovascular disease. ADA, B-level recommendation;
ACC/AHA, class IIa recommendation (level of evidence C).
Conversely, less stringent A1C goals than the general goal of <7% may be appropriate
for patients with a history of severe hypoglycemia, limited life expectancy, advanced
microvascular or macrovascular complications, or extensive comorbid conditions or
those with long-standing diabetes in whom the general goal is difficult to attain
despite diabetes self-management education, appropriate glucose monitoring, and effective
doses of multiple glucose-lowering agents including insulin. ADA, C-level recommendation;
ACC/AHA, class IIa recommendation (level of evidence C).
For primary and secondary CVD risk reduction in patients with diabetes, providers
should continue to follow the evidence-based recommendations for blood pressure treatment,
including lipid-lowering with statins, aspirin prophylaxis, smoking cessation, and
healthy lifestyle behaviors delineated in the ADA Standards of Medical Care in Diabetes
(6) and the AHA/ADA guidelines for primary CVD prevention (15).