Curr Cardiol Rep (2012) 14:79–88
`DOI 10.1007/s11886-011-0238-6
`
`DIABETES AND CARDIOVASCULAR DISEASE (ND WONG, SECTION EDITOR)
`
`Does Aggressive Glycemic Control Benefit
`Macrovascular and Microvascular Disease in Type 2
`Diabetes?: Insights from ACCORD, ADVANCE, and VADT
`
`Toni Terry & Kalyani Raravikar &
`Nalurporn Chokrungvaranon & Peter D. Reaven
`
`Published online: 13 December 2011
`# Springer Science+Business Media, LLC 2011
`
`Abstract Diabetes is increasing rapidly worldwide and
`frequently results in severe vascular complications. A target
`glycated hemoglobin of less than 7% has commonly been
`recommended in hopes of preventing both macrovascular and
`microvascular complications. Although results from trials of
`intensive glycemic control have generally supported the
`notion that lower glycated hemoglobin values reduce micro-
`vascular disease, the evidence for similar benefits for macro-
`vascular disease has been less clear. As macrovascular disease
`is the major cause of morbidity and mortality in type 2
`diabetes, this remains one of the more important unresolved
`
`T. Terry (*) : P. D. Reaven
`Division of Endocrinology,
`Phoenix VA Health Care System,
`650 East Indian School Road,
`Phoenix, AZ 85012, USA
`e-mail: toni.terry@va.gov
`
`P. Reaven
`e-mail: peter.reaven@va.gov
`
`K. Raravikar
`Research Department, Endocrine Section,
`Phoenix VA Health Care System,
`650 East Indian School Road,
`Phoenix, AZ 85012, USA
`e-mail: kate2kalyani@gmail.com
`
`N. Chokrungvaranon
`Endocrinology, University of Missouri Kansas City,
`2301 Holmes Street,
`Kansas City, MO 64108, USA
`e-mail: nalurporn@yahoo.com
`
`P. D. Reaven
`Arizona State University,
`Tempe, AZ, USA
`
`P. D. Reaven
`University of Arizona,
`Phoenix, AZ, USA
`
`clinical questions. Recent results from the ACCORD,
`ADVANCE, and VADT studies have challenged the conven-
`tional believe that lower glycated hemoglobin values should
`be pursued in all diabetic patients. Factors that may influence
`whether intensive glucose management is advisable include
`duration of diabetes, pre-existing macrovascular disease,
`hypoglycemic unawareness, and significant comorbidities.
`Glycated hemoglobin goals should account for these factors
`and be individualized for each patient.
`
`Keywords Type 2 diabetes . Macrovascular disease .
`Microvascular disease . Intensive glycemic control . UGDP.
`UKPDS . ACCORD . ADVANCE . VADT . Coronary artery
`calcium . Atherosclerosis . Diabetes duration .
`Hypoglycemic unawareness . Glycated hemoglobin .
`Advanced glycation end products . Metabolic memory
`
`Clinical Trial Acronyms
`ACCORD
`Action to Control Cardiovascular Risk in
`Diabetes
`ADVANCE Action in Diabetes and Vascular Disease:
`Preterax and Diamicron Modified Release
`Controlled Evaluation
`Diabetes Control and Complications Trial
`University Group Diabetes Program
`United Kingdom Prospective Diabetes Study
`Veterans Affairs Diabetes Trial
`
`DCCT
`UGDP
`UKPDS
`VADT
`
`Introduction
`
`By the year 2030, it is estimated that 366 million people
`worldwide will have diabetes mellitus [1]. This predicted
`increase parallels the advancing age of the population,
`rising rates of obesity throughout the world, and sedentary
`lifestyles. Diabetes can result in significant macrovascular
`
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`Curr Cardiol Rep (2012) 14:79–88
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`and microvascular complications. Coronary artery disease,
`peripheral vascular disease, and stroke are well-recognized
`macrovascular complications, whereas retinopathy, nephrop-
`athy, and neuropathy are the more common microvascular
`disease manifestations.
`The impact of hyperglycemia and its association with
`macrovascular disease has been examined in numerous
`studies. Several cohort studies,
`including the Diabetes
`Intervention Study [2], the San Antonio Heart Study [3],
`and the Framingham Study [4], have demonstrated a two-
`to fourfold increase in cardiovascular disease risk associated
`with either elevated glycated hemoglobin or fasting glucose.
`The consequences of cardiovascular disease are greater in
`patients with diabetes because death after acute myocardial
`infarction is 50% more common [5] and congestive heart
`failure is more common after acute myocardial infarction
`compared with nondiabetic patients [6]. Cardiovascular
`disease and stroke account for the highest percentage of
`deaths in people with diabetes even when other risk factors
`such as smoking, hyperlipidemia, and hypertension are
`considered.
`Intensive glycemic control has been suggested as an
`effective treatment to reduce the burden of both macro-
`vascular and microvascular disease. Until recently, guide-
`lines by most health organizations have recommend a
`glycated hemoglobin goal of 7% or below without clear
`guidance as to whether other patient characteristics such as
`duration of diabetes, patient frailty, presence of pre-existing
`vascular disease, or concomitant illnesses should modify
`this goal. However, the optimal goal for glycemic control
`has been disputed since the publication of results from
`several recent studies including ACCORD, ADVANCE,
`and VADT.
`This article reviews earlier studies as well as recent
`pivotal studies to help place these many diverse findings
`into a broader clinical context. An additional goal of this
`review is to help identify which subgroups may or may not
`benefit from more aggressive glycemic control.
`
`Earlier Studies in Type 2 Diabetes: UGDP and UKPDS
`
`UGDP
`
`tolbutamide had a higher rate of death from cardiovascular
`causes (12.7% vs 4.9%) than the placebo group. Even
`though there has been widespread criticism of UGDP, this
`study was one of the first to raise concern about glycemic
`management and its impact on cardiovascular mortality.
`
`UKPDS
`
`The UKPDS randomized 4209 patients with newly diag-
`nosed type 2 diabetes in 23 centers within the United
`Kingdom between 1977 and 1991 [8]. Consistent with their
`recent diagnosis of diabetes, participants were younger than
`those in ACCORD, ADVANCE, and VADT with a mean
`age of 53.3 years (Table 1). Baseline mean glycated
`hemoglobin was similar
`to mean entry values in the
`ADVANCE study at 7.1% but lower than those found in
`ACCORD and VADT studies. Participants in the UKPDS
`were assigned to receive conventional therapy with dietary
`restriction or
`intensive therapy (either sulfonylurea or
`insulin, or, in overweight patients, metformin). The UKPDS
`was designed to establish whether intensive blood glucose
`control reduced the risk of macrovascular or microvascular
`complications in type 2 diabetes. Although glucose levels
`fluctuated over the 10-year study duration,
`the median
`glycated hemoglobin in the intensive group was 7.0%
`compared with 7.9% in the conventional group. Intensive
`glycemic therapy was associated with a 25% reduction in
`microvascular disease; however, most of this reduction was
`attributed to fewer patients requiring photocoagulation.
`There was a nonsignificant reduction in relative risk of
`myocardial infarction (16% risk reduction; P=0.052), but
`no overall decrease in macrovascular disease. In subgroup
`analyses of intensive therapy patients allocated to metfor-
`min there was a risk reduction of 32% (P=0.0023) for any
`diabetes-related end point
`including macrovascular and
`microvascular complications, a 42% risk reduction (P=
`0.017) for diabetes-related death, and a 36% risk reduction
`for all-cause mortality (P= 0.011) compared with the
`conventional group. This data suggests that
`intensive
`glucose control with metformin appears to decrease the
`risk of diabetes-related end points in overweight diabetic
`patients [9].
`
`UKPDS Follow-Up
`
`the first
`The UGDP completed in 1969 was one of
`randomized controlled trials conducted to assess the benefit
`of lowering blood glucose on the incidence of diabetes
`complications [7]. A total of 823 type 2 diabetic patients
`were randomly assigned to placebo, sulfonylurea (tolbuta-
`mide), or insulin to determine if use of a hypoglycemic
`agent could decrease vascular complications compared with
`placebo and insulin. The study failed to demonstrate a
`benefit for cardiovascular risk reduction. In fact, patients on
`
`After completion of the active intervention study, differ-
`ences in glycated hemoglobin levels between the standard
`and intensive glycemic groups disappeared after the first
`year. Participants were followed for an additional 10 years,
`either at annual clinic visits for the first 5 years, or with
`follow-up questionnaires subsequently. In the combined
`group assigned to treatment with either sulfonylurea or
`insulin, persistent and now significant relative risk reduc-
`
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`Curr Cardiol Rep (2012) 14:79–88
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`81
`
`Trial
`massindex;FPGfastingplasmaglucose;HbA1chemoglobinA1c;NSnotstated;TZDthiazolidinedione;UKPDSUnitedKingdomProspectiveDiabetesStudy;VADTVeteransAffairsDiabetes
`ACCORDActiontoControlCardiovascularRiskinDiabetes;ADVANCEActioninDiabetesandVascularDisease:PreteraxandDiamicronModifiedReleaseControlledEvaluation;BMIbody
`aMedianachievedHbA1cover10years
`
`+3.4
`
`125/69
`86
`83
`42
`
`8.4
`5.6
`
`+7.8
`
`127/69
`88
`85
`53
`NS
`6.9
`5.6
`
`−1.0
`
`138/74
`55
`48
`11
`24
`7.3
`5.0
`
`−0.1
`
`136/74
`57
`46
`17
`41
`6.5
`5.0
`
`HbA1c≥9%
`treatment.Insulinif
`
`Halfdosesofintensive
`
`separationof1.5
`
`Planned
`Standard
`
`HbA1cof≥6%
`rosiglitazone.Insulinif
`<27kg/m2:glimepiride+
`rosiglitazone.BMI
`doseofmetformin+
`BMI>27kg/m2:max
`
`<6(actionif>6.5)
`Intensive
`52
`9.4
`
`40
`11.5
`60.4
`97/3
`1791
`
`VADT
`
`physician
`atdiscretionof
`othertreatment
`
`ofphysician
`atthediscretion
`othertreatment
`
`Nogliclazide,
`
`Gliclazide+
`
`localguidelines
`
`Goalbasedon
`Standard
`
`≤6.5
`Intensive
`1.5
`7.5
`
`32
`
`8
`
`65.8
`57/43
`11,140
`
`7.0–7.9
`Standard
`
`<6
`Intensive
`35
`8.3
`
`35
`10
`62.2
`61/39
`10,251
`
`+0.4
`
`+3.5
`
`127/68
`76
`88
`58
`55
`7.5
`3.4
`
`126/67
`76
`88
`91
`77
`6.4
`3.4
`
`physician
`thediscretionof
`and/orinsulinat
`loweringagent
`Differentglucose-
`
`NS
`
`NS
`NS
`NS
`NS
`23
`7.9a
`10
`
`NS
`
`NS
`NS
`NS
`NS
`55
`7.0a
`10
`
`Weightchanges(kg)
`studyend(mmHg)
`Meanbloodpressureat
`Onaspirinatstudyend(%)
`Onstatinatstudyend(%)
`OnTZDatstudyend(%)
`Oninsulinatstudyend(%)
`MedianHbA1cachieved
`Medianfollow-up(y)
`On-studycharacteristics
`
`ofdrugs
`thenaddition
`270mg/dL
`
`Diet,ifFPG>
`
`withdiet
`
`Bestachievable
`Standard
`
`metformin
`insulin,
`
`Sulfonylurea,
`
`FPG<108mg/dL
`Intensive
`
`0
`
`7.1
`
`6
`
`Newlydiagnosed
`53.3
`61/39
`3867
`
`Treatmentstrategy
`
`HbA1cgoal(%)
`
`Studyprotocol
`
`Oninsulin(%)
`MeanHbA1c(%)
`disease(%)
`Historyofmacrovascular
`Durationofdiabetes(y)
`Meanage(y)
`Gendermale/female(%)
`
`N
`
`Baselinecharacteristics
`
`ADVANCE
`
`ACCORD
`
`UKPDS
`
`Table1Baselineandon-studycharacteristicsofsubjectsintheUKPDS,ACCORD,ADVANCE,andVADTstudies
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`82
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`Curr Cardiol Rep (2012) 14:79–88
`
`tions of 15% for myocardial infarction and 13% for death
`of any cause were seen as more events occurred over time
`[10(cid:129)(cid:129)]. Furthermore, the significant reduction of 25% in the
`risk of microvascular disease observed during the interven-
`tional
`trial
`in the intensive therapy group persisted
`throughout the post-trial period (Table 2).
`improved
`Thus,
`the UKPDS showed a benefit of
`glycemic control
`in reducing the risk of microvascular
`disease during the interventional trial, but the risk reduction
`for myocardial infarction and death from any cause were
`observed only with extended post-trial follow-up. Persistent
`and long-term benefits for microvascular disease reduction
`noted in the post-trial UKPDS follow-up, despite the early
`loss of within-trial differences in glycated hemoglobin
`between the intensive therapy group and the conventional
`therapy group in the first year after trial completion, have
`been termed a “legacy effect.” One of
`the proposed
`concepts to explain this purported extended legacy effect
`is metabolic memory. This is the concept whereby the early
`glycemic environment is remembered by target organs and
`affects future vascular changes [11–13]. The legacy effect is
`also supported by long-term monitoring data after comple-
`tion of the DCCT. Results from this epidemiologic follow-
`up demonstrated that prior intensive diabetes therapy in
`
`type 1 diabetes reduced the risk of any cardiovascular
`disease event by 42% (P=0.02) and the risk of nonfatal
`myocardial infarction, stroke, or death from cardiovascular
`disease by 57% (P=0.02) [14].
`
`ACCORD
`
`The ACCORD trial was specifically designed to determine
`whether
`targeting normal glycated hemoglobin levels
`(<6.0%) would reduce the rate of cardiovascular events
`compared with targeting levels from 7.0% to 7.9% in type 2
`diabetic patients with established cardiovascular disease or
`additional risk factors [15(cid:129)(cid:129)]. The primary outcome was a
`composite of nonfatal myocardial
`infarction, nonfatal
`stroke, or death from cardiovascular causes. After recruit-
`ment, 10,251 participants were randomized to receive
`intensive glucose-lowering therapy with oral agents, insu-
`lin, or both to achieve specified glycated hemoglobin
`values. Participants had long-standing diabetes (~10 years),
`a mean age of 62.2 years, and a mean glycated hemoglobin
`level of 8.3% (Table 1). Previous cardiovascular events
`were reported in 35% of the study participants. Intensive
`and standard therapeutic strategies rapidly achieved differ-
`
`Table 2 Outcomes for subjects in the UKPDS, ACCORD, ADVANCE, and VADT studies
`
`Outcomes
`
`Primary outcome
`
`Risk for primary outcome (95% CI)
`
`UKPDS
`Aggregate of any diabetes-related
`end point, diabetes-related death,
`all-cause mortality
`RR any diabetes-related end
`point 0.88 (0.79–0.99)
`RR diabetes-related death 0.90
`(0.73–1.11)
`RR 0.94 (0.8–1.1)
`NS as combined end point
`RR fatal MI 0.94 (0.68–1.30)
`RR fatal stroke 1.17 (0.54–2.54)
`RR 0.79 (0.58–1.09)
`Risk for nonfatal MI (95% CI)
`RR 1.07 (0.68–1.69)
`Risk for nonfatal stroke (95% CI)
`Risk for microvascular disease (95% CI) RR 0.75 (0.6–0.93)
`
`Risk for total mortality (95% CI)
`Risk for CV mortality (95% CI)
`
`ACCORD
`Composite of nonfatal
`MI, nonfatal stroke,
`and CV death
`HR 0.90 (0.78–1.04)
`
`ADVANCE
`Composite of major macrovascular
`and microvascular events
`
`VADT
`Composite of major
`CV events
`
`HR 0.90 (0.82–0.98)
`
`HR 0.88 (0.74–1.05)
`
`HR 1.22 (1.01–1.46)
`HR 1.35 (1.04–1.76)
`
`HR 0.93 (0.83–1.06)
`HR 0.88 (0.74–1.04)
`
`HR 1.07 (0.81–1.42)
`HR 1.32 (0.81–2.14)
`
`HR 0.76 (0.62–0.92)
`HR 1.06 (0.75–1.50)
`NS
`
`HR 0.98 (0.78–1.23)
`HR 1.02 (0.85–1.24)
`HR 0.86 (0.77–0.97)
`
`NS
`NS
`NS
`
`Follow-up studies
`
`UKPDS
`
`ACCORD
`
`Microvascular intensive
`Sulfonylurea-insulin
`After 16.8 y, 25% relative
`reduction in risk of
`microvascular complication
`
`Microvascular intensive Macrovascular intensive
`Metformin
`Sulfonylurea-insulin
`No significant risk
`After 16.8 y, 15% risk
`reductions during
`reduction for MI
`or after the trial in
`13% risk reduction from
`microvascular
`death of any cause
`disease
`
`Macrovascular intensive
`Metformin
`After 17.7 y, 33%
`risk reduction in
`MI, 27% reduction
`from death
`of any cause
`
`After 5 y, reduced nonfatal
`MIs but increased 5-y
`mortality
`
`ACCORD Action to Control Cardiovascular Risk in Diabetes; ADVANCE Action in Diabetes and Vascular Disease: Preterax and Diamicron
`Modified Release Controlled Evaluation; CV cardiovascular; HR hazard ratio; MI myocardial infarction; NS not stated; RR relative risk; UKPDS
`United Kingdom Prospective Diabetes Study; VADT Veterans Affairs Diabetes Trial
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`Curr Cardiol Rep (2012) 14:79–88
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`83
`
`ent glycated hemoglobin levels, and within 4 months of
`randomization the level had fallen from 8.1% at baseline to
`6.7% in the intensive therapy group and to 7.5% in the
`standard therapy group. At 1 year, stable median levels of
`6.4% in the intensive group and 7.5% in the standard group
`had been achieved and were maintained until increased
`mortality was observed in the intensive therapy group.
`Differences in mortality emerged 1–2 years after random-
`ization. Compared with the standard therapy group, the
`intensive therapy group had a relative increase in mortality
`of 22%. The finding of higher mortality in the intensive
`therapy group led to discontinuation of intensive therapy
`after a mean of 3.5 years of follow-up. The increase in
`mortality was equivalent to approximately one extra death
`(primarily from cardiovascular causes) for every 95 patients
`treated for 3.5 years. As a result of these findings, intensive
`therapy group subjects were subsequently transitioned to
`standard therapy and followed until study completion
`(median of 5 years). After this transition,
`the median
`glycated hemoglobin level in the intensive group rose from
`6.4% to 7.2%.
`The lower glycated hemoglobin levels in the intensive
`therapy group were associated with a greater exposure to
`diabetes medications and participants within this group had
`more frequent changes in the dose or the number of study
`drugs used. In contrast to the standard therapy group, the
`intensive therapy group had significantly higher rates of
`hypoglycemia, weight gain, and fluid retention. Although
`many explanations for the increased mortality in ACCORD
`have been proposed,
`including rapid reduction of high
`glycated hemoglobin values or maintenance of glycated
`hemoglobin at near-normal levels, hypoglycemia, effects of
`drugs or drug combinations, and weight gain [16], none
`have been definitively supported in post hoc analyses. Of
`note, analyses by Riddle et al. [17] have implicated factors
`associated with persistent higher glycated hemoglobin
`levels rather than low glycated hemoglobin levels as likely
`contributors to the increased mortality associated with
`intensive glycemic control. Specifically, the risk of death
`appeared to be greater with intensive glycemic control
`compared with the standard therapy group only when the
`average glycated hemoglobin was greater than 7%.
`
`ACCORD Macrovascular Results
`
`At 3.5 years of follow-up, the primary outcome occurred in
`352 participants in the intensive therapy group compared
`with 371 participants in the standard therapy group (Table 2;
`hazard ratio, 0.90; P=0.16). Thus,
`the use of intensive
`therapy to target normal glycated hemoglobin levels
`resulted in increased mortality and did not significantly
`reduce major cardiovascular events. As previously men-
`tioned, participants in the intensive therapy group were
`
`transitioned to the standard therapy regimen and
`followed for
`the remaining 17 months to complete
`the planned 5-year trial. At the end of the 5-year trial,
`the median glycated hemoglobin levels were 7.2% in
`the intensive therapy group and 7.6% in the standard
`therapy group. The overall rate of nonfatal myocardial
`infarction in the intensive therapy group was lower
`than in the standard therapy group (1.18% vs 1.42%;
`hazard ratio, 0.82; 95% CI, 0.70–0.96; P= 0.01) [18(cid:129)(cid:129)].
`However, analysis at the end of 5 years showed a 19%
`higher rate of death from any cause in the intensive
`therapy group compared with the standard therapy group
`(1.53% vs 1.27%; 95% CI, 1.03–1.38; P= 0.02). There
`were no clear differences in any of the other predefined
`cardiovascular outcomes. Thus,
`the use of
`intensive
`therapy for 3.5 years to target a glycated hemoglobin
`level below 6% reduced 5-year nonfatal myocardial
`infarctions but
`increased 5-year mortality. Based on
`results from ACCORD, a similar strategy of intensive
`glycemic control aiming toward a glycated hemoglobin
`of
`less than 6% cannot be recommended in patients
`with advanced type 2 diabetes and a high risk of
`cardiovascular disease.
`Although there was no overall benefit for the whole
`group, prespecified subgroup analyses indicated there
`were fewer cardiovascular events in patients without a
`previous history of cardiovascular disease events (~5%
`vs 11%) or with a baseline glycated hemoglobin of
`8.0% or
`less
`(~6% vs 8%). This
`indicates
`that
`participants with less “advanced” diabetes may in fact
`benefit
`from intensive glycemic control.
`In contrast,
`those with pre-existing cardiovascular disease or higher
`baseline glycated hemoglobin levels may be at greater
`risk of cardiovascular events if aggressive glycemic
`control
`is rapidly achieved following the ACCORD
`approach.
`
`ACCORD Microvascular Results
`
`ACCORD also had predefined secondary end points to
`assess the effect of intensive therapy on the incidence and
`progression of retinopathy, nephropathy, and neuropathy.
`Composite outcomes of advanced nephropathy, diabetic eye
`complications, and neuropathy did not differ between
`groups at the point of transition or at the official study
`end. However, intensive therapy was associated with a 21%
`reduction in the development of microalbuminuria at the
`point of transition and a 15% reduction at the end of the 5-
`year study. Furthermore,
`the risk of development of
`macroalbuminuria was 31% lower with intensive therapy
`at transition and 28% lower at study end. Macroalbumi-
`nuria is a known risk factor for renal insufficiency [19] and
`cardiovascular disease [20]. These findings support
`the
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`
`benefits of glycemic control for reduction of albuminuria
`and raise the possibility that longer-term follow-up may
`reveal improvements in clinical renal disease and possibly
`macrovascular outcomes.
`
`reduction (particularly albuminuria) with intensive therapy
`but there was no significant difference in major macro-
`vascular events or all-cause mortality between intensive
`therapy and standard control groups.
`
`ADVANCE
`
`VADT
`
`The ADVANCE trial was designed to assess the effects of
`lowering the glycated hemoglobin value to a target of 6.5%
`or less on major macrovascular and microvascular out-
`comes in an international cross-section of patients with type
`2 diabetes [21]. The global study included 11,140 partic-
`ipants whose original diagnosis of diabetes occurred at ≥
`30 years of age. Participants were older with a longer
`duration of diabetes, had a history of microvascular (27%
`of participants had microalbuminuria) or major macro-
`vascular disease (32% of participants), or at least one other
`risk factor for vascular disease (Table 1). Subjects were
`randomized to intensive glucose-lowering therapy (target
`glycated hemoglobin of ≤6.5%) or standard therapy where
`target glycated hemoglobin was locally established.
`After a mean of 5 years of follow-up,
`the glycated
`hemoglobin was lower in the intensive control group
`(6.5%) than in the standard control group (7.3%).
`There was a significant 10% relative reduction in the
`combined outcome of major macrovascular and microvas-
`cular events seen in the intensive glucose control group in
`this study. However, this was mainly the result of a 21%
`relative reduction in the risk of new or worsening
`nephropathy. There were no significant differences between
`intensive and standard control groups in all-cause mortality
`(hazard ratio with intensive control, 0.93; 95% CI, 0.83–
`1.06; P=0.28) or death from cardiovascular causes (hazard
`ratio with intensive control, 0.88; 95% CI, 0.74–1.04; P=
`0.12). The development of macroalbuminuria (2.9% vs
`4.9%; hazard ratio, 0.70; 95% CI, 0.57–0.85; P<0.001) was
`significantly reduced in the intensive therapy arm compared
`with the standard control. No significant treatment effect
`was seen with retinopathy. Rates of severe hypoglycemia
`were 2.7% in the intensive therapy group compared with
`1.5% in the standard control group (P<0.001).
`Even though ADVANCE participants were diverse in
`locality and ethnicity,
`the effects of intensive glycemic
`control were not significantly different between regions for
`any outcome, including mortality, vascular end points, and
`severe hypoglycemic episodes [22(cid:129)]. Similar to the AC-
`CORD study, ADVANCE participants without a history of
`macrovascular disease tended to have slightly better
`responses to intensive glycemic control; specifically, a
`nonsignificant 14% versus 4% relative risk reduction for
`combined major macrovascular and microvascular events.
`Overall,
`there was a clear benefit
`for microvascular
`
`The VADT randomized 1791 military veterans with type 2
`diabetes who had a suboptimal response to therapy (mean
`baseline glycated hemoglobin 9.4%). The mean age of
`participants was 60.4 years, mean number of years since the
`diagnosis of diabetes was 11.5, and 40% had a previously
`documented cardiovascular event (Table 1). Participants
`were randomized to either
`intensive therapy (goal of
`absolute reduction by 1.5 percentage points in the glycated
`hemoglobin level) or standard therapy. The primary
`outcome was the time from randomization to the first
`occurrence of any composite of cardiovascular events with
`all-cause mortality assessed as a secondary outcome [23(cid:129)(cid:129)].
`Median follow-up for participants was 5.6 years. The
`median glycated hemoglobin levels stabilized after 6 months
`of treatment at 8.4% in the standard therapy group and
`6.9% in the intensive therapy group.
`Comparison between intensive therapy and standard
`therapy failed to show any statistical differences in both
`primary and secondary outcomes. The primary outcome
`was observed in 264 patients in the standard therapy group
`versus 235 patients in the intensive therapy group (Table 2,
`hazard ratio, 0.88). Death from any cause was nonsignif-
`icantly higher in the intensive therapy group (hazard ratio,
`1.07). Although intensive glycemic control did not show
`any significant benefit with regard to reduction in retinop-
`athy, major nephropathy, or neuropathy compared with
`standard therapy,
`there was a significant reduction in
`worsening of albuminuria. In particular, participants with
`pre-existing microvascular eye disease, greater body
`weight, lower diastolic blood pressure, and higher levels
`of baseline albuminuria appeared to have the greatest
`attenuation in progression of albuminuria when intensive
`glucose-lowering therapy was pursued [24(cid:129)].
`As in several other intensive glucose-lowering therapy
`trials,
`there was a significant amount of hypoglycemia
`observed in the VADT trial (1566 hypoglycemic episodes
`per 100 patient-years in the intensive control group vs 432
`hypoglycemic episodes per 100 patient-years in the
`conventional control group). A recent severe hypoglycemic
`episode was an important predictor for cardiovascular death
`(hazard ratio, 3.72; 95% CI, 1.34–10.4; P<0.01) and all-
`cause mortality (hazard ratio, 6.37; 95% CI, 2.57–15.8; P=
`0.001) as reported by Duckworth et al. [25] at the American
`Diabetes Association Scientific Sessions in 2009 in New
`Orleans, Louisiana. In summary, in the whole cohort, the
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`85
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`overall benefit of decreasing glycated hemoglobin from 8.4%
`to 6.9% over a period of 5–6 years was modest and was
`primarily limited to reduced progression of albuminuria. Since
`97% of participants were men, one cannot extrapolate these
`findings to women; although the results are consistent with
`those in the ACCORD and ADVANCE studies.
`
`Baseline Atherosclerosis Indicates Response to Therapy
`in the VADT
`
`In a substudy cohort of 301 type 2 diabetes participants in
`VADT, baseline coronary atherosclerosis was assessed
`using coronary artery calcium (CAC) measured by com-
`puted tomography to determine whether the initial extent of
`vascular disease influenced responsiveness to glucose-
`lowering therapy [26(cid:129)]. In fact, the benefit of intensive
`glycemic control was impressive (hazard ratio, 0.08; 95%
`CI, 0.008–0.77; P=0.03) for those with lower CAC (<100
`Agatston units) but no significant improvement in cardio-
`vascular outcomes was seen between intensive therapy and
`standard therapy when CAC scores were greater than 100.
`Importantly, the level of risk factors was not significantly
`different between these two groups of subjects, and
`adjustment for relevant risk factors did not reduce the
`importance of baseline CAC as a predictor of response to
`therapy. Thus, this subgroup analysis indicates that inten-
`sive glycemic therapy may be most effective in those with
`less extensive coronary atherosclerosis, whereas those with
`more extensive underlying atherosclerosis may not experi-
`ence a significant reduction in macrovascular outcomes. As
`nearly 60% of this VADT subset of participants had CAC
`greater than 100 units, and this group appeared represen-
`tative of the entire VADT cohort, this may explain the
`overall negative results in the VADT.
`Just as underlying cardiovascular disease may predict
`whether a patient benefits from intensive glycemic control,
`duration of diabetes may also be an important factor to
`consider. In post hoc analyses of the VADT data, duration
`of diabetes at baseline was significantly related to cardio-
`vascular outcomes with intensive glucose-lowering treat-
`ment. In subjects with less than 15 years of diabetes at the
`time of enrollment, intensive glycemic control significantly
`reduced cardiovascular outcomes. In contrast, with more
`than 15 years of diabetes, intensive treatment was associ-
`ated with increased cardiovascular events and was signif-
`icantly worse than standard therapy after 20 years or more
`of diabetes [25]. One possible explanation for this lack of
`benefit in those with a greater duration of diabetes may
`involve the accumulation of advanced glycation end
`products (AGEs) that exert atherogenic effects [27, 28].
`Prolonged elevation of glucose concentrations over many
`years results in increased accumulation of AGEs, which
`may take years to be cleared. This phenomenon could
`
`potentially account for the limited reduction in macro-
`vascular disease seen with intensive glycemic control in
`patients with poorly controlled, well-established diabetes.
`
`Meta-Analyses of Trials of Intensive Glucose-Lowering
`Therapy
`
`intensive glucose lowering affects all-cause
`Whether
`mortality, cardiovascular death, and microvascular events
`in type 2 diabetes has also been evaluated in several meta-
`analyses of randomized controlled trials. In the largest and
`most recent meta-analysis by Boussageon et al. [29(cid:129)(cid:129)], 13
`studies were included. Of the 34,533 patients evaluated,
`18,315 received intensive glucose-lowering treatment and
`16,218 standard treatment. Intensive treatment did not
`significantly affect all-cause mortality or cardiovascular
`death. However,
`intensive therapy was associated with
`reductions in the risk of nonfatal myocardial
`infarction
`(hazard ratio, 0.85; 99% CI, 0.74–0.96; P<0.001) and
`microalbuminuria (hazard ratio, 0.90; 99% CI, 0.85–0.96;
`P<0.001). Over a treatment period of 5 years, 117–150
`patients would need to be treated to avoid one nonfatal
`myocardial infarction and 32–142 patients treated to avoid
`one episode of microalbuminuria. Moreover, a greater than
`twofold increase in the risk of severe hypoglycemia was
`seen with intensive therapy compared with standard
`therapy. With intensive therapy, one severe episode of
`hypoglycemia would occur for every 15–52 patients. When
`analyses were restricted to high-quality studies, intensive
`treatment was not associated with any reduction in
`microvascular or macrovascular complications but instead
`was associated with a 47% increase in the risk of
`congestive heart failure. In summary, the results of this
`meta-analysis showed limited benefit of intensive glucose-
`lowering therapy on all-cause mortality and deaths from
`cardiovascular causes and a 10% reduction in the risk of
`microalbuminuria.
`[30(cid:129)(cid:129)]
`A separate meta-analysis by Turnbull et al.
`included a total of 27,049 participants and 2370 major
`vascular events. Allocation to more intensive glucose
`control reduced the risk of major cardiovascular events by
`9% (hazard ratio, 0.91; 95% CI, 0.84–0.99) during an
`average follow-up of 4.4 years, primarily because of a 15%
`reduced risk of myocardial infarction. Mortality was not
`decreased, with nonsignificant hazard ratios for all-cause
`mortality and cardiovascular death. However, in subgroup
`analysis, participants who did not have a history of
`macrovascular disease prior to randomization appeared to
`benefit
`from more intensive glycemic control
`(major
`cardiovascular events hazard ratio, 0.84; 95% CI, 0.74–
`0.94; P=0.04), whereas those with pre-existing macro-
`vascular disease did not appear to benefit (major cardio-
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`vascular events hazard ratio, 1.00; 95% CI, 0.89–1.19; P=
`0.04). Once again,
`intensively treated participants had
`significantly more major hypoglycemic events. Because of
`significant heterogeneity among the four studies (UKPDS,
`ACCORD, ADVANCE, VADT), the possibility of harm
`with more intensive glycemic treatment c