Received: 29 April 2022 Revised: 28 July 2022 Accepted: 1 August 2022

DOI: 10.1111/dom.14830

REVIEW ARTICLE

Reconsidering the role of glycaemic control in cardiovascular

disease risk in type 2 diabetes: A 21st century assessment

Vanita R. Aroda MD1 | Robert H. Eckel MD2

1
Division of Endocrinology, Diabetes, and
Hypertension, Brigham and Women's Hospital, Abstract
Boston, Massachusetts
It is well known that the multiple factors contributing to the pathogenesis of type
2
Division of Endocrinology, Metabolism, and
Diabetes, and the Division of Cardiology, 2 diabetes (T2D) confer an increased risk of developing cardiovascular disease (CVD).
University of Colorado School of Medicine, Although the relationship between hyperglycaemia and increased microvascular risk
Aurora, Colorado
is well established, the relative contribution of hyperglycaemia to macrovascular
Correspondence events has been strongly debated, particularly owing to the failure of attempts to
Vanita R. Aroda MD, Division of
Endocrinology, Diabetes, and Hypertension,
reduce CVD risk through normalizing glycaemia with traditional therapies in high-risk
Brigham and Women's Hospital, Boston, MA populations. The debate has been further fuelled by the relatively recent discovery of
02115, USA.
Email: varoda@bwh.harvard.edu
the cardioprotective properties of glucagon-like peptide-1 receptor agonists and
sodium-glucose cotransporter-2 inhibitors. Further, as guidelines now recommend
Funding information
Writing support for this manuscript was
individualizing glycaemic targets, highlighting the importance of achieving glycated
funded by Sanofi US. The journal's article haemoglobin (HbA1c) goals safely, the previously observed negative influences of
processing charges were also funded by Sanofi
US. The authors received writing support in intensive therapy on CVD risk might not present if trials were repeated using
the preparation of this manuscript provided by current-day treatments and individualized HbA1c goals. Emerging longitudinal data
Helen Jones, PhD, CMPP, and Carolyn Bowler,
PhD, of Evidence Scientific Solutions Inc, illuminate the overall effect of excess glucose, the impacts of magnitude and duration
funded by Sanofi US. of hyperglycaemia on disease progression and risk of CVD complications, and the
importance of glycaemic control at or early after diagnosis of T2D for prevention of
complications. Herein, we review the role of glucose as a modifiable cardiovascular
(CV) risk factor, the role of microvascular disease in predicting macrovascular risk,
and the deleterious impact of therapeutic inertia on CVD risk. We reconcile new and
old data to offer a current perspective, highlighting the importance of effective, early
treatment in reducing latent CV risk, and the timely use of appropriate therapy indi-
vidualized to each patient's needs.

KEYWORDS
cardiovascular disease, diabetes complications, glycaemia, hyperglycaemia, macrovascular
disease, type 2 diabetes

1 | I N T RO DU CT I O N 1.6- and 2.3-fold.2 The availability of effective cholesterol and blood

pressure treatments facilitated a shift in the management approach
The increased risk of cardiovascular disease (CVD) in people with for type 2 diabetes (T2D) from the glucocentric focus of decades ago,
diabetes is well established,1 and is now estimated to be between to one of CVD risk reduction.3 Indeed, one study reported that

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© 2022 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Diabetes Obes Metab. 2022;1–12. wileyonlinelibrary.com/journal/dom 1

2 ARODA AND ECKEL

targeting multiple risk factors in people with T2D reduced the risk of TABLE 1 Key take-home messages and clinical perspective
CVD and microvascular events by approximately 50%.4 This resulted 1 Microvascular disease predicts macrovascular disease;
in the widely adopted “ABC” (glycated haemoglobin [HbA1c], blood achieving and maintaining glycaemic control plays a
pressure, and cholesterol) approach to T2D treatment, which coin- critical role in reducing microvascular and
macrovascular complications for people with T2D
cided with the identification of metabolic syndrome as a cluster of
2 Separately, and independent of glycaemic control,
glucose intolerance, hypertension, dyslipidaemia, and central obesity,
5
agents from the SGLT2 inhibitor and GLP-1RA class
with insulin resistance as the source of pathogenesis, all of which
have been shown to reduce CV risk in individuals with
increase the risk for developing T2D and atherosclerotic CVD established/high risk of CVD
(ASCVD).6,7 More recently, the exceptional findings of cardiovascular 3 Holistically, both achievement of glucose control and
outcome trials (CVOTs) demonstrating unequivocal reductions in CVD choice of appropriate therapy are equally important
risk with the newer sodium-glucose cotransporter-2 (SGLT2) inhibi- for reducing risk of complications

tors8-12 and glucagon-like peptide-1 receptor agonists (GLP- 4 One size does not fit all in T2D; HbA1c goals and
treatments need to be individualized, with glycaemic
1RAs)13-17 have perhaps overshadowed the place of glucose control
targets achieved safely
in the ABC management of T2D, reinvigorating the debate on
5 Avoidance of therapeutic inertia is key to achieving
whether glucose control itself matters in the efforts to minimize
HbA1c targets in all people with T2D, with early,
cardiovascular (CV) risk. sustained glycaemic control associated with reduced
Despite the advances in treatment approaches and the availabil- complication risk
ity of newer classes of therapy, data from the National Health and 6 Physiological control (e.g., less glycaemic variability,
Nutrition Examination Survey have revealed that the proportion of more time in range) is associated with a lower risk of
CV complications; monitoring technology has the
people with T2D who achieved HbA1c <48 mmol/mol has not
potential to facilitate more physiological control and
improved, and has actually declined over time, from 57.4% for 2007
guide therapeutic needs
to 2010, to 50.5% for 2015 to 2018.18 Other estimates (2006-2017)
Abbreviations: CVD, cardiovascular disease; CVOT, cardiovascular
suggest that the global glycaemic control target achievement rate is
19
outcomes trial; GLP-1RA, glucagon-like peptide-1 receptor agonist;
currently only 42.8%. This is despite guidelines from the American HbA1c, glycated haemoglobin; SGLT2, sodium-glucose cotransporter-2.
Diabetes Association (ADA),20 the American Association of Clinical
Endocrinologists,21 and the American College of Physicians (ACP),22
which universally recommend achievement and maintenance of glu- 2 | T H E CO N S E Q U E N C E S OF
cose control to reduce the risk of long-term complications. Thera- THERAP EU TIC I NERT IA ARE WELL K NO WN,
peutic inertia—defined as “the failure to initiate or intensify therapy B U T WH Y I S I T S T I L L SO P R E V A L E N T ?
in a timely manner according to evidence-based clinical guidelines in
individuals who are likely to benefit from such intensification”23— Findings from a systematic review revealed that the median time to
remains commonplace, resulting in years of unnecessary exposure to treatment intensification ranges from 0.3 to over 7.2 years, increasing
hyperglycaemia. With more devastating consequences, between with the number of antihyperglycaemic agents used.23 Initiation of
2007 and 2017, CVD affected approximately one-third of people injectable therapy is particularly challenging, with intensification to
24
with T2D across the globe, and caused one-half of all deaths, a insulin therapy typically being delayed by more than 7 years,26 and
figure that is projected to increase in tandem with the increasing started only when HbA1c is 75 mmol/mol or above, dramatically
prevalence of diabetes.25 There is therefore a need to evaluate the decreasing the likelihood of achieving glycaemic targets.27 Longitudi-
risk of uncontrolled glycaemia on CVD in people living with T2D and nal studies have highlighted the increased CVD risk with increasing
to mitigate this risk moving forward. glycaemia,28 including within the normoglycaemic range.29 Coupling
This review aims to reconcile the debate on the role of glycae- this fact with the demonstration that delay of treatment intensifica-
mic control in mitigating CVD risk, with a focus on chronic ambula- tion in people with T2D and HbA1c 53 mmol/mol or above by just
tory care. We consider the effect of treatment inertia on CVD risk 1 year increases the risk of myocardial infarction (MI), stroke and
through reviewing the evidence that supports a key role for hyper- heart failure (HF) at 5.3 years by 67%, 51% and 64%, respectively,30 it
glycaemia as a key risk modifier for the macrovascular complica- is worthwhile to consider the potential reasons for therapeutic inertia.
tions associated with T2D. We compare the results of landmark Multiple reasons have been cited as contributing to therapeutic
T2D trials with those of the newer CVOTs in consideration of the inertia26; these are categorized as either patient-level factors (eg, per-
improved outcomes with newer T2D therapies and the evolution ceptions about medication use and side effects), provider-level factors
of guidelines for the treatment of T2D. In particular, the potential (eg, competing demands, discomfort or lack of familiarity with new
effect of early control of blood glucose in reducing macrovascular medications, delays in guideline adoption), or health system factors
risk is discussed, and current recommendations for translating (eg, cost and access). We believe that debate around the evidence and
such insights into improvements in patient care to reduce the differing interpretations of existing evidence (eg, by different guide-
overall burden of diabetes-related complications are highlighted lines and professional societies) may contribute to therapeutic inertia
(Table 1). within the broader society, and we explore this further here.
ARODA AND ECKEL 3

(A) UKPDS UKPDS (B)

Active Follow-up
Intervention
Myocardial Infarction
ends
10 1.0
P=0.01

Conventional
9 0.8

Proportion with event

Biochemical
Median HbA1c (%)

data no
8 longer 0.6
Intensive collected
Conventional
therapy
0.4
7

0.2
6
Sulfonylurea–insulin

0.0
0 5 10 15 5 10 0 5 10 15 20 25
1977 1997 2007 Years since randomization
Years
(C)

9
Median HbA1c (%)

Conventional treatment
Glucose
8 similar BUT
CV events
still higher
Intensive treatment
7
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Years
DCCT (intervention period) EDIC (observational follow-up)

(D) Conventional
0.06 treatment
57% risk reduction in nonfatal MI, stroke, or CVD death*
Cumulative incidence (%)†

0.04

0.02 Intensive treatment

0.00
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Years
DCCT (intervention period) EDIC (observational follow-up)

F I G U R E 1 Benefits of early treatment of diabetes to reduce latent cardiovascular disease (CVD) risk: The legacy effect. A, UK Prospective
Diabetes Study (UKPDS): glycated haemoglobin (HbA1c) over time; B, UKPDS: cardiovascular (CV) outcomes; C, Diabetes Control and
Complications Trial (DCCT)/ Epidemiology of Diabetes Interventions and Complications (EDIC): HbA1c over time; D, DCCT/EDIC: CV outcomes.
MI, myocardial infarction. A, C and D Reprinted from Ramachandran et al. J Diabetes Metab. 2015;6:4 https://doi.org/10.4172/2155-6156.
1000520 under Creative Commons Attribution License. B From N Engl J Med., B Holman RR, et al. 10-Year Follow-up of Intensive Glucose
Control in Type 2 Diabetes, 359, 1577-89. Copyright © 2008. Massachusetts Medical Society. Reprinted with permission from Massachusetts
Medical Society

Although the UK Prospective Diabetes Study (UKPDS) defini- These results were similar to the “legacy effect” observed in the Dia-
tively linked intensive glucose control with a reduction in CVD risk betes Control and Complications Trial (DCCT)/ Epidemiology of Dia-
31,3231
and mortality in people with T2D, the delayed macrovascular betes Interventions and Complications (EDIC) study33 (Figure 1C,D).
risk benefit was not observed until after 10 years, at which time the While the delayed benefit supports the concept of improved out-
between-group glycaemic differences had been lost (Figure 1A,B).32 comes with early control, the loss of between-group glycaemic
4 ARODA AND ECKEL

differences over time perhaps calls us to question whether ongoing glycaemic targets and were conducted on background treatment that
control would result in an even greater benefit. The importance of gly- comprised current standards of care. Improvements in the risk of com-
caemic control was challenged when landmark studies (ADVANCE, posite major adverse CV events (MACE), hospitalization for heart fail-
Veterans Affairs Diabetes Trial [VADT], ACCORD) failed to show a ure (HHF), and renal outcomes8,9 with SGLT2 inhibitors were
34-
reduction in mortality or CVD risk with intensive glycaemic control. observed in as little as 3 months.10-12 Similarly, GLP-1RAs proved par-
36
However, importantly, unlike the UKPDS, the ADVANCE, ACCORD ticularly effective in reducing ASCVD outcomes, including MI and
and VADT studies enrolled people with poorly controlled T2D of long stroke.13-17 While these predominantly high-risk populations are not
34-36
duration who had established CVD or additional risk factors. Fur- representative of many patients with T2D who have multiple CVD
thermore, these intensive treatment studies extensively employed risk factors without established CVD, a small number of CVOTs
pharmacological approaches associated with increased risk of hypo- (DECLARE-TIMI 58: 59% without CVD10; REWIND: 69% without
glycaemia (eg, sulphonylureas; insulin) and weight gain (sulphonylur- CVD15) demonstrated benefits of SGLT2 inhibitors and GLP-1RAs
eas; insulin; thiazolidinediones), and aimed for what some might even in those without established ASCVD. The benefits of some
consider nonphysiological glycaemic targets (eg, HbA1c < 42 mmol/ agents have been shown to be independent of baseline glycaemic
mol) based on the therapies available at the time. To illustrate, hypo- status,40 potentially fuelling the debate on whether glycaemic control
glycaemic episodes requiring medical assistance occurred in 10.5% of is necessary in the quest to reduce CVD risk.
individuals in the intensive treatment group of the ACCORD study,37
and in 21% of those in the VADT,38 with severe hypoglycaemia being
associated with increased occurrence of CV events in the subsequent 3 | THE PRESENCE OF MICROVASCULAR
3 months. Significant weight gain also occurred in these studies, with DISEASE PREDICTS CVD RISK
nearly 28% of participants in the intensive treatment group of the
ACCORD study gaining more than 10 kg over the study.37 This level Although it is widely acknowledged that blood glucose control lowers
of hypoglycaemia and weight gain would not be accepted in current microvascular risk,31,32,34,36,41 because of the complex relationship
clinical trial design or care and likely reflects a mismatch between between glycaemia and macrovascular events, the potential benefit of
therapeutic goals and therapeutic modalities available at the time of blood glucose control on macrovascular risk remains an area of great
the study. debate. Although the temporal relationship between microvascular
While primary care-focused guidelines have appropriately empha- disease and macrovascular risk remains poorly understood, clinical
sized blood pressure and lipid management for CV risk reduction in data strongly support the role of microvascular disease in predicting
people with T2D, the interpretation of these treat-to-target trials has macrovascular risk.
paradoxically led to clinical recommendations for less stringent glycae- A bidirectional interaction between the macro- and microvascula-
mic targets, and for deintensification of therapy. The ACP, for exam- ture is known to exist, which maintains a deleterious relationship
ple, in 2018 issued its updated recommendations that “Clinicians between diabetes and the circulatory system. For example, increased
should aim to achieve an HbA1c level between 53 and 64 mmol/mol large artery stiffness accentuates pulse waves, causing microvascular
in most patients with type 2 diabetes” and that “Clinicians should con- damage.42,43 Similarly, abnormalities in microvascular structure and
sider deintensifying pharmacologic therapy in patients with type 2 dia- function may increase the risk of macrovascular events.42 Also, neo-
22
betes who achieve HbA1c levels less than 48 mmol/mol”. These vascularization of the vasa vasorum is increased in people with versus
conflict with recommendations from diabetes societies (eg, the ADA, without diabetes, which precedes endothelial dysfunction and
ADA-European Association for the Study of Diabetes [EASD] Consen- increases plaque inflammation.44,45 The presence of microvascular
sus)39 that promote individualized targets, but generally recommend complications predicts CVD and coronary artery disease death in indi-
an HbA1c target of lower than 53 mmol/mol in most adults with dia- viduals with T2D but without CVD.46-48 Diabetic retinopathy has
betes, with consideration of lower goals for those in whom they can been associated with an excess risk of HF49 and CVD,50 while the
be achieved safely without significant hypoglycaemia or adverse results of the Look AHEAD study suggest that microvascular disease
effects of treatment, and without deintensification of treatment when was associated with an overall 2.5-fold increase in risk of incident HF,
lower targets can be safely achieved. Such discrepancies in recom- with individual hazard ratios for nephropathy, retinopathy and neu-
mendations probably contribute to a level of uncertainty in the man- ropathy of 2.22, 1.30 and 1.33, respectively.51 Data from the CVOTs
agement of care and introduce a dimension of therapeutic inertia at also support the role of microvascular disease, with further analysis of
the societal level. It is important to reconcile these conflicting mes- the LEADER trial showing that the risk reduction with liraglutide for
sages and highlight the importance of both glycaemic control and the composite CV outcome of CV death, nonfatal MI, or nonfatal
therapeutic approach to achieve the optimal treatment for each indi- stroke was greater in patients with an estimated glomerular filtration
vidual with T2D. rate of less than 60 mL/min/1.73 m2 versus 60 mL/min/1.73 m2 or
Adding to the debate on the relevance of glucose control, recent greater,52 although this could be secondary to hypertension or other
CVOTs have shown unequivocal benefits of both SGLT2 inhibitors renal anomalies. Similarly, a post hoc analysis of the LEADER and
and GLP-1RAs in reducing CVD events in people with T2D at high risk SUSTAIN-6 studies showed that microvascular disease was associated
for or who have ASCVD. Notably, these CVOTs did not have intensive with increased risk of MACE,53 and analysis of the EMPA-REG
ARODA AND ECKEL 5

30 No microvascular disease state lower than 31 mmol/mol, an HbA1c level higher than 36 mmol/mol
1 microvascular disease state was associated with an increased risk of ASCVD, an HbA1c level higher
2 microvascular disease states
CVD risk, number of events
3 microvascular disease states than 44 mmol/mol with an increased risk of chronic kidney disease,
and an HbA1c level of 53 mmol/mol with an increased risk of HF, sug-
20
gesting that a significant gradient of risk exists across HbA1c levels well
below the diagnostic cutoff for diabetes.29 The above observations
concur with physiological findings that moderate hyperglycaemia (11.1
10 mmol/L) impairs endothelial cell function, thus augmenting vasocon-
striction and promoting inflammation, thrombosis64 and vascular dam-
age65-67 (Figure 3). Hyperglycaemia also directly affects both the
microvasculature and macrovasculature by causing phenotypic switch-
0
HbA1c < 7% ≥ 7% ≥ 7% ≥ 7%
ing of vascular smooth muscle cells to an activated state68 or to foam
Blood pressure < 140/90 mmHg < 140/90 mmHg ≥ 140/90 mmHg ≥ 140/90 mmHg cells,69 resulting in an increased inflammatory response,70 B-cell activa-
LDL cholesterol < 2.5 mmol/L < 2.5 mmol/L < 2.5 mmol/L ≥ 2.5 mmol/L
tion, and epigenetic changes that persist even after return to normogly-
Risk factors
caemia.71 In the heart, hyperglycaemia can cause vascular changes
F I G U R E 2 Microvascular disease is predictive of cardiovascular independently of atherosclerosis, resulting in the accumulation of
disease (CVD) risk. Analysis of 49 027 people with type 2 diabetes advanced glycation end-products which, together with proinflammatory
and no established CVD at baseline. Participants were followed for a cytokines and chemokines, recruit leukocytes to the vascular endothe-
median of 5.5 years for the primary outcome of time to first
lium, causing fibrosis.72 Postprandial hyperglycaemic excursions also
cardiovascular (CV) event. LDL, low-density lipoprotein. Reprinted
augment oxidative stress, systemic inflammation, and endothelial dys-
from The Lancet, Vol. 4, Brownrigg JRW, et al. Microvascular disease
and risk of cardiovascular events among individuals with type function, all of which contribute to atherosclerosis and CVD risk.73,74
2 diabetes: a population-level cohort study, 588-597, Copyright 2016, While not designed to study the value of glucose control in
with permission from Elsevier reducing CVD risk,8,75-77 mediation analyses of GLP-1RA studies sug-
gest that the lower CVD risk with this class tracks with their glycaemic
effect (possibly in addition to other associated factors).78,79 For exam-
OUTCOME study showed that the presence of microvascular disease ple, an exploratory analysis of the LEADER trial suggested that mean
at baseline was associated with a higher risk of HHF and CVD death HbA1c is a potential mediator of the CV protective effect of liraglu-
(but not three-point MACE), with a trend for worsening HF as the tide.78 Likewise, an analysis of the REWIND study reported that 50%
54
number of microvascular complications increased, similar to that to 60% of the reduction in stroke risk with weekly dulaglutide 1.5 mg
reported by Brownrigg et al55 (Figure 2). Diabetic cardiomyopathy56 is was related to glucose reduction.80 Further, a meta-analysis of dipep-
57
also associated with the presence of microvascular complications tidyl peptidase-4 inhibitor, GLP-1RA, and SGLT2 inhibitor CVOTs
and is proposed to be caused by microangiopathy.58 demonstrated a significant association between HbA1c and MACE
risk,81 predicting a 33% reduction in MACE if all CVOTs achieved an
HbA1c reduction of 9.8 mmol/mol. The authors noted that the only
4 | R E C O N C I L I N G OL D A N D N E W CVOT to achieve an HbA1c reduction of this magnitude was
DATA-GLUCOSE IS A MODIFIABLE SUSTAIN-6 (9 mmol/mol), which had an associated 26% reduction in
F A C T O R F O R CV D R I S K MACE risk in a population composed largely (83%) of individuals with
established CVD.14,81 This consideration contrasts with those in
Risk factors for CVD are numerous, with multiple classic factors—age, another recently published article, in which the authors concluded
sex, obesity, dyslipidaemia, hypertension—and also more recently iden- that because of the benefits shown by some of these agents in people
tified factors—oxidative stress, epigenetics, inflammation, and endothe- without diabetes, the MACE benefits of GLP-1RAs and SGLT2 inhibi-
lial dysfunction—being linked with T2D.59 Together with metabolic tors are “exclusive of their glucose-reducing actions”,82 querying
60,61
syndrome, these factors are known to increase CVD risk. Further, whether glucose reduction perhaps prevents early atherosclerosis, but
it has been shown that people with versus without T2D have higher not the final processes leading to CVD events.
atheroma volume, greater atherosclerotic plaque burden, and impaired Parallels can be drawn for landmark trials. Despite initial reports of a
compensatory positive remodelling of arteries.62 Although the mecha- lack of benefit of intensive glycaemic control in ACCORD, post hoc ana-
nisms for these changes have not been completely characterized, many lyses have produced findings more consistent with the UKPDS, in that
studies support a role for hyperglycaemia. participants without prior CVD or those with baseline HbA1c less
Results of a large retrospective analysis of the US Veterans Affairs than 64 mmol/mol who received intensive treatment had fewer CV
Healthcare System showed a linear relationship between increased events than those receiving standard therapy.35 Of those who received
CVD mortality and mean HbA1c levels higher than 53 mmol/mol ver- intensive treatment, only those with mean baseline HbA1c above 69
sus HbA1c levels of 42 to 52 mmol/mol.63 Similarly, a study of demo- mmol/mol were found to have a higher mortality risk,83 with a higher
graphically adjusted models showed that, compared with an HbA1c mean on-treatment HbA1c being associated with an increased mortality
6 ARODA AND ECKEL

Impaired endothelial Diabetes Thrombosis

cell function

Hyperglycemia
Reduction in fibrinolytic balance

B-cell, monocyte, and

Multiple pathways macrophage activation
Reduction in NO-mediated
endothelial-dependent
vasodilation Inflammation

Activation of arterial smooth Upregulation of inflammatory Microvascular disease

muscle cells to become cytokine production and cellular and fibrosis
foam cells adhesion molecule expression
• Conversion of
cells to
fibroblast-like
phenotype
Foam cells
• Matrix
SMC phenotypic switch synthesis

Vascular damage

• ASCVD (e.g., myocardial infarction, stroke) • Chronic kidney failure

• Heart failure, cardiomyopathy

F I G U R E 3 Contributory mechanisms of hyperglycaemia to vascular and kidney disease. ASCVD, atherosclerotic cardiovascular disease; NO,
nitric oxide; SMC, smooth muscular cells

risk.84 Several meta-analyses have shown an association between glu- a meta-analysis suggested that the benefit of intensive glycaemic con-
cose control and reduction in CVD events. Two meta-analyses that trol on macrovascular risk was particularly prominent in younger people
included data from the UKPDS, ACCORD, ADVANCE, and VADT trials with shorter duration of diabetes.91 In further agreement, the use of
showed that intensive versus conventional therapy reduced the risk of intensive glycaemic control in military veterans (mean age 60.4 years)
MACE by 9%, nonfatal MI by 15%,85 and CVD by 10%.86 Another two with T2D diagnosed a mean of 11.5 years earlier, 40% of whom had a
meta-analyses that included data from the UKPDS, ACCORD, prior CVD event, did not improve the rates of MACE, death, or micro-
ADVANCE, VADT and PROACTIVE trials reported that a decrease in vascular complications (except for progression of albuminuria).34
mean HbA1c of 9.9 mmol/mol with intensive therapy reduced the likeli- Related to this, even the presence of prediabetes is known to be associ-
hood of CVD events by 11%, MI by 14% to 17%, and coronary artery ated with substantial CVD risk.29 Although results of the Diabetes Pre-
diease by 15%.87,88 Other findings suggested that intensive glucose con- vention Program/Diabetes Prevention Program Outcomes Study
89
trol was associated with a 10% to 15% reduction in nonfatal MI. showed that metformin decreased coronary artery calcification in men
with prediabetes,92 recently published findings confirmed that the use
of metformin did not reduce the occurrence of nonfatal MI, stroke, or
5 | THE LEGACY EFFECT: A MATTER OF CV death.93 Results of the VA-IMPACT study, which was also designed
T I M I N G A N D E A R L Y G L Y C A E M I C CO N T R O L to assess whether metformin can reduce mortality and CVD morbidity
in people with prediabetes and established ASCVD, are awaited.94
The opportunity to meaningfully reduce CVD risk during the early The importance of early blood glucose control on the risk of later
stages of T2D fits with the findings of the UKPDS, which reported a complications is highlighted by several longitudinal studies. The Dia-
benefit of intensive treatment on CVD endpoints in individuals with betes and Aging study95 showed that early glycaemic control
newly diagnosed T2D who were younger (mean age 53 years) than par- (HbA1c < vs. >) was associated with a lower risk of microvascular
ticipants of other trials.90 Also supportive of this hypothesis, findings of complications, macrovascular complications, and mortality, which
ARODA AND ECKEL 7

persisted for 7 years. Newer data from a control-matched cohort of represent overtreatment. That said, the use of combination therapy
individuals with T2D from the Swedish National Diabetes Register96 later in the course of diabetes has been shown to impact the durabil-
revealed that among five risk factors (elevated HbA1c, elevated low- ity of glycaemic effect. The results of the DUAL VIII study showed
density lipoprotein cholesterol, albuminuria, smoking, and elevated that after failure of oral therapy, treatment with the basal insulin/
blood pressure), an HbA1c level outside of the target range was con- GLP-1RA fixed-ratio combination IDegLira was associated with longer
sistently the most important risk marker/predictor for stroke and time to treatment intensification versus insulin glargine 100 U/mL
acute MI, although it was not a predictor for death or HHF. Follow-up (median >2 vs. 1 year) with fewer participants requiring treatment
of the DCCT demonstrated that for the same average HbA1c over intensification over 104 weeks (37% vs. 66%).104 Further analysis
20 years, reaching goal early versus late was associated with a 33% confirmed greater reduction in HbA1c with lower hypoglycaemia
reduction in the risk of CVD and a 52% reduction in estimated glo- rates for the fixed-ratio combination compared with basal insulin
97
merular filtration rate worsening. In reviewing DCCT/EDIC and alone.107
UKPDS data, the same group concluded that the concepts of meta-
bolic memory for type 1 diabetes and the legacy effect for T2D are
likely to be biologically similar, endorsing use of early intensive ther- 7 | HYPOGLYCAEMIA/GLYCAEMIC
apy to maintain normal glycaemia for as long as possible to limit the VARIABILITY AS A MODIFIABLE CVD
risk of complications.98 RIS K FACT OR
A unique challenge in T2D management is the high rate of natural
progression of disease, even despite therapy. This is highlighted by The ACCORD study was the first to identify increased mortality asso-
follow-up of UKPDS participants, which showed that maintenance of ciated with intensive glycaemic goals of lower than 6% in high-risk
target glycaemic levels declined markedly over 9 years, with only 24% patients with T2D.35 Although severe hypoglycaemia was associated
of those who received sulphonylurea monotherapy achieving a fasting with increased risk of mortality, a post hoc analysis showed that the
plasma glucose (FPG) level lower than 7.8 mmol/L, and 24% achieving risk of death was in fact lower for those who received intensive ver-
99
HbA1c lower than 53 mmol/mol. Whether higher-efficacy therapies sus conventional therapy,108 which could reflect the increased risk of
such as GLP-1RAs can affect the natural course of T2D is not known, hypoglycaemia in older adults with diabetes. Further, another analysis
although it is plausible that higher-efficacy approaches, and approaches of the ACCORD study demonstrated that the risk of mortality in the
that dually support glucose and weight reduction, will help alter the subset of individuals who received intensive control increased linearly
100
natural course of T2D and prolong control. with HbA1c (from 42 to 75 mmol/mol) and was highest in those
unable to achieve target glycaemia (HbA1c < 53 mmol/mol).84 Sepa-
rate analyses have confirmed that intensive therapy increases the risk
6 | IMPROVING EARLY GLYCAEMIC of severe hypoglycaemia by two- to threefold85-89 and a meta-
CONTROL: A ROLE FOR COMBINATION analysis showed a correlation between risk of severe hypoglycaemia
THERAPY? and CVD death with intensive therapy.87 Collectively, these results
suggest that intensive glucose control may reduce CVD events in peo-
Whereas traditional approaches have used stepwise, sequential addi- ple with T2D, but this needs to be balanced against CV events associ-
tion of therapy, recent data suggest that the use of early combination ated with severe hypoglycaemia. It is pertinent to note that these
therapy may achieve and sustain glycaemic control more effectively. trials were conducted some time ago using intensive treatment
Indeed the recently updated ADA Standards of Care101 support the modalities that do not reflect the current standard of care. Increases
use of initial combination therapy for either more rapid attainment of in hypoglycaemia rates are not observed with SGLT2 inhibitors and
102,103 104
glycaemic goals or longer durability of glycaemic effect, GLP-1RAs;10-12,109 furthermore, guidelines now recommend individu-
recommending that “initial combination therapy should be considered alizing glycaemic targets, highlighting the importance of achieving
in patients presenting with HbA1c values 15.9 mmol/mol above tar- HbA1c goals safely.20 As such, these negative influences on CVD risk
get.”101 Furthermore, results from the VERIFY study confirmed that might not be present if trials were repeated using current-day
initial metformin/vildagliptin combination therapy in people with treatments.
newly diagnosed T2D resulted in better long-term glycaemic control How glycaemic control is monitored and assessed also has con-
than metformin monotherapy105 (a 49% reduction in the time to initial siderable potential to guide advancement of therapy and more fully
treatment failure) and also reduced the risk of time to secondary address the relationship between glycaemia and CV risk. Although
105,106
treatment failure by 26%. Although the trial was not powered HbA1c reflects the average glucose concentrations over a 3-month
to assess CV outcomes, early combination therapy was associated period, it does not account for day-to-day glucose variability, which is
with a numerically longer time to first adjudicated macrovascular proposed to be more deleterious to CV health than the average
event than metformin monotherapy.105 However, it is important to change in HbA1c over time.82,110 Indeed, data from the FinnDiane
note that, in this study, 40% of people who received metformin study in people with type 1 diabetes showed that HbA1c variability
monotherapy had no treatment failure after 5 years. As such, it is pos- rather than mean HbA1c better predicted CVD events.111 Similarly,
sible that initiation of dual treatment in this population could the ALLHAT study112 revealed that increased visit-to-visit variability
8 ARODA AND ECKEL

of FPG is associated with increased mortality risk in individuals with- studied, with factors such as trial design, study population, and
out CVD. High variability in HbA1c has been shown to be associated length of follow-up producing variability in outcomes. The modali-
with increased risk of MACE and all-cause mortality, even in individ- ties by which glycaemic control is achieved are continually evolving;
uals with no history of diabetes or CVD.113 Moreover, it is known that however, overcoming therapeutic inertia is key to effecting a change
HbA1c is contributed to by both FPG and postprandial glucose in the current rates of T2D-related complications. The data reviewed
(PPG).114 Epidemiological studies suggest that PPG is an independent herein suggest that, in addition to blood pressure and lipid control,
115
risk factor for CVD and MI, in people both without and with diabe- to reduce CVD risk in people with T2D, intensive treatment of
tes.116 In people with T2D, PPG (but not FPG) has been shown to be hyperglycaemia should be initiated early with the goal of achieving
a predictor of CVD-related mortality,117 this topic having been and maintaining control and will be particularly beneficial in the long
reviewed by Ceriello both in 2005118 and in 2021.119 Moreover, the run when used at the early stages of disease (ie, in individuals with
contribution of PPG to HbA1c is greater for people aged 65 years and short duration of diabetes and at low CVD risk). Multiple advances
older versus those under 65 years,120 thus raising the CVD and mor- in technology and assessments of glycaemic control (and linkage to
tality risk in older adults with T2D. outcomes) and the availability of more efficacious therapies and
The International Consensus on Use of Continuous Glucose Moni- approaches to achieve control, as well as novel therapies that have
toring from the 2017 advanced technologies & treatments for diabetes demonstrated CV benefit, are essential for appropriate care. These
(ATTD) Congress recommended the use of time in range (TIR) as a mea- advances need to be coupled with consistent clinical guidance on
sure of short-term glycaemic control.121 People with diabetes are thus the prioritization of safe and early achievement of glycaemic control
advised that TIR, that is, a blood glucose of 3.9 to 10.0 mmol/L should to benefit the population at large. The growing prevalence of diabe-
be maintained for at least 70% (16 hours and 48 minutes) of each day. tes and burden of complications worldwide make even more appar-
Hypoglycaemia with blood glucose lower than 3.9 mmol/L (time below ent the importance of such advances and need for concerted
range; TBR) should be limited to less than 4% (1 hour) of the day, integration and transformation of care.
and with blood glucose lower than 3.0 mmol/L to less than 1%
(15 minutes) of the day. Hyperglycaemia with blood glucose higher AUTHOR CONTRIBU TIONS
than 10 mmol/L or higher than should be limited to less than 25% Vanita R. Aroda and Robert H. Eckel provided their expertise and
(6 hours) and less than 5% (1 hour 12 minutes), respectively, of each intellectual feedback regarding the concept and structure of the man-
day. Because of the increased risk of hypoglycaemia in older adults, the uscript, and contributed to outlining, drafting, and critically revising
updated version of the guidelines recommends lowering the TIR target the manuscript at each stage of development. Both Vanita R. Aroda
from greater than 70% to greater than 50% and reducing TBR to less and Robert H. Eckel approved the final manuscript for publication.
than 1% at blood glucose levels lower than 3.9 mmol/L to place greater
emphasis on reducing hypoglycaemia and less emphasis on maintaining ACKNOWLEDG MENTS
122
target glucose levels. Writing support for this manuscript was funded by Sanofi US. The jour-
Metrics from continuous glucose monitoring, including TIR, time nal's article processing charges were also funded by Sanofi US. The
above range, and time below range, can facilitate the safe achievement authors received writing support in the preparation of this manuscript
of glycaemic control and mitigation of the risks associated with hypogly- provided by Helen Jones, PhD, CMPP, and Carolyn Bowler, PhD, of
caemia. Several studies have determined that a decrease in TIR is Evidence Scientific Solutions Inc, funded by Sanofi US.
strongly associated with an increased risk of microvascular complications,
including microalbuminuria and retinopathy,123 peripheral neuropathy,124 CONFLIC T OF INT ER E ST
as well as an increased risk of macrovascular disease.125 Furthermore, Vanita R. Aroda reports serving as a consultant to Applied Therapeu-
lower TIR has been shown to be associated with an increased risk of all- tics, Fractyl, Novo Nordisk, Pfizer and Sanofi, has a spouse employed
cause and CVD mortality among patients with T2D.126 by Janssen, and has had research support (institutional clinical trial
contracts) from Applied Therapeutics, Eli Lilly, Fractyl, Novo Nordisk,
and Sanofi. Robert H. Eckel reports work for Amarin, Kaleido, KOWA,
8 | C O N CL U S I O N S Novo Nordisk, The Healthy Aging Company, UpToDate, and WW.

In summary, hyperglycaemia is at the core of both microvascular and PE ER RE VIEW

macrovascular complications in T2D, with microvascular complications The peer review history for this article is available at https://publons.
increasing the risk of macrovascular complications. Although results of com/publon/10.1111/dom.14830.
observational studies consistently point to hyperglycaemia as the most
important risk factor for both microvascular and macrovascular complica- DATA AVAILABILITY STAT EMEN T
tions, interventional studies have shown consistent benefits of intensive Not applicable.
glucose control on microvascular complications in T2D, with a more
complex relationship between intervention and macrovascular complica- OR CID
tions. These results probably relate to the stage of disease and therapies Vanita R. Aroda https://orcid.org/0000-0002-7706-4585
ARODA AND ECKEL 9

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