Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)

Abstract

The American Diabetes Association and the European Association for the Study of Diabetes convened a panel to update the prior position statements, published in 2012 and 2015, on the management of type 2 diabetes in adults. A systematic evaluation of the literature since 2014 informed new recommendations. These include additional focus on lifestyle management and diabetes self-management education and support. For those with obesity, efforts targeting weight loss, including lifestyle, medication and surgical interventions, are recommended. With regards to medication management, for patients with clinical cardiovascular disease, a sodium–glucose cotransporter-2 (SGLT2) inhibitor or a glucagon-like peptide-1 (GLP-1) receptor agonist with proven cardiovascular benefit is recommended. For patients with chronic kidney disease or clinical heart failure and atherosclerotic cardiovascular disease, an SGLT2 inhibitor with proven benefit is recommended. GLP-1 receptor agonists are generally recommended as the first injectable medication.

Full text

CONSENSUS REPORT
Management of hyperglycaemia in type 2 diabetes, 2018. A consensus
report by the American Diabetes Association (ADA) and the European
Association for the Study of Diabetes (EASD)
Melanie J. Davies
1,2
&David A. D’Alessio
3
&Judith Fradkin
4
&Walter N. Kernan
5
&Chantal Mathieu
6
&
Geltrude Mingrone
7,8
&Peter Rossing
9,10
&Apostolos Tsapas
11
&Deborah J. Wexler
12,13
&John B. Buse
14
#European Association for the Study of Diabetes and American Diabetes Association 2018
Abstract
The American Diabetes Association and the European Association for the Study of Diabetes convened a panel to update the prior
position statements, published in 2012 and 2015, on the management of type 2 diabetes in adults. A systematic evaluation of the
literature since 2014 informed new recommendations. These include additional focus on lifestyle management and diabetes self-
management education and support. For those with obesity, efforts targeting weight loss, including lifestyle, medication and surgical
interventions, are recommended. With regards to medication management, for patients with clinical cardiovascular disease, a sodium–
glucose cotransporter-2 (SGLT2) inhibitor or a glucagon-like peptide-1 (GLP-1) receptor agonist with proven cardiovascular benefit is
recommended. For patients with chronic kidney disease or clinical heart failure and atherosclerotic cardiovascular disease, an SGLT2
inhibitor with proven benefit is recommended. GLP-1 receptor agonists are generally recommended as the first injectable medication.
Keywords Cardiovascular disease .Chronic kidney disease .Costs .Glucose-lowering therapy .Guidelines .Heart failure .
Hypoglycaemia .Patient-centred care .Type 2 diabetes mellitus .Weight management
Abbreviations
ARR Absolute risk reduction
ASCVD Atherosclerotic cardiovascular
disease
CANVAS Canagliflozin Cardiovascular
Assessment Study
CKD Chronic kidney disease
CVD Cardiovascular disease
CVOT Cardiovascular outcomes trial
DKA Diabetic ketoacidosis
DPP-4 Dipeptidyl peptidase-4
DPP-4i Dipeptidyl peptidase-4 inhibitor
DSMES Diabetes self-management
education and support
EMPA-REG OUTCOME Empagliflozin, Cardiovascular
Outcome Event Trial in Type 2
Diabetes Mellitus Patients
ESRD End-stage renal disease
EXSCEL Exenatide Study of
Cardiovascular Event Lowering
GLP-1 Glucagon-like peptide-1
GLP-1 RA Glucagon-like peptide-1 receptor
agonist
HF Heart failure
LEADER Liraglutide Effect and Action in
Diabetes: Evaluation of of
Cardiovascular Outcomes Results
MACE Major adverse cardiac events
MI Myocardial infarction
MNT Medical nutrition therapy
RCT Randomised clinical trial
SGLT2 Sodium–glucose cotransporter-2
M. J. Davies and J. B. Buse were co-chairs for the Consensus Statement
Writing Group. D. A. D’Alessio, J. Fradkin, W. N. Kernan and D. J.
Wexler were the writing group members for the ADA. C. Mathieu, G.
Mingrone, P. Rossing and A. Tsapas were writing group members for the
EASD.
This article is being simultaneously published in Diabetes Care and
Diabetologia by the American Diabetes Association and the European
Association for the Study of Diabetes.
*Melanie J. Davies
Melanie.davies@uhl-tr.nhs.uk
Extended author information available on the last page of the article
Diabetologia
https://doi.org/10.1007/s00125-018-4729-5

SGLT2i Sodium–glucose cotransporter-2
inhibitor
SMBG Self-monitoring of blood glucose
SU Sulfonylurea
SUSTAIN 6 Trial to Evaluate Cardiovascular
and Other Long-term Outcomes
with Semaglutide in Subjects
with Type 2 Diabetes
T2DM Type 2 diabetes mellitus
TZD Thiazolidinedione
UKPDS UK Prospective Diabetes Study
Introduction
The goals of treatment for type 2 diabetes are to prevent or
delay complications and maintain quality of life (Fig. 1). This
requires control of glycaemia and cardiovascular risk factor
management, regular follow-up and, importantly, a patient-
centred approach to enhance patient engagement in self-care
activities [1]. Careful consideration of patient factors and pre-
ferences must inform the process of individualising treatment
goals and strategies [2,3].
This consensus report addresses the approaches to manage-
ment of glycaemia in adults with type 2 diabetes, with the goal
of reducing complications and maintaining quality of life in
the context of comprehensive cardiovascular risk manage-
ment and patient-centred care. The principles of how this
can be achieved are summarised in Fig. 1and underpin the
approach to management and care. These recommendations
are not generally applicable to patients with monogenic dia-
betes, secondary diabetes or type 1 diabetes, or to children.
Data sources, searches and study selection
The writing group accepted the 2012 [4] and 2015 [5] editions
of this position statement as a starting point. To identify newer
evidence, a search was conducted on PubMed for randomised
clinical trials (RCTs), systematic reviews and meta-analyses
published in English between 1 January 2014 and 28
February 2018; eligible publications examined the effective-
ness or safety of pharmacological or non-pharmacological in-
terventions in adults with type 2 diabetes mellitus. Reference
lists were scanned in eligible reports to identify additional arti-
cles relevant to the subject. Details on the keywords and the
search strategy are available at https://doi.org/10.17632/
h5rcnxpk8w.1. Papers were grouped according to subject and
the authors reviewed this new evidence to inform the consensus
recommendations. The draft consensus recommendations were
peer reviewed (see Acknowledgements), and suggestions
incorporated as deemed appropriate by the authors.
Nevertheless, though evidence based, the recommendations
presented herein are the opinions of the authors.
The rationale, importance and context
of glucose-lowering treatment
Lifestyle management, including medical nutrition therapy
(MNT), physical activity, weight loss, counselling for
smoking cessation, and psychological support, often delivered
in the context of diabetes self-management education and sup-
port (DSMES), are fundamental aspects of diabetes care. The
expanding number of glucose-lowering treatments—from be-
havioural interventions to medications and surgery—and
growing information about their benefits and risks provides
more options for people with diabetes and providers, but can
complicate decision making. In this consensus statement, we
attempt to provide an approach that summarises a large body
of recent evidence for practitioners in the USA and Europe.
Marked hyperglycaemia is associated with symptoms in-
cluding frequent urination, thirst, blurred vision, fatigue and
recurring infections. Beyond alleviating symptoms, the aim of
blood glucose lowering (hereafter, referred to as glycaemic
management) is to reduce long-term complications of diabe-
tes. Good glycaemic management yields substantial and en-
during reductions in onset and progression of microvascular
complications. This benefit has been demonstrated most clear-
ly early in the natural history of the disease in studies using
metformin,sulfonylureasand insulin but is supported by more
recent studies with other medication classes. The greatest ab-
solute risk reduction (ARR) comes from improving poor
glycaemic control, and a more modest reduction results from
near normalisation of glycaemia [6]. The impact of glucose
control on macrovascular complications is less certain.
Because the benefits of intensive glucose control emerge
slowly, while the harms can be immediate, people with longer
life expectancy have more to gain from intensive glucose con-
trol. A reasonable HbA
1c
target for most non-pregnant adults
with sufficient life expectancy to see microvascular benefits
(generally ~10 years) is around 53 mmol/mol (7%) or less [6].
Glycaemic treatment targets should be individualised based
on patient preferences and goals, risk of adverse effects of
therapy (e.g. hypoglycaemia and weight gain) and patient
characteristics, including frailty and comorbid conditions [2].
Atherosclerotic cardiovascular disease (ASCVD) is the
leading cause of death in people with type 2 diabetes [7].
Diabetes confers substantial independent ASCVD risk, and
most people with type 2 diabetes have additional risk factors
such as hypertension, dyslipidaemia, obesity, physical inactiv-
ity, chronic kidney disease (CKD) and smoking. Numerous
studies have demonstrated the benefits of controlling modifi-
able ASCVD risk factors in people with diabetes. Substantial
reductions in ASCVD events and death are seen when multi-
ple ASCVD risk factors are addressed simultaneously, with
long-standing benefits [8,9]. Comprehensive implementation
of evidence-based interventions has likely contributed to the
significant reductions in ASCVD events and mortality seen in
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Fig. 1 Decision cycle for patient-centred glycaemic management in type 2 diabetes
Diabetologia

people with diabetes in recent decades [10]. ASCVD risk
management in its many forms is an essential part of diabetes
management that is beyond the scope of this statement, but
physiciansshould be aware of the importance of multifactorial
treatment in type 2 diabetes [7].
Glucose management: monitoring
Glycaemic management is primarily assessed with the HbA
1c
test, which was the measure studied in trials demonstrating the
benefits of glucose lowering [2]. The performance of the test is
generally excellent for National Glycohemoglobin
Standardization Program (NGSP)-certified assays and laborato-
ries (www.ngsp.org)[11]. As with any laboratory test, HbA
1c
has limitations [2]. Because there is variability in the
measurement of HbA
1c
, clinicians should exercise judgement,
particularly when the result is close to the threshold that might
prompt a change in therapy. HbA
1c
results may be discrepant
from the patient’s true mean glycaemia in certain racial and
ethnic groups, and in conditions that alter red blood cell
turnover, such as anaemia, end-stage renal disease (ESRD; es-
pecially with erythropoietin therapy), and pregnancy, or if an
HbA
1c
assay sensitive to haemoglobin variants is used in some-
one with sickle cell trait or other haemoglobinopathy.
Discrepancies between measured HbA
1c
and measured or re-
ported glucose levels should prompt consideration that one of
these may not be reliable [12].
Regular self-monitoring of blood glucose (SMBG) may
help with self-management and medication adjustment, partic-
ularly in individuals taking insulin. SMBG plans should be
individualised. People with diabetes and the healthcare team
should use the data in an effective and timely manner. In peo-
ple with type 2 diabetes not using insulin, routine glucose
monitoring is of limited additional clinical benefit while adding
burden and cost [13,14]. However, for some individuals, glu-
cose monitoring can provide insight into the impact of lifestyle
and medication management on blood glucose and symptoms,
particularly when combined with education and support.
Novel technologies, such as continuous or flash glucose mon-
itoring, provide more information. However, in type 2 diabe-
tes, they have been associated with only modest benefits [15].
Principles of care
Providing patient-centred care that acknowledges multi-mor-
bidity, and is respectful of and responsive to individual patient
preferences and barriers, including the differential costs of
therapies, is essential to effective diabetes management [16].
Shared decision making, facilitated by decision aids that show
the absolutebenefit and riskof alternative treatment options, is
a useful strategy to arrive at the best treatment course for an
individual [17–20]. Providers should evaluate the impact of
any suggested intervention, including self-care regimens, in
the context of cognitive impairment, limited literacy, distinct
cultural beliefs and individual fears or health concerns given
their impact on treatment efficacy.
DSMES
DSMES is a key intervention to enable people with diabetes to
make informed decisions and to assumeresponsibility for day-
to-day diabetes management. DSMES is central to establish-
ing and implementing the principles of care (Fig. 1). DSMES
programmes usually involve face-to-face contact in group or
individual sessions with trained educators, and key compo-
nents are shown in the Table 1[21–25]. While DSMES should
be available on an ongoing basis, critical junctures when
DSMES should occur include at diagnosis, annually, when
complications arise and during transitions in life and care [22].
DSMES programmes delivered from diagnosis can pro-
mote medication adherence,healthy eating and physical activ-
ity, and increase self-efficacy. In type 2 diabetes, high-quality
evidence has consistently shown that DSMES is a cost-
effective intervention in the healthcare systems studied.
DSMES significantly improves clinical and psychological
outcomes, improves glycaemic control, reduces hospital ad-
missions, improves patient knowledge, and reduces the risk of
all-cause mortality [22,26–31]. The best outcomes are
achieved in those programmes with a theory-based and struc-
tured curriculum, and with contact time of over 10 h. While
online programmes may reinforce learning, there is little evi-
dence they are effective when used alone [27].
Suboptimal adherence, including poor persistence, to ther-
apy affects almost half of people with diabetes, leading to
suboptimal glycaemic and cardiovascular disease (CVD) risk
factor control as well as increased risk of diabetes complica-
tions, mortality, hospital admissions and healthcare costs
[32–36]. Though this consensus recommendation focuses on
medication adherence (including persistence), the principles
Consensus recommendation
Providers and healthcare systems should prioritise the
delivery of patient-centred care.
Consensus recommendation
All people with type 2 diabetes should be offered access
to ongoing DSMES programmes.
Consensus recommendation
Facilitating medication adherence should be specifi-
cally considered when selecting glucose-lowering
medications.
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are pertinent to all aspects of diabetes care. Multiple factors
contribute to inconsistent medication use and treatment dis-
continuation, including patient-perceived lack of medication
efficacy, fear of hypoglycaemia, lack of access to medication
and adverse effects of medication [37]. Medication adherence
(including persistence) varies across medication classes and
careful consideration of these differences may help improve
outcomes [38]. Ultimately, patient preference is a major
factor driving the choice of medication. Even in cases
where clinical characteristics suggest the use of a particular
medication based on the available evidence from clinical
trials, patient preferences regarding route of administra-
tion, injection devices, side effects or cost may prevent
their use by some individuals [39].
Therapeutic inertia, sometimes referred to as clinical iner-
tia, refers to failure to intensify therapy when treatment targets
are not met. The causes of therapeutic inertia are multifacto-
rial, occurring at the level of the practitioner, patient and/or
healthcare system [40]. Interventions targeting therapeutic in-
ertia have facilitated improved glycaemic control and timely
insulin intensification [41,42]. For example, multidisciplinary
teams that include nurse practitioners or pharmacists may help
reduce therapeutic inertia [43,44]. A fragmented healthcare
system may contribute to therapeutic inertia and impair deliv-
ery of patient-centred care. A coordinated chronic care model,
including self-management support, decision support, deliv-
ery system design, clinical information systems, and commu-
nity resources and policies, promotes interaction between
more empowered patients and better prepared and proactive
healthcare teams [45].
Recommended process for glucose-lowering
medication selection: where does new
evidence from cardiovascular outcomes trials
fit in?
In prior consensus statements, efficacy in reducing
hyperglycaemia, along with tolerability and safety were pri-
mary factors in glucose-lowering medication selection. Patient
preferences, glycaemic targets, comorbidities, polypharmacy,
side effects and cost were additional important considerations.
For every individual, the choice of glucose-lowering medica-
tion should be underpinned by lifestyle management, DSMES
and the patient-centred care principles outlined in Fig. 1.
Figure 2describes our new consensus approach to glucose
lowering with medications in type 2 diabetes. Because of the
new evidence for the benefit of specific medications to reduce
mortality, heart failure (HF) and progression of renal disease
in the setting of established CVD,their use was considered
Table 1 Key components of DSMES [21,23–25]
Table 1. Key components of DSMES [21, 23–25]
●
●
●
●
●
●
●
●
●
●
●
Evidence-based
Individualised to the needs of the person, including language and culture
Has a structured theory-driven written curriculum with supporting materials
Delivered by trained and competent individuals (educators) who are quality assured
Delivered in group or individual settings
Aligns with the local population needs
Supports the person and their family in developing attitudes, beliefs, knowledge and skills to
self-manage diabetes
Includes core content, i.e. diabetes pathophysiology and treatment options; medication usage; moni-
toring, preventing, detecting and treating acute and chronic complications; healthy coping with
psychological issues and concerns; problem solving and dealing with special situations (i.e. travel,
fasting)
Available to patients at critical times (i.e. at diagnosis, annually, when complications arise and when
transitions in care occur)
Includes monitoring of patient progress, including health status, quality of life
Quality audited regularly
DSMES is a critical element of care for all people with diabetes and is the ongoing process of facilitating the knowledge, skills and ability
necessary for diabetes self-care as well as activities that assist a person implementing and sustaining behaviours needed to manage
their diabetes on an ongoing basis
National organisations in the USA and Europe have published standards to underpin DSMES. In the USA these are defined as DSMES
‘Services’ whereas in Europe they are often referred to as ‘programmes’. Nevertheless, the broad components are similar
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Fig. 2 Glucose-lowering medication in type 2 diabetes: overall approach
Diabetologia

compelling in this patient group. Thus, we recommend that
providers consider a history of CVD very early in the process
of treatment selection. Other factors affect the choice of
glucose-lowering medications, particularly in the setting of
patient-centred care. In addition to CVD, we recommend early
consideration of weight, hypoglycaemic risk, treatment cost
and other patient-related factors that may influence treatment
selection (Figs 2,3,4,5,6).
Implications of new evidence from cardiovascular
outcomes trials
The major change from prior consensus reports is based on
new evidence that specific sodium–glucose cotransporter-2
(SGLT2) inhibitors or glucagon-like peptide-1 (GLP-1) recep-
tor agonists improve cardiovascular outcomes, as well as sec-
ondary outcomes such as HF and progression of renal disease,
in patients with established CVD or CKD. Therefore, an im-
portant early step in this new approach (Fig. 3)istoconsider
the presence or absence of ASCVD, HF and CKD, conditions
in aggregate affecting 15–25% of the population with type 2
diabetes. While the new evidence supporting the use of par-
ticular medications in patients who also have established CVD
or are at high risk of CVD is derived from large cardiovascular
outcomes trials (CVOTs) demonstrating substantial benefits
over 2–5 years, it is important to remember that each trial
constitutes a single experiment. Within each drug class, results
have been heterogeneous. It is not clear whether there are true
drug class effects with different findings for individual medi-
cations due to differences in trial design and conduct, or
whether there are real differences between medications within
a drug class due to properties of the individual compounds.
Where the current evidence is strongest for a specific medica-
tion within a class, it is noted. The ADA’s‘Standards of med-
ical care in diabetes’will align with this document and will be
updated to reflect new evidence as it emerges from ongoing
clinical trials.
ASCVD is defined somewhat differently across trials, but all
trials enrolled individuals with established CVD (e.g. myocar-
dial infarction [MI], stroke, any revascularisation procedure)
while variably including related conditions compatible with
clinically significant atherosclerosis (e.g. transient ischaemic
attack, hospitalised unstable angina, amputation, congestive
heart failure New York Heart Association [NYHA] class II–
III, >50% stenosis of any artery, symptomatic or asymptomatic
coronary artery disease documented by imaging, CKD with
estimated GFR [eGFR] <60 ml min
-1
[1.73 m]
-2
). Most trials
also included a ‘risk factor only’group with entry criteria based
on age and usually the presence of two or more cardiac risk
factors [46]. Trials were designed to evaluate cardiovascular
safety (i.e. statistical non-inferiority compared with placebo),
but several showed ASCVD outcome benefit (i.e. statistical
superiority compared with placebo), including, in some cases,
mortality.
Among GLP-1 receptor agonists, liraglutide, studied in the
Liraglutide Effect and Action in Diabetes: Evaluation of
Cardiovascular Outcomes Results (LEADER) trial (n= 9340)
demonstrated an ARR of 1.9% with an HR of 0.87 (95% CI
0.78, 0.97; p= 0.01 for superiority) for the primary composite
outcome of cardiovascular death, non-fatal MI and non-fatal
stroke (major adverse cardiac events [MACE]) compared with
placebo over 3.8 years. Each component of the composite con-
tributed to the benefit, and the HR for cardiovascular death was
0.78 (95% CI 0.66, 0.93; p= 0.007; ARR 1.7%). The LEADER
trial also demonstrated an HR of 0.85 (95% CI, 0.74 to 0.97;
p= 0.02; ARR 1.4%) for all-cause mortality [47]. In the Trial to
Evaluate Cardiovascular and Other Long-term Outcomes with
Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN 6)
(n= 3297), semaglutide compared with placebo demonstrated
an ARR of 2.3% with HR 0.74 for MACE (95% CI 0.58, 0.95;
p= 0.02 for superiority) over 2.1 years, but the reduction in
events appeared to be driven by the rate of stroke, rather than
CVD death [48]. The Exenatide Study of Cardiovascular Event
Lowering (EXSCEL) compared exenatide extended-release
with placebo over 3.2 years in 14,752 participants with type 2
diabetes. While the medication was safe (non-inferior), the HR
for MACE in the entire trial was 0.91 (95% CI 0.83, 1.0; p=
0.06) not reaching the threshold for demonstrated superiority vs
placebo; ARR was 0.8% [49]. All-cause death was lower in the
exenatide arm (ARR 1%, HR 0.86 [95% CI 0.77, 0.97]), but it
was not considered to be statistically significant in the hierar-
chical testing procedure applied. Lixisenatide, a short-acting
GLP-1 receptor agonist, did not demonstrate CVD benefit or
harm in a trial of patients recruited within 180 days of an acute
coronary syndrome admission [50]. Taken together, it appears
that among patients with established CVD, some GLP-1 recep-
tor agonists may provide cardiovascular benefit, with the evi-
dence of benefit strongest for liraglutide, favourable for
semaglutide, and less certain for exenatide. There is no evi-
dence of cardiovascular benefit with lixisenatide. Adverse ef-
fects for the class are discussed in the section ‘The full range of
therapeutic options: lifestyle management, medication and obe-
sity management’.
Among the SGLT2 inhibitors, empagliflozin compared with
placebo was studied in the Empagliflozin, Cardiovascular
Outcome Event Trial in Type 2 Diabetes Mellitus Patients
Consensus recommendation
Among patients with type 2 diabetes who have
established ASCVD, SGLT2 inhibitors or GLP-1
receptor agonists with proven cardiovascular benefit
are recommended as part of glycaemic management
(Figs 2 and 3).
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Fig. 3 Choosing glucose-lowering medication in those with established atherosclerotic cardiovascular disease (ASCVD) or chronic kidney disease
(CKD)
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Fig. 4 Choosing glucose-lowering medication if compelling need to minimise weight gain or promote weight loss
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Fig. 5 Choosing glucose-lowering medication if compelling need to minimise hypoglycaemia
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(EMPA-REG OUTCOME) in 7020 participants with type 2
diabetes and CVD. With a median follow-up of 3.1 years, the
ARR was 1.6% and the HR was 0.86 (95% CI 0.74, 0.99; p=
0.04 for superiority) for the primary composite endpoint of non-
Fig. 6 Choosing glucose-lowering medication if cost is a major issue
Diabetologia

fatal MI, non-fatal stroke and cardiovascular death. The ARR
was 2.2% and the HR was 0.62 (95% CI 0.49, 0.77; p<0.001)
for cardiovascular death [51]. The ARR was 2.6% and the HR
was 0.68 (95% CI, 0.57, 0.82; p< 0.001) for death from any
cause.Canagliflozincomparedwithplacebowasstudiedinthe
Canagliflozin Cardiovascular Assessment Study (CANVAS)
Program (comprised of two similar trials, CANVAS and
CANVAS-Renal; n= 10,142) in participants with type 2 diabe-
tes, 66% of whom had a history of CVD. Participants were
followed for a median of 3.6 years. In the combined analysis
of the two trials, the primary composite endpoint of MI, stroke
or cardiovascular death was reduced with canagliflozin (26.9 vs
31.5 participants per patient-year with placebo; HR 0.86, 95%
CI 0.75, 0.97; p= 0.02) for superiority in the pooled analysis,
with consistent findings in the component studies. Though
there was a trend towards benefit for cardiovascular death, the
difference from placebo was not statistically significant in the
CANVAS Program [52]. For the SGLT2 inhibitors studied to
date, it appears that among patients with established CVD,there
is likely cardiovascular benefit, with the evidence of benefit
modestly stronger for empagliflozin than canagliflozin.
Adverse effects for the class are discussed in the section ‘The
full range of therapeutic options: lifestyle management, medi-
cation and obesity management’.
While the evidence of an ASCVD outcomes benefit for
GLP-1 receptor agonists and SGLT2 inhibitors has been dem-
onstrated for people with established ASCVD, the evidence of
benefit beyond glucose lowering has not been demonstrated in
those without ASCVD. Indeed, in subgroup analyses of these
trials, lower risk individuals have not been observed to have an
ASCVD benefit. While this may be due to the short time frame
of the studies and the low event rate in those without ASCVD,
the finding is consistent across the reported trials. Overall,
CVOTs of dipeptidyl peptidase-4 (DPP-4) inhibitors have dem-
onstrated safety, i.e. non-inferiority relative to placebo, for the
primary MACE endpoint, but not cardiovascular benefit.
The available evidence for cardiovascular event reduction
in patients with type 2 diabetes and clinical CVD is derived
from trials in which the participants were not meeting
glycaemic targets (HbA
1c
≥53 mmol/mol [≥7%] at baseline).
Furthermore, most (~70% across trials) participants were
treated with metformin at baseline. Thus, we recommend that
patients with clinical CVD not meeting individualised
glycaemic targets while treated with metformin (or in whom
metformin is contraindicated or not tolerated) should have an
SGLT2 inhibitor or GLP-1 receptor agonist with proven ben-
efit for cardiovascular risk reduction added to their treatment
programme. There are no clinical trial data that support pre-
scribing an SGLT2 inhibitor or GLP-1 receptor agonist with
theintentofreducingcardiovascularriskinpatientswithan
HbA
1c
<53 mmol/mol (<7%). Limited data suggest that there
is no heterogeneity in the cardiovascular benefits of SGLT2
inhibitors or GLP-1 receptor agonists as a function of
background glucose-lowering therapy. Thus, background
glucose-lowering therapy in patients with clinical CVD argu-
ably is not pertinent in clinical decision making. However,
dose adjustment or discontinuation of background medica-
tions may be required to avoid hypoglycaemia when adding
a new agent to a regimen containing insulin, sulfonylurea or
glinide therapy, particularly in patients at or near glycaemic
goals. Full efforts to achieve glycaemic and blood pressure
targets and to adhere to lipid, antiplatelet, antithrombotic and
tobacco cessation guidelines [7] should continue after an
SGLT2 inhibitor or GLP-1 receptor agonist is added, as such
efforts were integral to all studies that have demonstrated car-
diovascular benefit of these agents.
Patients with type 2 diabetes are at increased risk of HF
[53]. In the EMPA-REG OUTCOME and CANVAS CVOT
studies testing SGLT2 inhibitors, which enrolled participants
with ASCVD, >85% of participants did not have symptomatic
HF at baseline. Yet, in both trials there was a clinically and
statistically significant reduction in hospitalisation for HF for
the SGLT2 inhibitor as compared with placebo. In the EMPA-
REG OUTCOME study with empagliflozin [54], the ARR
was 1.4%, and the HR 0.65 (95% CI 0.50, 0.85) and in the
CANVAS Program with canagliflozin the HR was 0.67 (95%
CI 0.52, 0.87), with a rate of hospitalised HF of 5.5 vs 8.7
events per 1000 patient-years [55]. Because HF was neither
well characterised at baseline nor as carefully adjudicated as it
wouldhavebeeninatrialspecificallydesignedtoevaluateHF
outcomes, and because HF was a secondary endpoint in the
trials, further ongoing studies are required to conclusively ad-
dress the issue. That said, the significant reduction in
hospitalisation for HF demonstrated in the two study popula-
tions and the consistency across two independent trial
programmes suggest to us that treatment with SGLT2 inhibi-
tors in the setting of clinical HF may provide substantial ben-
efit and should be specifically considered in people with type
2 diabetes and ASCVD and HF.
In the GLP-1 receptor agonist studies LEADER,
SUSTAIN 6 and EXSCEL, there was no significant effect
on hospitalization for HF with HR 0.86 (95% CI 0.71, 1.06),
1.11 (95% CI 0.77, 1.61) and 0.94 (95% CI 0.78, 1.13), re-
spectively [47–49]. Two short-term studies of liraglutide in
patients with reduced ejection fraction suggested a lack of
benefit in this setting [56,57].
Among the recent cardiovascular safety outcomes trials
testing DPP-4 inhibitors, the Saxagliptin Assessment of
Vascular Outcomes Recorded in Patients with Diabetes
Consensus recommendation
Among patients with ASCVD in whom HF coexists or is
of special concern, SGLT2 inhibitors are recommended
(Figs 2 and 3).
Diabetologia

Mellitus –Thrombolysis in Myocardial Infarction 53
(SAVOR-TIMI 53) study evaluating saxagliptin demonstrated
a significant increased risk of HF, with 3.5% risk of
hospitalisation for HF vs 2.8% for placebo (HR 1.27; 95%
CI 1.07, 1.51; p= 0.007) [58]. In the subsequent
Examination of Cardiovascular Outcomes with Alogliptin versus
Standard of Care (EXAMINE) study of alogliptin there was no
statistically significant difference in HF hospitalisation (3.9% vs
3.3% with placebo) [59],andintheTrialEvaluating
Cardiovascular Outcomes with Sitagliptin (TECOS), the rate of
hospitalisation for HF was 3.1% in both sitagliptin- and placebo-
treated patients [60].
Patients with type 2 diabetes and kidney disease are at an
increased risk for cardiovascular events. A substantial number
of participants with an eGFR of 30–60 ml min
−1
[1.73 m]
−2
were
included in EMPA-REG OUTCOME, CANVAS, LEADER
and SUSTAIN 6. An important finding in the studies was reduc-
tion of the primary ASCVD outcome even among participants
with stage 3 CKD (eGFR 30–60 ml min
−1
[1.73 m]
−2
). For
SGLT2 inhibitors, this contrasts with the glucose-lowering effect,
which diminishes with declining eGFR.
In addition to the primary cardiovascular endpoints, most
of the SGLT2 inhibitor and GLP-1 receptor agonist CVOTs
reported benefit in renal endpoints, albeit as secondary out-
comes. The renal outcome benefit has been most pronounced
and consistent for SGLT2 inhibitors. EMPA-REG
OUTCOME (empagliflozin) demonstrated an ARR 6.1%,
HR of 0.61 (95% CI 0.53, 0.70) for the composite outcome
of new or worsening nephropathy (progression to urine
albumin/creatinine ratio >33.9 mg/mmol (>300 mg/g), dou-
bling of serum creatinine and ESRD, or death by ESRD). The
most prevalent outcome component was the development of
sustained albuminuria, but the other components were each
significantly reduced relative to placebo [61]. CANVAS
(canagliflozin) reported an HR of 1.7 (95% CI 1.51, 1.91)
for regression of albuminuria and a 40% reduction in risk in
the composite outcome of eGFR, ESRD or renal death (5.5 vs
9.0 participants per 1000 patient-years; HR 0.60; 95% CI
0.47, 0.77) [52]. Additional trials with primary renal endpoints
are ongoing in high-risk renal populations. The Canagliflozin
and Renal Endpoints in Diabetes with Established
Nephropathy Clinical Evaluation (CREDENCE) trial examin-
ing canagliflozin in CKD withproteinuria has been stopped at
a planned interim analysis for achieving the primary efficacy
endpoint [62].
In LEADER and SUSTAIN 6, the GLP-1 receptor agonist
liraglutide was associated with an ARR of 1.5% and an HR of
0.78 (95% CI 0.67, 0.92) for new or worsening nephropathy
[63], and semaglutide demonstrated an ARR of 2.3% and an
HR of 0.64 (95% CI 0.46, 0.88) for new or worsening ne-
phropathy [48]. Progression of albuminuria was the most
prevalent component of the composite renal endpoint, where-
as the other components (doubling of serum creatinine, ESRD
or renal death) did not contribute substantially to the benefit.
In the DPP-4 inhibitor CVOTs, the DPP-4 inhibitors have
been shown to be safe from a renal perspective, with modest
reduction in albuminuria [64].
The full range of therapeutic options: lifestyle
management, medication and obesity
management
This section summarises the lifestyle, medication and obe-
sity management therapies that lower glucose or improve
other outcomes in patients with type 2 diabetes. A more
comprehensive discussion of these issues is available else-
where [3,21,65]. For more details on weight loss medi-
cations and metabolic surgery, see the section ‘Obesity
management beyond lifestyle intervention’. Basic infor-
mation about specific options in each category of therapy
is summarised in Table 2.
Lifestyle interventions, including MNT and physical activ-
ity, are effective and safe for improving glucose control in type
2 diabetes. For these reasons, they are recommended as first-
line therapies from the time of diagnosis and as co-therapy for
patients who also require glucose-lowering medications or
metabolic surgery. Lifestyle management should be part of
the ongoing discussion with individuals with type 2 diabetes
at each visit.
Lifestyle management
Medical nutrition therapy
MNT comprises education and support to help patients
adopt healthy eating patterns. The goal of MNT is to
manage blood glucose and cardiovascular risk factors to
reduce risk for diabetes-related complications while pre-
serving the pleasure of eating [21]. Two basic dimen-
sions of MNT include dietary quality and energy restric-
tion. Strategies directed at each dimension can improve
glycaemic control.
Consensus recommendation
An individualised programme of MNT should be offered
to all patients.
Consensus recommendation
For patients with type 2 diabetes and CKD, with or
without CVD, consider the use of an SGLT2 inhibitor
shown to reduce CKD progression or, if contraindicated
or not preferred, a GLP-1 receptor agonist shown to
reduce CKD progression (Figs 2 and 3).
Diabetologia

Table 2 Glucose-lowering medications and therapies available in the USA or Europe and specific characteristics that may guide individualised treatment choices in non-pregnant adults with type 2
diabetes
Class Medications/therapies in
class
Primary physiological
action(s)
Advantages Disadvantages/adverse effects Efficacy
Lifestyle
Diet quality •Mediterranean type
•DASH
•Low carbohydrate
•Vegetarian
•Others
•Depends on diet •Inexpensive
•No side effects
•Requires instruction
•Requires motivation
•Requires lifelong behavioural change
•Social barriers may exist
Intermediate
Physical activity •Running, walking
•Bicycling (including
stationary)
•Swimming
•Resistance training
•Yog a
•Tai chi
•Many others
•Energy expenditure
•Weight management
•↑Insulin sensitivity
•Inexpensive
•↓Fall risk by increasing
balance/strength
•? Improves mental health
•↑Bone density
•↓Blood pressure
•↓Weight
•Improves ASCVD risk factors
•Risk of musculoskeletal injury
•Requires motivation
•Risk of foot trauma in patients with
neuropathy
•Requires lifelong behavioural change
Intermediate
Energy restriction •Individual energy
restriction with or without
energy tracking
•Programmes with
counselling
•Food substitution
programmes
•Energy restriction
•Weight management
•↓Hepatic and pancreatic fat
•↑Insulin sensitivity
•Lowers glycaemia
•Reduces need for diabetes and
other medications
•No serious side effects
•Improves ASCVD risk factors
•Requires motivation
•Requires lifelong behavioural change
Variable, with potential
for very high efficacy;
often intermediate
Oral medications
Biguanides •Metformin •↓Hepatic glucose production
•Multiple other
non-insulin-mediated
mechanisms
•Extensive experience
•No hypoglycaemia
•Inexpensive
•GI symptoms
•Vitamin B
12
deficiency
•Use with caution or dose adjustment
for CKD stage 3B (eGFR
30–44 ml min
−1
[1.73 m]
−2
)
•Lactic acidosis (rare)
High
SGLT2 inhibitors •Canagliflozin
•Dapagliflozin
•Empagliflozin
•Ertugliflozin
•Blocks glucose reabsorption
by the kidney, increasing
glucosuria
•? Other tubulo-glomerular
effects
•No hypoglycaemia
•↓Weight
•↓Blood pressure
•Effective at all stages of T2DM
with preserved glomerular function
•↓MACE, HF, CKD with some
agents (see text)
•Genital infections
•UTI
•Polyuria
•Volume depletion/
hypotension/dizziness
•↑LDL-C
•↑Creatinine (transient)
•Dose adjustment/avoidance for renal
disease
•↑Risk for amputation (canagliflozin)
•↑Risk for fracture (canagliflozin)
•↑Risk for DKA (rare)
•Fournier’s gangrene (rare)
•Expensive
Intermediate–high
(dependent on GFR)
Diabetologia

Tab l e 2 (continued)
Class Medications/therapies in
class
Primary physiological
action(s)
Advantages Disadvantages/adverse effects Efficacy
DPP-4 inhibitors •Sitagliptin
•Vildagliptin
a
•Saxagliptin
•Linagliptin
•Alogliptin
•Glucose dependent:
↑Insulin secretion
↓Glucagon secretion
•No hypoglycaemia
•Weight neutral
•Well tolerated
•Rare urticaria/angioedema
•↑HF hospitalisation (saxagliptin)
•Dose adjustment/avoidance for renal
disease depending on agent
•? Pancreatitis
•? Arthralgia
•? Bullous pemphigoid
•Expensive (USA); variable in Europe
Intermediate
Sulfonylureas •Glibenclamide/glyburide
•Glipizide
•Gliclazide
a
•Glimepiride
•↑Insulin secretion •Extensive experience
•↓Microvascular risk (UKPDS)
•Inexpensive
•Hypoglycaemia
•↑Weight
•Uncertain cardiovascular safety
•Dose adjustment/avoidance for renal
disease
•High rate of secondary failure
High
TZDs •Pioglitazone
•Rosiglitazone
b
•↑Insulin sensitivity •Low risk for hypoglycaemia
•Durability
•↑HDL-C
•↓Triacylglycerols (pioglitazone)
•↓ASCVD events (pioglitazone: in
a post-stroke insulin-resistant
population and as secondary
endpoint in a high-CVD-risk
diabetes population)
•Lower cost
•↑Weight
•Oedema/heart failure
•Bone loss
•↑Bone fractures
•↑LDL-C (rosiglitazone)
•? Bladder cancer
•? Macular oedema
High
Meglitinides (Glinides) •Repaglinide
•Nateglinide
•↑Insulin secretion •↓Postprandial glucose excursions
•Dosing flexibility
•Safe in advanced renal disease with
cautious dosing (especially
repaglinide)
•Lower cost
•Hypoglycaemia
•↑Weight
•Uncertain cardiovascular safety
•Frequent dosing schedule
Intermediate—high
α-Glucosidase inhibitors •Acarbose
•Miglitol
•Slows carbohydrate
digestion/absorption
•Low risk for hypoglycaemia
•↓Postprandial glucose excursions
•Non-systemic mechanism of action
•Cardiovascular safety
•Lower cost
•Frequent GI side effects
•Frequent dosing schedule
•Dose adjustment/avoidance for renal
disease
Low–intermediate
Bile acid sequestrants •Colesevelam
b
•?↓Hepatic glucose
production
•?↑Incretin levels
•No hypoglycaemia
•↓LDL-C
•Constipation
•↑Triacylglycerols
•May ↓absorption of other medications
•Intermediate expense
Low–intermediate
Dopamine-2 agonists •Quick-release
bromocriptine
b
•Modulates hypothalamic
regulation of metabolism
•↑Insulin sensitivity
•No hypoglycaemia
•?↓ASCVD events
•Headache/dizziness/syncope
•Nausea
•Fatigue
•Rhinitis
•High cost
Low–intermediate
Diabetologia

Tab l e 2 (continued)
Class Medications/therapies in
class
Primary physiological
action(s)
Advantages Disadvantages/adverse effects Efficacy
Injectable medications
Insulins
Long acting (basal) •Degludec (U100, U200)
•Detemir
•Glargine (U100, U300)
•Activates insulin receptor
•↑Glucose disposal
•↓Glucose production
•Nearly universal response
•Theoretically unlimited efficacy
•Once daily injection
•Hypoglycaemia
•Weight gain
•Training requirements
•Frequent dose adjustment for optimal
efficacy
•High cost
Very high
Intermediate acting
(basal)
•Human NPH •Activates insulin receptor
•↑Glucose disposal
•↓Glucose production
•Nearly universal response
•Theoretically unlimited efficacy
•Less expensive than analogues
•Hypoglycaemia
•Weight gain
•Training requirements
•Often given twice daily
•Frequent dose adjustment for optimal
efficacy
Very high
Rapid acting •Aspart (conventional and
fast-acting)
•Lispro (U100, U200)
•Glulisine
•Activates insulin receptor
•↑Glucose disposal
•↓Glucose production
•Nearly universal response
•Theoretically unlimited efficacy
•↓Postprandial glucose
•Hypoglycaemia
•Weight gain
•Training requirements
•May require multiple daily injections
•Frequent dose adjustment for optimal
efficacy
•High cost
Very high
Inhaled rapid acting •Human insulin inhalation
powder
b
•Activates insulin receptor
•↑Glucose disposal
•↓Glucose production
•Nearly universal response
•↓Postprandial glucose
•More rapid onset and shorter
duration than rapid-acting
analogues
•Spirometry (FEV
1
) required before
initiating, after 6 months and annually
•Contraindicated in chronic lung
disease
•Not recommended in smokers
•Hypoglycaemia
•Weight gain
•Training requirements
•May require multiple inhalations daily
•Frequent dose adjustment for optimal
efficacy; limited options in dosing
interval
•High cost
•Respiratory side effects (e.g.
bronchospasm, cough, decline in
FEV
1
)
High
Short acting •Human regular (U100,
U500)
•Activates insulin receptor
•↑Glucose disposal
•↓Glucose production
•Nearly universal response
•Theoretically unlimited efficacy
•↓Postprandial glucose
•Less expensive than analogues
•Hypoglycaemia
•Weight gain
•Training requirements
•Frequent dose adjustment for optimal
efficacy
•May require multiple daily injections
Very high
Diabetologia

Tab l e 2 (continued)
Class Medications/therapies in
class
Primary physiological
action(s)
Advantages Disadvantages/adverse effects Efficacy
Premixed •Many •Activates insulin receptor
•↑Glucose disposal
•↓Glucose production
•Nearly universal response
•Theoretically unlimited efficacy
•Fewer injections than basal/bolus
before every meal
•Recombinant human analogues are
less expensive
•Hypoglycaemia
•Weight gain
•Training requirements
•Frequent dose adjustment for optimal
efficacy
•High cost (except human insulin
premix)
•Canleadtoobligateeating
Very high
GLP-1 RA
Shorter acting •Exenatide
•Lixisenatide
•Glucose dependent:
↑Insulin secretion
↓Glucagon secretion
•Slows gastric emptying
•↑Satiety
•No hypoglycaemia as
monotherapy
•↓Weight
•Excellent postprandial glucose
efficacy for meals after injections
•Improves cardiovascular risk
factors
•Frequent GI side effects that may be
transient
•Modestly ↑heart rate
•Training requirements
•Dose adjustment/avoidance in renal
disease
•Acute pancreatitis (rare/uncertain)
•Very high c o s t
Intermediate–high
Longer acting •Dulaglutide
•Exenatide
extended-release
•Liraglutide
•Semaglutide
•Glucose dependent:
↑Insulin secretion
↓Glucagon secretion
•↑Satiety
•No hypoglycaemia as
monotherapy
•↓Weight
•↓Postprandial glucose excursions
•Improves cardiovascular risk
factors
•↓MACE with some agents (see
text)
•↓Albuminuria with some agents
(see text)
•Greater lowering of fasting glucose
vs short-acting preparations
•Once weekly dosing (except
liraglutide, which is daily)
•GI side effects, including gall bladder
disease
•Greater ↑heart rate
•Training requirements
•Dose adjustment/avoidance for some
agents in renal disease
•Acute pancreatitis (rare/uncertain)
•C cell hyperplasia/medullary thyroid
tumours (rare/uncertain; observed in
animals only)
•Very high c o s t
High–very high
Other injectables
Amylin mimetics •Pramlintide
b
•↓Glucagon secretion
•Slows gastric emptying
•↑Satiety
•↓Postprandial glucose excursions
•↓Weight
•Hypoglycaemia
•Frequent dosing schedule
•Training requirements
•Frequent GI side effects
•Very high c o s t
Intermediate
Fixed-dose
combination of GLP-1
RA and basal insulin
analogues
•Liraglutide/degludec
•Lixisenatide/glargine
•Combined activities of
components
•Enhanced glycaemic efficacy vs
components
•Reduced adverse effects (e.g. GI,
hypoglycaemia) vs components
•Less weight loss than GLP-1 receptor
agonist alone
•Very high c o s t
Very high
Diabetologia

Tab l e 2 (continued)
Class Medications/therapies in
class
Primary physiological
action(s)
Advantages Disadvantages/adverse effects Efficacy
Weight loss medications •Lorcaserin
b
•Naltrexone/bupropion
•Orlistat
•Phentermine/topiramate
b
•Liraglutide 3 mg
•Reduced appetite
•Fat malabsorption (orlistat)
•Mean 3–9 kg weight loss vs
placebo
•High discontinuation rates from side
effects
•<50% achieve ≥5% weight loss
•Drug-specific side effects
•Limited durability
•High cost
Intermediate
Metabolic surgery •VSG
•RYGB
•Adjustable gastric band
•BPD
•Restriction of food intake
(all)
•Malabsorption (RYGB,
BPD)
•Changes in hormonal and
possibly neuronal signalling
(VSG, RYGB, BPD)
•Sustained weight reduction
•↑Rate of remission of diabetes
•↓Number of diabetes drugs
•↓Blood pressure
•Improved lipid metabolism
•High initial cost
•↑Risk for early and late surgical
complications
•↑Risk for reoperation
•↑Risk for dumping syndrome
•↑Nutrient and vitamin malabsorption
•↑Risk for new-onset depression
•↑Risk for new-onset opioid use
•↑Risk for gastroduodenal ulcer
•↑Risk for hypoglycaemia
•↑Risk for alcohol use disorder
Very high
More details available in ADA’s‘Standards of Medical Care in Diabetes—2018’[3]
Glucose-lowering efficacy of drugs by change in HbA
1c
: >22 mmol/mol (2%) very high, 11–22 mmol/mol (1–2%) high, 6–11 mmol/mol (0.5–1.5%) intermediate, <6 mmol/mol (0.5%) low
a
Not licensed in the USA for type 2 diabetes
b
Not licensed in Europe for type 2 diabetes
BPD, biliopancreatic diversion; DASH, Dietary Approaches to Stop Hypertension; DKA, diabetic ketoacidosis; FEV
1
, forced expiratory volume in 1 s on pulmonary function testing; GI, gastrointestinal;
HDL-C, HDL-cholesterol; LDL-C, LDL-cholesterol; RYGB, Roux-en-Y gastric bypass; VSG, vertical sleeve gastroplasty; UTI, urinary tract infection
Diabetologia

Dietary quality and eating patterns There is no single ratio of
carbohydrate, proteins and fat intake that is optimal for every
person with type 2 diabetes. Instead, there are many good
options and professional guidelines usually recommend indi-
vidually selected eating patterns that emphasise foods of dem-
onstrated health benefit, that minimise foods of demonstrated
harm and that accommodate patient preference and metabolic
needs, with the goal of identifying healthy dietary habits that
are feasible and sustainable. Three trials of a Mediterranean
eating pattern reported modest weight loss and improved
glycaemic control [66–68]. In one of these, people with
new-onset diabetes assigned to a low-carbohydrate
Mediterranean eating pattern were 37% less likely to require
glucose-lowering medications over 4 years compared with
patients assigned to a low-fat diet (HR 0.63; 95% CI 0.51,
0.86). A meta-analysis of RCTs in patients with type 2 diabe-
tes showed that the Mediterranean eating pattern reduced
HbA
1c
more than control diets (mean difference −3.3 mmol/
mol, 95% CI −5.1, −1.5 mmol/mol [−0.30%, 95% CI −0.46%,
−0.14%]) [69]. Low-carbohydrate, low-glycaemic index and
high-protein diets, and the Dietary Approaches to Stop
Hypertension (DASH) diet all improve glycaemic control,
but the effect of the Mediterranean eating pattern appears to
be the greatest [70–72]. Low-carbohydrate diets (<26% of
total energy) produce substantial reductions in HbA
1c
at
3 months (−5.2 mmol/mol, 95% CI −7.8, −2.5 mmol/mol
[−0.47%, 95% CI −0.71%, −0.23%]) and 6 months
(4.0 mmol/mol, 95% CI −6.8, −1.0 mmol/mol [−0.36%,
95% CI −0.62%, −0.09%]), with diminishing effects at 12
and 24 months; no benefit of moderate carbohydrate restric-
tion (26–45%) was observed [73]. Vegetarian eating patterns
have been shown to lower HbA
1c
, but not fasting glucose,
compared with non-vegetarian ones [74]. Very recent trials
of different eating patterns in type 2 diabetes have typically
also included weight reduction, hindering firm conclusions
regarding the distinct contribution of dietary quality.
Non-surgical energy restriction for weight loss If a patient
wishes to aim for remission of type 2 diabetes, particularly
within 6 years of diagnosis, evidence-based weight manage-
ment programmes are often successful.
The most effective non-surgical strategies for weight reduc-
tion involve food substitution and intensive, sustained counsel-
ling (e.g. 12–26 individual counselling sessions over 6–
12 months). Among adults with type 2 diabetes, meal replace-
ment (825–853 kcal/day [3450–3570 kj/day] formula-diet for
3–5 months) followed by gradual reintroduction of food and
intensive counselling resulted in 9 kg placebo-adjusted weight
loss at 1 year and high rates of diabetes remission (46% vs 4%;
OR 19.7; 95% CI 7.8, 49.8) compared with best usual practice
[75]. In terms of intensive behavioural interventions, the Action
for Health in Diabetes (Look AHEAD) trial [76]randomised
5145 overweight or obese patients with type 2 diabetes to an
intensive lifestyle programme that promoted energy restriction,
incorporating meal replacements to induce and sustain weight
loss, along with increased physical activity compared with stan-
dard diabetes education and support in the control group. After
9.6 years, weight loss was greater in the intervention group
(8.6%vs0.7%at1year;6.0%vs3.5%atstudyend;bothp
<0.05). HbA
1c
also fell in the intervention group despite less
use of glucose-lowering medications. Cardiovascular event
rates were not reduced but there were numerous other benefits.
In a 12 month trial, 563 adults with type 2 diabetes who were
randomised to Weight Watchers compared with standard care
had a 2.1% net weight loss (−4.0% vs −1.9%; p< 0.001), a
5.3 mmol/mol (−3.5 vs +1.8 mmol/mol; p= 0.020) net absolute
improvement in HbA
1c
(0.48% [−0.32% vs +0.16%]), and a
greater reduction in use of glucose-lowering medications
(−26% vs +12%; p<0.001) [77]. Similar programmes have
resulted in a net 3 kg weight loss over 12–18 months [78–80].
Physical activity
Aerobic exercise, resistance training, and the combination of
the two are effective in reducing HbA
1c
by about 6.6 mmol/
mol (0.6%) [81–84]. Of these modalities, some evidence
suggests that aerobic exercise and the combination of aerobic
exercise and resistance training may be more effective than
resistance training alone [85], but this remains controversial.
When considering exercise interventions, special consider-
ations are required for individuals with CVD, uncontrolled
retinopathy or nephropathy and severe neuropathy. A wide
range of physical activity, including leisure time activities
(e.g. walking, swimming, gardening, jogging, tai chi and
yoga) can significantly reduce HbA
1c
[86–90]. In general,
supervision of exercise and motivational strategies, such as
monitoring using a step counter, can improve the effect of
exercise on HbA
1c
compared with advice alone [84,91].
The combination of dietary change for weight reduction and
physical exercise improves hyperglycaemia and reduces
cardiovascular risk factors more than dietary interventions or
physical activity alone [92].
Consensus recommendation
All overweight and obese patients with diabetes should
be advised of the health benefits of weight loss and
encouraged to engage in a programme of intensive
lifestyle management, which may include food
substitution.
Consensus recommendation
Increasing physical activity improves glycaemic control
and should be encouraged in all people with type 2
diabetes.
Diabetologia

Medications for lowering glucose
Metformin
Metformin is an oral medication that reduces plasma glucose
via multiple mechanisms. It is available as an immediate-
release formulation that is typically administered twice a day
and as extended-release formulations for once-daily or twice-
daily administration. The formulations are equally effective
with no consistent differences in side effect profile [93].
Dosages of immediate-release metformin start at 500 mg once
or twice a day with meals, andshould be increased as tolerated
to a target dosage of 1000 mg twice a day. The maximum daily
dose is 2550 mg in the USA and 3000 mg in the European
Union, though doses above 2000 mg are generally associated
with little additional efficacy and poorer tolerability [94].
Gastrointestinal symptoms are common and dose-dependent,
and may improve over time or with dose reduction. Metformin
should not be used in patients with an eGFR <30 ml min
−1
[1.73 m]
−2
and dose reduction should be considered when the
eGFR is <45 ml min
−1
[1.73 m]
−2
[95–97]. Caution should be
taken when conditions are present that may reduce eGFR.
Advantages of metformin include its high efficacy, low cost,
minimal hypoglycaemia risk when used as monotherapy, and
the potential for some weight loss. Some studies have sug-
gested a benefit for preventing CVD [98], but this has not
been supported by the results of a recent meta-analysis [99].
However, metformin may lower risk for cardiovascular mor-
tality compared with sulfonylurea therapy [100]. Rare cases of
lactic acidosis have been reported, usually in the setting of
severe illness or acute kidney injury. Therefore, metformin
should be omitted in the setting of severe illness, vomiting
or dehydration. Metformin may result in lower serum vitamin
B
12
concentration; therefore, periodic monitoring and supple-
mentation is generally recommended if levels are deficient,
particularly in those with anaemia or neuropathy [101].
Because of its high efficacy in lowering HbA
1c
,goodsafety
profile and low cost, metformin remains the first-line medica-
tion for management of type 2 diabetes.
SGLT2 inhibitors
SGLT2 inhibitors are oral medications that reduce plasma glu-
cose by enhancing urinary excretion of glucose [102]. The
glucose-lowering efficacy of these medications is dependent
on renal function. Initiation and continuation of SGLT2 inhib-
itors are restricted by eGFR and require intermittent monitor-
ing of renal function (refer to European Medicines Agency
and US Food and Drug Administration prescribing informa-
tion for current recommendations). These medications are of
high efficacy in lowering glucose in the setting of normal renal
function [51,52,103]. All SGLT2 inhibitors are associated
with a reduction in weight and blood pressure. Alone or with
metformin, they do not increase the risk for hypoglycaemia.
Empagliflozin and canagliflozin have cardiac and renal bene-
fits in patients with established or at high risk of ASCVD.
Cardiac and renal benefits have been demonstrated down to
an eGFR of 30 ml min
−1
[1.73 m]
−2
, though currently none of
the SGLT2 inhibitors have been approved for use by regula-
tors at an eGFR below 45 ml min
−1
[1.73 m]
−2
(see the section
‘Recommended process for glucose-lowering medication se-
lection: where does new evidence from cardiovascular out-
comes trials fit in?’)[51,52,61]. The class is associated with
increased risk for mycotic genital infections (mostly vaginitis
in women, balanitis in men) [51,52,104,105]. Case reports of
diabetic ketoacidosis with SGLT2 inhibitors in type 2 diabetes
continue to raise concern, though increased rates have not
been confirmed in large trials [102,106]. Therefore, the
SGLT2 inhibitors should be used with caution and appropriate
patient education should be provided for those with insulin
deficiency. SGLT2 inhibitors have been associated with an
increased risk of acute kidney injury, dehydration and ortho-
static hypotension; caution should be taken when SGLT2 in-
hibitors are used in combination with diuretics and/or ACE
inhibitors and angiotensin receptor blockers. Canagliflozin
has been associated with increased risk for lower limb ampu-
tation (6.3 canagliflozin vs 3.4 per 1000 patient-years with
placebo after 3.1 years; HR 1.97; 95% CI 1.41, 2.75;) [52].
Similarly, fracture risk has been reported with canagliflozin
(15.4 vs 11.9 participants with fracture per 1000 patient-
years; HR 1.26; 95% CI 1.04, 1.52) [52]. It is uncertain wheth-
er amputation and fractures are class effects.
GLP-1 receptor agonists
GLP-1 receptor agonists are currently delivered by subcutane-
ous injection. These medications stimulate insulin secretion
and reduce glucagon secretion in a glucose-dependent manner,
improve satiety and promote weight loss [107,108]. Structural
differences among GLP-1 receptor agonists affect duration of
action, and their formulation and dosing may affect efficacy
for glucose-lowering and weight reduction as well as side
effect profile and cardiovascular effects [109]. Dulaglutide,
exenatide extended-release and semaglutide are administered
once weekly [108,109]. Liraglutide and lixisenatide are ad-
ministered once daily, and exenatide is available in a twice-
daily formulation. GLP-1 receptor agonists have high glucose-
lowering efficacy, but with variation within the drug class
[110,111]. Evidence suggests that the effect may be greatest
for semaglutide once weekly, followed by dulaglutide and
liraglutide, closely followed by exenatide once weekly, and
then exenatide twice daily and lixisenatide [110,112–116].
The short-acting medications exenatide twice daily and
lixisenatide have greater postprandial effects, at least after
the meals with which they are administered. All GLP-1 recep-
tor agonists reduce weight [110]; the reduction ranges from
Diabetologia

about 1.5 kg to 6.0 kg over about 30 weeks of therapy [110,
117]. Liraglutide and semaglutide have been shown to im-
prove cardiovascular outcomes [47,48] (see the section
‘Recommended process for glucose-lowering medication se-
lection: where does new evidence from cardiovascular out-
comes trials fit in?’). The most common side effects of GLP-
1 receptor agonists are nausea, vomiting and diarrhoea, though
these tend to diminish over time. GLP-1 receptor agonists
have minimal risk for hypoglycaemia, but may increase the
hypoglycaemic potential of insulin and sulfonylureas when
combined with those medications [118]. Contrary to early sig-
nals, GLP-1 receptor agonists do not seem to substantially
increase risk for pancreatitis, pancreatic cancer or bone disease
[119]. They are associated with increased risk of gallbladder
events [120]. Semaglutide was associated with increased reti-
nopathy complications in the SUSTAIN 6 trial (HR 1.76, 95%
CI 1.11, 2.78), largely among those with baseline retinopathy
who had rapid improvement of glycaemic control [48]. While
this observation remains unexplained, this is also a recognised
effect of intensification of glycaemic control with insulin.
DPP-4 inhibitors
DPP-4 inhibitors are oral medications that increase insulin se-
cretion and reduce glucagon secretion in a glucose-dependent
manner. They have moderate glucose-lowering efficacy [121,
122]. DPP-4 inhibitors are well tolerated, have a neutral effect
on weight and have minimal risk of hypoglycaemia when used
as monotherapy [123]. When added to sulfonylurea therapy,
however, the risk for hypoglycaemia is increased 50% com-
pared with sulfonylurea therapy alone [124]. The recommend-
ed dose foreach DPP-4 inhibitor is determined and needs to be
adjusted based on renal function; linagliptin is the exception as
it has minimal renal excretion. Rare but increased rates of
pancreatitis [125] and musculoskeletal side effects have been
reported [126]. CVOTs demonstrated the cardiovascular safety
but no cardiovascular benefit of three DPP-4 inhibitors
(saxagliptin, alogliptin and sitagliptin) as well as imbalances
regarding HF for saxagliptin and alogliptin [127,128](seethe
section ‘Recommended process for glucose-lowering medica-
tion selection: where does new evidence from cardiovascular
outcomes trials fit in?’.
Thiazolidinediones
Thiazolidinediones (TZDs) (pioglitazone and rosiglitazone)
are oral medications that increase insulin sensitivity and are
of high glucose-lowering efficacy [129–131]. TZDs increase
HDL-cholesterol [132,133], and pioglitazone has been shown
to reduce cardiovascular endpoints [132,134–138] and hepat-
ic steatohepatitis [139], but without conclusive evidence for
benefit. TZDs are associated with the best evidence among
glucose-lowering medications for glycaemic durability
[140]. However, these notable benefits must be balanced with
safety concerns regarding fluid retention and congestive heart
failure [136,140,141], weight gain [132,136,140–142],
bone fracture [143,144] and, possibly, bladder cancer [145].
Lower dose therapy (e.g. pioglitazone 15–30 mg) mitigates
weight gain and oedema, but the broader benefits and harms
of low-dose TZD therapy have not been evaluated.
Sulfonylureas
Sulfonylureas are oral medications that lower glucose by stim-
ulating insulin secretion from pancreatic beta cells. They are
inexpensive, widely available, and have high glucose-
lowering efficacy [146]. Sulfonylureas were used as part of
the glucose-lowering regimen in the UK Prospective Diabetes
Study (UKPDS) [147] and Action in Diabetes and Vascular
Disease: Preterax and Diamicron MR Controlled Evaluation
(ADVANCE) [148] trials, which both demonstrated reduc-
tions in microvascular complications. Sulfonylureas are asso-
ciated with weight gain and risk for hypoglycaemia and down
titration of dose to reduce the risk of hypoglycaemia results in
higher HbA
1c
[146,149,150]. Sulfonylureas are known to be
associated with a lack of durable effect on glucose lowering
[144,151].Theweightgainassociatedwithsulfonylureasis
relatively modest in large cohort studies and the incidence of
severe hypoglycaemia is lower than with insulin [152].
Important differences among sulfonylureas affect both safety
and efficacy. Glibenclamide (known as glyburide in the USA
and Canada) has a higher risk of hypoglycaemia compared
with other sulfonylureas [153]. Glipizide, glimepiride and
gliclazide may have a lower risk for hypoglycaemia compared
with other sulfonylureas [152,154]. Adverse cardiovascular
outcomes with sulfonylureas in some observational studies
have raised concerns, although findings from recent system-
atic reviews have found no increase in all-cause mortality
compared with other active treatments [152]. As newer-
generation sulfonylureas appear to confer a lower risk of
hypoglycaemia and have favourable cost, efficacy and safety
profiles, sulfonylureas remain a reasonable choice among
glucose-lowering medications, particularly when cost is an
important consideration. Patient education and use of low or
variable dosing with later-generation sulfonylureas may be
used to mitigate the risk of hypoglycaemia. Greatest caution
in this regard is warranted for people at high risk of
hypoglycaemia, such as older patients and those with CKD.
Insulin
Numerous formulations of insulin are available with differing
durations of action. ‘Human’insulins (NPH, regular [R], and
premixed combinations of NPH and R) are recombinant
DNA-derived human insulin, while insulin analogues have
been designed to change the onset or duration of action. The
Diabetologia

main advantage of insulin over other glucose-lowering medi-
cations is that insulin lowers glucose in a dose-dependent
manner over a wide range, to almost any glycaemic target as
limited by hypoglycaemia. Older formulations of insulin have
also demonstrated reduction in microvascular complications
and with long-term follow-up, all-cause mortality and
diabetes-related death [147,155]. Beyond hypoglycaemia,
the disadvantages of insulin include weight gain and the need
for injection, frequent titration for optimal efficacy and glu-
cose monitoring [156].
The effectiveness of insulin is highly dependent on its ap-
propriate use; patient selection and training; adjustment of
dose for changes in diet, activity or weight; and titration to
acceptable, safe glucose targets. Formulations of intermediate-
and long-acting insulin have different timings of onset, dura-
tions of action and risks of hypoglycaemia. However, the way
in which insulin is administered, including the dose, timing of
injection and glycaemic targets, has a greater impact on the
adverse effects of insulin than differences among insulin
formulations.
Basal insulin Basal insulin refers to longer-acting insulin that
is meant to cover the body’s basal metabolic insulin
requirement (regulating hepatic glucose production), in
contrast to bolus or prandial insulin, which is meant to reduce
glycaemic excursions after meals. Basal insulin is the
preferred initial insulin formulation in patients with type 2
diabetes. Options include once- or twice-daily administration
of intermediate-acting NPH or detemir insulin and the once-
daily administration of glargine (U100 or U300) or degludec
(U100 or U200). Long-acting insulin analogues (degludec
[U100 or U200], glargine [U100 and U300], detemir) have a
modestly lower absolute risk for hypoglycaemia compared
with NPH insulin, but cost more [157–160]. However, in
real-world settings where patients are treated to conventional
treatment targets, initiation of NPH compared with determir or
glargine U100 did not increase hypoglycaemia-related
emergency department visits or hospital admissions [161].
When comparing human and analogue insulins, cost
differences can be large while differences in hypoglycaemia
risk are modest and differences in glycaemic efficacy
minimal.
Degludec is associated with a lower risk of severe
hypoglycaemia compared with glargine U100 insulin when
targeting intensive glycaemic control in patients with long-
standing type 2 diabetes at high risk of CVD; absolute inci-
dence difference of 1.7% over 2 years (rate ratio 0.60; p<
0.001 for superiority; OR 0.73; p< 0.001 for superiority)
[162]. Biosimilar formulations are now available for glargine
with similar efficacy profile and lower cost [163]. No insulin
has been shown to reduce risk for CVD [156], but data suggest
that glargine U100 and degludec do not increase risk for
MACE [162,164].
Concentrated formulationsof degludec (U200) and glargine
(U300) are available that allow injection of a reduced volume,
a convenience for patients on higher doses. Glargine U300 is
associated with a lower risk of nocturnal hypoglycaemia com-
pared with glargine U100 but requires a 10–14% higher dose
of glargine for equivalent efficacy [165–167].
Not all patients have their blood glucose adequately con-
trolled with basal insulin. In particular, patients with higher
pre-treatment HbA
1c
, higher BMI, longer duration of disease,
and a greater number of oral glucose-lowering medications are
more likely to require intensified therapy [168].
Other insulin formulations Short- and rapid-acting insulin
formulations administered at mealtime are generally used
to intensify basal insulin therapy in patients not meeting
glycaemic targets. Options include human regular insulin,
various analogues (aspart, glulisine and lispro), formula-
tions (faster insulin aspart, lispro U200), biosimilars
(lispro), and insulins with different routes of administration
(inhaled). Rapid-acting insulin analogues have a modestly
lower risk for hypoglycaemia compared with human regular
insulin but at a higher cost. Various premixed formulations
of human and analogue insulins are available and continue
to be widely used in some regions, though they tend to have
an increased risk of hypoglycemia as compared with basal
insulin alone (Table 2and Fig. 7).
Other glucose-lowering medications
Other oral glucose-lowering medications (i.e. meglitinides,
α-glucosidase inhibitors, colesevelam, quick-release bro-
mocriptine, pramlintide) are not used commonly in the
USA and some are not licensed at all in Europe. No major
new scientific information on these medications has
emerged in recent years. Their basic characteristics are
listed in Table 2.
Obesity management beyond lifestyle intervention
Medications for weight loss
Several clinical practice guidelines recommend weight loss
medications as an optional adjunct to intensive lifestyle man-
agement for patients with obesity, particularly if they have dia-
betes [169–171]. Others do not [172]. Several medications and
medication combinations approved in the USA or Europe for
weight loss have been found to improve glucose control in
people with diabetes [173,174]. One glucose-lowering medica-
tion, liraglutide, is also approved for the treatment of obesity at a
higher dose [175]. Cost, side effects and modest efficacy limit
the role of pharmacotherapy in long-term weight management.
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Fig. 7 Intensifying to injectable therapies
Diabetologia

Metabolic surgery
Metabolic surgery is highly effective in improving glucose con-
trol [176–178] and often produces disease remission [179–182].
The effects can be sustained for at least 5 years [177,182].
Benefits include a reduction in the number of glucose-lowering
medications needed to achieve glycaemic targets [178,179].
Several clinical practice guidelines and position statements
recommend consideration of metabolic surgery as a treatment
option for adults with type 2 diabetes and (1) a BMI ≥40.0 kg/
m
2
(BMI ≥37.5 kg/m
2
in people of Asian ancestry) or (2) a
BMI of 35.0–39.9 kg/m
2
(32.5–37.4 kg/m
2
in people of Asian
ancestry) who do not achieve durable weight loss and im-
provement in comorbidities with reasonable non-surgical
methods [65,183]. Because baseline BMI does not predict
surgical benefits on glycaemia or hard outcomes and the im-
provement in glyacemic control occurs early through weight-
independent mechanisms [183], metabolic surgery may be
considered for those with a BMI of 30.0–34.9 kg/m
2
(27.5–
32.4 in people of Asian ancestry) who do not achieve durable
weight loss and improvement in comorbidities with reason-
able non-surgical methods.
Adverse effects of bariatric surgery which vary by proce-
dure include surgical complications (e.g. anastomotic or staple
line leaks, gastrointestinal bleeding,intestinal obstruction, the
need for re-operation), late metabolic complications (e.g. pro-
tein malnutrition, mineral deficiency, vitamin deficiency,
anaemia, hypoglycaemia) and gastroesophageal reflux [184,
185]. Patients who undergo metabolic surgery may be at risk
for substance use, including drug and alcohol use and cigarette
smoking [186]. People with diabetes presenting for metabolic
surgery also have increased rates of depression and other ma-
jor psychiatric disorders [187]. These factors should be
assessed pre-operatively and during follow-up. Metabolic sur-
gery should be performed in high-volume centres with multi-
disciplinary teams that are experienced in the management of
diabetes and gastrointestinal surgery. Long-term lifestyle sup-
port and routine monitoring of micronutrient and nutritional
status must be provided to patients after surgery [188,189].
Putting it all together: strategies for implementation
For an increasing number of patients, presence of specific co-
morbidities (e.g. ASCVD, HF, CKD, obesity), safety concerns
(e.g. risk of hypoglycaemia) or healthcare environment (e.g.
cost of medications) mandate a specific approach to the choice
of glucose-lowering medication. These are considered in Figs
2,3,4,5,6. For patients not reaching their target HbA
1c
,itis
important to re-emphasise lifestyle measures, assess adherence
and arrange timely follow-up (e.g. within 3–6 months) (Fig. 1).
Initial monotherapy
Metformin remains the preferred option for initiating glucose-
lowering medication in type 2 diabetes and should be added to
lifestyle measures in newly diagnosed patients. This recom-
mendation is based on the efficacy, safety, tolerability, low
cost and extensive clinical experience with this medication.
Results from a substudy of the UKPDS (n= 342) showed
benefits of initial treatment with metformin on clinical out-
comes related to diabetes, with less hypoglycaemia and
weight gain than with insulin or sulfonylureas [98].
Initial combination therapy compared with stepwise
addition of glucose-lowering medication
In most patients, type 2 diabetes is a progressive disease, a
consequence generally attributed to a steady decline of insulin
secretory capacity. The practical impact of gradual loss of beta
cell function is that achieving a glycaemic target with mono-
therapy is typically limited to several years. Stepwise therapy
(i.e. adding medications to metformin to maintain HbA
1c
at
target) is supported by clinical trials [3]. While there is some
support for initial combination therapy due to the greater initial
reduction of HbA
1c
than can be provided by metformin alone
[190,191], there is little evidence that this approach is superior
to sequential addition of medications for maintaining
glycaemic control, or slowing the progression of diabetes.
However, since the absolute effectiveness of most oral medi-
cations rarely exceeds an 11 mmol/mol (1%) reduction in
HbA
1c
, initial combination therapy may be considered in pa-
tients presenting with HbA
1c
levels more than 17 mmol/mol
(1.5%) above their target. Fixed-dose formulations can im-
prove medication adherence when combination therapy is used
[192], and may help achieve glycaemic targets more rapidly
[100]. Potential benefits of combination therapy need to be
weighed against the exposure of patients to multiple
Consensus recommendation
Metformin is the preferred initial glucose-lowering
medication for most people with type 2 diabetes.
Consensus recommendation
The stepwise addition of glucose-lowering medication is
generally preferred to initial combination therapy.
Consensus recommendation
Metabolic surgery is a recommended treatment option
for adults with type 2 diabetes and (1) a BMI ≥ 40.0
kg/m2 (BMI ≥ 37.5 kg/m2 in people of Asian ancestry) or
(2) a BMI of 35.0–39.9 kg/m2 (32.5–37.4 kg/m2 in people
of Asian ancestry) who do not achieve durable weight
loss and improvement in comorbidities with reasonable
non-surgical methods.
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medications and potential side effects, increased cost and, in
the case of fixed combination medications, less flexibility in
dosing.
Choice of glucose-lowering medication
after metformin
As detailed in the ‘Medications for lowering glucose’section,
the glucose-lowering medications that can be added to met-
formin have distinct profiles of action, efficacy and adverse
effects [100,193]. The early introduction of basal insulin is
well established, in particular when HbA
1c
levels are very
high (>97 mmol/mol [>11%]), symptoms of hyperglycaemia
are present or there is evidence of ongoing catabolism (e.g.
weight loss). This constellation of symptoms can occur in type
2 diabetes but suggest insulin deficiency and raise the possi-
bility of autoimmune (type 1) or pancreatogenic diabetes in
which insulin would be the preferred therapy. While this re-
mains the usual strategy for patients when HbA
1c
levels are
very high, SGLT2 inhibitors [194] and GLP-1 receptor ago-
nists [195] have demonstrated efficacy in patients with HbA
1c
levels exceeding 75 mmol/mol (9%), with the additional ben-
efits of weight reduction and reduced risk of hypoglycaemia.
Evidence from clinical trials supports the use of several of
the SGLT2 inhibitors and GLP-1 receptor agonists as add-on
therapy for people with type 2 diabetes with an HbA
1c
>53 mmol/mol (>7%) and established CVD [48,51,52].
However, since only 15–20% of patients with type 2 diabetes
conform to the characteristics of patients in these trials, other
clinical features need to be considered in the majority when
selecting second medications to add to metformin (Figs 2,3,
4,5,6)[149,196–204].
Sulfonylureas and insulin are associated with an increased
risk for causing hypoglycaemia and would not be preferred for
patients in whom this is a concern. Furthermore,
hypoglycaemia is distressing and so may reduce treatment ad-
herence (Fig. 5). For patients prioritizing weight loss or weight
maintenance (Fig. 4), important considerations include the
weight reduction associated with SGLT-2 inhibitors and
GLP-1 receptor agonists, the weight neutrality ofDPP-4 inhib-
itors, and the weight gain associated with sulfonylureas, basal
insulin and TZDs. An important consideration for society in
general and for many patients in particular is the cost of med-
ications; sulfonylureas, pioglitazone and recombinant human
insulins are relatively inexpensive, although their cost may
vary across regions. Short-term acquisition costs, longer-term
treatment cost and cost-effectiveness should be considered in
clinical decision making when data are available (Fig. 6).
Intensification beyond two medications
The lack of a substantial response to one or more non-insulin
therapies should raise the issue of adherence and, in those with
weight loss, the possibility that the patient has autoimmune
(type 1) or pancreatogenic diabetes. However, it is common in
people with long-standing diabetes to require more than two
glucose-lowering agents, often including insulin. Compared
with the knowledge base guiding dual therapy of type 2 dia-
betes, there is less evidence guiding these choices [205]. In
general, intensification of treatment beyond two medications
follows the same general principles as the addition of a second
medication, with the assumption that the efficacy of third and
fourth medications will be generally less than expected. No
specific combination has demonstrated superiority except for
those that include insulin and GLP-1 receptor agonists that
have broad ranges of glycaemic efficacy. As more medica-
tions are added, there is an increased risk of adverse effects.
It is important to consider medication interactions and whether
regimen complexity may become an obstacle to adherence.
Finally, with each additional medication comes increased
costs, which can affect patient burden, medication-taking be-
haviour and medication effectiveness. [193,205–211].
While most patients require intensification of glucose-
lowering medications, some require medication reduction
or discontinuation of medication, particularly if the therapy
is ineffective or is exposing patients to a higher risk of side
effects such as hypoglycaemia, or when glycaemic goals
have changed due to a change in clinical circumstances
(e.g. development of comorbidities or even healthy age-
ing). A guiding principle is that for all therapies the re-
sponse should be reviewed at regular intervals, including
the impact on efficacy (HbA
1c
, weight) and safety; the
therapy should be stopped, or the dose reduced if there
are minimal benefits or if harm outweighs any benefit. In
particular, ceasing or reducing the dose of medications that
have an increased risk of hypoglycaemia is important when
any new glucose-lowering treatment (lifestyle or medica-
tion) is started (Fig. 7)[40]. HbA
1c
levels below 48 mmol/
mol (6.5%) or substantially below the individualised
glycaemic target should prompt consideration of stopping
Consensus recommendation
Intensification of treatment beyond dual therapy to
maintain glycaemic targets requires consideration of the
impact of medication side effects on comorbidities, as
well as the burden of treatment and cost.
Consensus recommendation
The selection of medication added to metformin is
based on patient preference and clinical characteristics.
Important clinical characteristics include the presence of
established ASCVD and other comorbidities such as HF
or CKD; the risk for specific adverse medication effects,
particularly hypoglycaemia and weight gain; as well as
safety, tolerability and cost (Figs 2–6).
Diabetologia

or reducing the dose of medications with risk of
hypoglycaemia or weight gain.
Addition of injectable medications
See the ‘Insulin’and ‘Basal insulin’sections in ‘Medications
for lowering glucose’for more medication details.
Patients often prefer combinations of oral medications
to injectable medications. The range of combinations avail-
able with current oral medications allows many people to
reach glycaemic targets safely. However, there is currently
no evidence that any single medication or combination has
durable effects and, for many patients, injectable medica-
tions become necessary within 5–10 years of diabetes
diagnosis.
Evidence from trials comparing GLP-1 receptor agonists
and insulin (basal, premixed or basal-bolus) shows similar or
even better efficacy in HbA
1c
reduction [212,213]. GLP-1
receptor agonists have a lower risk of hypoglycaemia and
are associated with reductions in body weight compared with
weight gain with insulin [212,214]. Some GLP-1 receptor
agonists allow for once weekly injections, as opposed to daily
or more often for insulin. Based on these considerations, a
GLP-1 receptor agonist is the preferred option in a patient with
a definite diagnosis of type 2 diabetes who needs injectable
therapy. However, the tolerability and high cost of GLP-1
receptor agonists are important limitations to their use. If ad-
ditional glucose lowering is needed despite therapy with a
long-acting GLP-1 receptor agonist, the addition of basal in-
sulin is a reasonable option [215,216].
Alternatively, the addition of insulin to oral medica-
tion regimens is well established. In particular, using
basal insulin in combination with oral medications is
effective, and has less hypoglycaemia and weight gain
than combinations using premixed insulin formulations
or prandial insulin [217]. A standard approach for
optimising basal insulin regimens is to titrate the dose
based on a target fasting glucose concentration, which
is a simple index of effectiveness. Either NPH insulin
or long-acting insulin analogues are efficacious for con-
trolling fasting glucose, although basal analogue formu-
lations show reduced risks of hypoglycaemia, particularly
overnight, when titrated to the same fasting glucose tar-
get as NPH insulin [157,218].
Beyond basal insulin
It has become common practice to approach insulin use in
people with type 2 diabetes by following the established par-
adigms developed for those with type 1 diabetes. This in-
cludes multiple daily injections with doses of insulin ana-
logues before meals that are adjusted based on ambient blood
glucose and meal constituents. While this is reasonable for
people with type 2 diabetes who are lean, insulinopenic and
sensitive to exogenous insulin, it ignores the substantial dif-
ferences in pathophysiology between most people with type 2
diabetes and type 1 diabetes. Most people withtype 2 diabetes
are obese and insulin resistant, requiring much larger doses of
insulin and experiencing lower rates of hypoglycaemia than
those with type 1 diabetes. In patients with type 2 diabetes,
weight gain is a particularly problematic side effect of insulin
use. Recent evidence supports the effectiveness of combina-
tions of insulin with glucose-lowering medications that do not
increase body weight. For example, SGLT2 inhibitors can be
added to insulin regimens to lower blood glucose levels with-
out increasing insulin doses, weight gain or hypoglycaemia
[219–221]. In a meta-analysis that studied the combination of
either SGLT2 inhibitors or DPP-4 inhibitors with insulin, the
SGLT2 inhibitor–insulin combination was associated with a
greater reduction in HbA
1c
, an advantage in terms of body
weight and no increase in the rates of hypoglycaemia [222,
223]. Depending on baseline HbA
1c
, glycaemic profile and
individual response, the insulin dose may need to be reduced
to prevent hypoglycaemia when adding an SGLT2 inhibitor.
The combination of basal insulin and a GLP-1 receptor
agonist has high efficacy, with recent evidence from clinical
trials demonstrating the benefits of this combination to lower
HbA
1c
and limit weight gain and hypoglycaemia compared
with intensified insulin regimens [224,225]. Most data come
from studies in which a GLP-1 receptor agonist is added to
basal insulin. However, there is evidence that insulin added to
a GLP-1 receptor agonist can also effectively lower HbA
1c
,
although some weight gain results [215]. Fixed-ratio combi-
nations of insulin and GLP-1 receptor agonists are available
and can decrease the number of injections compared with
administering the medications separately [226–228].
A final approach to glycaemic management when basal
insulin plus oral medications is insufficient to achieve
HbA
1c
targets is intensified insulin regimens (Figs 7and 8).
DSMES focused on insulin therapy is particularly helpful
when intensified insulin therapy is considered. Referral to a
Consensus recommendation
Patients who are unable to maintain glycaemic targets
on basal insulin in combination with oral medications
can have treatment intensified with GLP-1 receptor
agonists, SGLT2 inhibitors or prandial insulin (Figs 7
and 8).
Consensus recommendation
In patients who need the greater glucose-lowering effect
of an injectable medication, GLP-1 receptor agonists
are the preferred choice to insulin. For patients with
extreme and symptomatic hyperglycaemia, insulin is
recommended (Fig. 7).
Diabetologia

diabetes specialist team should be considered in cases where
the provider is uncomfortable or unfamiliar with intensifica-
tion, poor outcomes continue despite intensification, or pa-
tients have other issues that complicate intensification.
Intensified insulin regimens include (1) one or more daily in-
jections of rapid- or short-acting insulin before meals (prandial
insulin) or (2) switching to one to three daily administrations of
a fixed combination of short- and long-acting insulin
(premixed or biphasic insulins) [229,230]. When adding pran-
dial insulin, giving one injection with the largest meal of the
day is a simple and safe approach [231]. Over time, if
glycaemic targets are not met with one dose of prandial insulin
daily, additional prandial injections can be added to other
meals [232]. Results of meta-analyses suggest a modestly
Fig. 8 Considering oral therapy in combination with injectable therapies
Diabetologia

greater reduction in HbA
1c
with basal-prandial regimens com-
pared with biphasic insulin regimens, but at the expense of
greater weight gain [233–235]. While still commonly used,
we do not generally advocate premixed insulin regimens, par-
ticularly those administered three times daily, for routine use
when intensifying insulin regimens (Fig. 7).
Continuous insulin infusion using insulin pumps may have
a role in a small minority of people with type 2 diabetes [236].
Access and cost
The availability of glucose-lowering medications, patient sup-
port systems and blood glucose-monitoring devices can differ
worldwide, depending on a region’s economy, culture and
healthcare system. Cost of and access to newer medications
and insulin remain important issues throughout the world.
Although the economics of diabetes care is complex and
broadly includes the costs to society of diabetic complications
and long-term outcomes, the cost of drugs and the affordability
of treatment are often the primary basis for decision making.
Within healthcare systems, variance in medication coverage is
based on different assessments of cost-effectiveness. This re-
sults in huge disparities in the cost of new and old glucose-
lowering medications in some countries, limiting access to the
full range of diabetes therapies in large segments of the popu-
lation and creating a two-tiered system of treatment. Since
glycaemic management remains a cornerstone of the preven-
tion of diabetes complications, these disparities raise questions
of fairness, equity and overall public health. Nonetheless, the
use of less expensive agents, such as metformin, sulfonylureas
and human insulin, remain effective options (Figs 2and 6).
Redoubling lifestyle management efforts can also have great
impact, but behavioural intervention and support can also be
costly, and socioeconomic barriers to improving lifestyle are
well-described [237].
Emerging technology
There is an increasing call for the use of technology and tele-
medicine to improve patients’health [238]. Many types of in-
puts can be digitalised, such as blood glucose levels, time spent
exercising, steps walked, energy ingested, medication doses
administered, blood pressure and weight. Patterns in these var-
iables can be identified by software, leading to specific treat-
ment recommendations supported by real-time algorithms.
Telemedicine incorporates multiple types of communication
services, such as two-way video, email, texting, smartphones,
tablets, wireless monitors, decision support tools and other
forms of telecommunication technologies. Results overall sug-
gest a modest improvement in glycaemic control [239,240].
Key knowledge gaps
Despite over 200 years of research on lifestyle management of
diabetes and more than 50 years of comparative-effectiveness
research in diabetes, innumerable unanswered questions re-
garding the management of type 2 diabetes remain. In the
context of our current consensus recommendations, the fol-
lowing is an incomplete discussion of vexing issues that must
be addressed.
Evolving areas of current investigation will provide im-
provements in diabetes care and hold great hope for new
treatments.
&Implementation science. The tools available to prevent
and treat diabetes are vastly improved. However, imple-
mentation of effective innovation has lagged behind.
&Basic science. Our understanding of the basic mechanisms
of diabetes, the development of complications, and the
treatment of both, though continuously advancing, has
highlighted how much we do not know.
&Personalised/precision medicine. Though promising,
these -omics and big data approaches addressing both per-
sonal and environmental factors and their interaction are
largely unrealised in diabetes care and will require large
investments and coordination to have impact.
&Informatics. The benefits and role of enhanced monitoring
of glucose and other variables leveraged with real-time in-
formatics-based approaches to adapt treatment on an indi-
vidual basis has great potential but has not been elucidated.
&Overweight/obesity. Current therapy is clearly inadequate.
Innovation in methods and implementation would trans-
form diabetes prevention and care. Understanding the bi-
ology, psychology and sociology of obesity to identify
pharmacological, behavioural and political approaches to
preventing and treating this principal cause of type 2 dia-
betes is essential.
&Lifestyle management and DSMES. Though the benefits
of these approaches are clear, better paradigms on how to
target, individualise and sustain the effects are needed.
&Beta-cell function. Preserving and enhancing beta cell
function is perceived as the holy grail of diabetes and yet
effective techniques are inadequately developed.
&Translational research. There is a huge gap between the
knowledge gained from clinical trials and application of
that information in clinical practice. This gap should be
filled with pragmatic studies and other designs that include
costs, measures of patient preference and other patient-
recorded outcome measures. Patients and other
Consensus recommendation
Access, treatment cost and insurance coverage should
all be considered when selecting glucose-lowering
medications.
Diabetologia

stakeholders should have more input into trial designs and
outcomes. Pragmatic designs will enhance generalisability
of resultsand reduce cost. Better application of‘real-world
evidence’will complement randomised trial evidence.
&Drug development. New medications will require demon-
stration of broad efficacy for glucose, comorbidities and/
or complications as well as safety and tolerability to com-
pete in the marketplace.
&Complications. Steatohepatitis, HF, non-albuminuric
CKD, chronic mental illness and other emerging issues
are complications in diabetes that may supplant classical
microvascular and macrovascular disease in importance
and impact. Understanding optimal diagnostic, screen-
ing and treatment strategies is urgently needed.
Other areas of importance include better segmentation of
‘type 2 diabetes’, as well as appropriate diagnosis of secondary
diabetes, which should allow more informed individualisation of
care. Better data on optimal approaches to diabetes management
in frail and older adult patients is urgently required considering
the controversy around glycaemic targets and the benefits and
harms of specific treatments from lifestyle management to med-
ications. Current approaches to the management of type 2 diabe-
tes in adolescents and young adults do not seem to alter the loss
of beta cell function and most individuals in this age group
quickly transition to insulin therapy. Studies to guide optimal
therapyinthisemergingpopulationwithaterrifyinglyhighrisk
of early disability is an immediate need.
There are enduring questions that continue to challenge
guideline development. For example, does metformin provide
cardiovascular benefit in patients with type 2 diabetes early in
the natural history of diabetes, as suggested by the UKPDS
study? Is metformin’s role as first-line medication manage-
ment truly evidence-based or a quirk of history? Though the
rationale for early combinationtherapy targeting normal levels
of glycaemia in early diabetes is seductive, clinical trial evi-
dence to support specific combinations and targets is essen-
tially non-existent. As the cost implications for these ap-
proaches is enormous, evidence is desperately needed.
Different models of care are being implemented globally.
Defining optimal cost-effective approaches to care, particular-
ly in the management of patients (multi-morbidity), is
essential.
New questions arise from the recent cardiovascular out-
comes studies. Do the cardiovascular and renal benefits of
SGLT2 inhibitors and GLP-1 receptor agonists demonstrated
in patients with established CVD extend to lower-risk pa-
tients? Is there additive benefit of use of GLP-1 receptor ago-
nists and SGLT2 inhibitors for prevention of cardiovascular
and renal events? If so, in what populations?
Addressing these and other vital clinical questions will re-
quire additional investment in basic, translational, clinical and
implementation research. More time- and cost-efficient research
paradigms to address patient-centred endpoints will need to be
developed through regulatory reform and leveraging informat-
ics and coordinated learning healthcare systems. The increasing
burden of cardiorenal metabolic disease in terms of incidence,
prevalence and cost is an existential threat to society. Urgent
attention to improve prevention and treatment is of the essence.
The management of hyperglycaemia in type 2 diabetes has
become extraordinarily complex with the number of glucose-
lowering medications now available. Patient-centred decision
making and support and consistent efforts to improve diet and
exercise remain the foundation of all glycaemic management.
Initial use of metformin, followed by addition of glucose-
lowering medications based on patient comorbidities and con-
cerns is recommended as we await answers to the many ques-
tions that remain.
Acknowledgements The authors would like to acknowledge Mindy
Saraco (Associate Director, Scientific & Medical Communication),
Gedeon Topacio (Finance & Project Manager, Research & Scientific
Programs) and Erika Berg (PhD, Director, Scientific and Medical
Affairs) from the American Diabetes Association as well as Mary Hata
(Executive Assistant) and Petra Niemann (Executive Assistant) from
EASD for their help with the development of the consensus report and
related meetings/presentations.
The authors would like to also acknowledge Mike Bonar (Creative
Director) and Charlie Franklin (Design Assistant) from the Leicester
Diabetes Centre, Leicester, UK, who provided considerable support in
drafting and amending the figures. The authors also acknowledge
Francesco Zaccardi (PhD, Clinical Research Fellow, University of
Leicester, Leicester, UK) and David Kloecker (Medical Student, University
of Leicester) who assisted with extracting PubMed articles and identifying
relevant records by title and abstract; Francesco Zaccardi helped to define the
initial search strategy and prepare the Excel file.
The authors acknowledge the invited peer reviewers who provided com-
ments on an earlier draft of this report: Amanda Adler (Addenbrooke’s
Hospital, Cambridge, UK), Kåre I. Birkeland (University of Oslo, Oslo,
Norway), James J. Chamberlain (St. Mark’s Hospital, Salt Lake City, UT,
USA), Jill P. Crandall (Albert Einstein College of Medicine, New York City,
NY, USA), Ian H. de Boer (University of Washington, Seattle, WA, USA),
Stefano Del Prato (University of Pisa, Pisa, Italy), George Dimitriadis (Athens
University, Athens, Greece), Sean Dinneen (National University of Ireland,
Galway, Ireland), Vivian A. Fonseca (Tulane University, New Orleans, LA,
USA), Simon R. Heller (University of Sheffield, Sheffield, UK), Richard I. G.
Holt (University of Southampton, Southampton, UK), Silvio E. Inzucchi
(Yale University, New Haven, CT, USA), Eric L. Johnson (University of
North Dakota, Grand Forks, ND, USA), Joshua J. Neumiller (Washington
State University, Spokane, WA, USA), Kamlesh Khunti (University of
Leicester, Leicester, UK), Harald H. Klein (Ruhr University of Bochum,
Bochum, Germany), Line Kleinebreil (Hôpital national de Saint Maurice,
Saint-Maurice, France), José Manuel Fernández-Real (Universitat de
Girona, Girona, Spain), Sally M. Marshall (Newcastle University,
Newcastle upon Tyne, UK), Manel Mata-Cases (Institut Universitari
d’Investigació en Atenció Primària Jordi Gol [IDIAP Jordi Gol], Barcelona,
Spain), David R. Matthews (University of Oxford, Oxford, UK), David M.
Nathan (Massachusetts General Hospital, Boston, MA, USA), Michael A.
Nauck (Diabetes Center Bochum-Hattingen, St Josef-Hospital, Ruhr-
University, Bochum, Germany), Frank Nobels (OLV-Hospital, Aalst,
Belgium), Richard E. Pratley (Florida Hospital Diabetes Institute, Orlando,
FL, USA), Maria Jose Redondo (Baylor College of Medicine, Houston, TX,
USA), Michael R. Rickels (University of Pennsylvania, Philadelphia, PA,
USA), Matthew C. Riddle (Oregon Health & Science University, Portland,
OR, USA), Julio Rosenstock (Diabetes and Endocrine Center, Dallas, TX,
Diabetologia

USA), Giorgio Sesti (Magna Graecia University of Catanzaro, Catanzaro,
Italy), Neil Skolnik (Abington Family Medicine, Jenkintown, PA, USA),
Krzysztof Strojek (Silesian Medical University, Zabrze, Poland), Jennifer
Trujillo (University of Colorado, Denver, CO, USA), Guillermo E.
Umpierrez (Emory University, Atlanta, GA, USA) and Jennifer Wyckoff
(University of Michigan, Ann Arbor, MI, USA).
Data availability The details of the search strategy, the results and the
classification for the included articles are available at https://doi.org/10.
17632/h5rcnxpk8w.1.
Funding This activity was funded by the American Diabetes Association
and the European Association for the Study of Diabetes.
Duality of interest M. J. Davies reports personal fees and grants from
Boehringer Ingelheim, Janssen, Novo Nordisk and Sanofi and personal
fees from AstraZeneca, Eli Lilly, Gilead Sciences Ltd., Intarcia/Servier,
Merck Sharp & Dohme, Mitsubishi Tanabe Pharma Corporation and
Takeda Pharmaceuticals International Inc.
D. D’Alessio reports personal fees from Eli Lilly, Merck, Novo
Nordisk, and Intarcia, and grants from Merck, and Ligand during the con-
duct of the study; personal fees from Eli Lilly, Merck, Novo Nordisk, and
Intarcia, and grants from Merck, and Ligand outside the submitted work.
J. Fradkin has nothing to disclose. J. Fradkin’s input into this consen-
sus report is from her own perspective and the Report does not reflect the
view of the National Institutes of Health, Department of Health and
Human Services or the US Government.
W. N. Kernan has nothing to disclose.
C. Mathieu reports grants and personal fees from Novo Nordisk,
grants and personal fees from Sanofi, grants and personal fees from
Merck Sharp & Dohme Ltd., grants and personal fees from Eli Lilly
and Company, grants and personal fees from Novartis, personal fees from
Bristol-Myers Squibb, personal fees from AstraZeneca, grants and per-
sonal fees from Boehringer Ingelheim, personal fees from Hanmi
Pharmaceuticals, grants and personal fees from Roche Diagnostics, grants
and personal fees from Medtronic, grants and personal fees from
Intrexon, grants and personal fees from Abbott, and personal fees from
UCB, outside the submitted work.
G Mingrone reports grants and personal fees from Novo Nordisk,
personal fees from Johnson & Johnson, personal fees from Fractyl Inc.,
during the conduct of the study.
P. Rossing reports grants, non-financial support and other from Novo
Nordisk, grants and other from AstraZeneca, other from Bayer, other
from Boehringer Ingelheim, other from MSD, other from Eli Lilly, during
the conduct of the study.
A. Tsapas reports non-financial support from the European Association
for the Study of Diabetes, during the conduct of the study; grants and other
from Boehringer Ingelheim, grants and other from Novo Nordisk, other
from Novartis, grants and other from Sanofi, grants and other from
AstraZeneca, grants from GSK, grants and other from European
Foundation for the Study of Diabetes (EFSD), outside the submitted work.
D. J. Wexler has nothing to disclose.
J. B. Buse has provided consultation to Adocia, AstraZeneca, Eli
Lilly, GI Dynamics, Intarcia, MannKind, NovaTarg, Novo Nordisk,
Senseonics, and vTv Therapeutics with fees paid to the University of
North Carolina. He has received grant support from AstraZeneca,
Johnson & Johnson, Novo Nordisk, Sanofi, and vTv Therapeutics. He
is a consultant to Neurimmune AG. He holds stock options in Mellitus
Health, PhaseBio and Stability Health. He is supported by a grant from
the National Institutes of Health (UL1TR002489).
Contribution statement All authors were responsible for drafting the
article and revising it critically for important intellectual content. All
authors approved the version to be published.
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12987-z
Affiliations
Melanie J. Davies
1,2
&David A. D’Alessio
3
&Judith Fradkin
4
&Walter N. Kernan
5
&Chantal Mathieu
6
&
Geltrude Mingrone
7,8
&Peter Rossing
9,10
&Apostolos Tsapas
11
&Deborah J. Wexler
12,13
&John B. Buse
14
1
Diabetes Research Centre, University of Leicester, Leicester, UK
2
Leicester Diabetes Centre, Leicester General Hospital,
Leicester, LE5 4PW, UK
3
Department of Medicine, Duke University School of Medicine,
Durham, NC, USA
4
National Institute of Diabetes and Digestive and Kidney Diseases,
National Institutes of Health, Bethesda, MD, USA
5
Departmentof Medicine, Yale School of Medicine, NewHaven, CT,
USA
6
Clinical and Experimental Endocrinology, UZ Gasthuisberg, KU
Leuven, Leuven, Belgium
7
Department of Internal Medicine, Catholic University, Rome, Italy
8
Diabetes and Nutritional Sciences, King’s College London,
London, UK
9
Steno Diabetes Center Copenhagen, Gentofte, Denmark
10
University of Copenhagen, Copenhagen, Denmark
11
Second Medical Department, Aristotle University Thessaloniki,
Thessaloniki, Greece
12
Department of Medicine and Diabetes Unit, Massachusetts General
Hospital, Boston, MA, USA
13
Harvard Medical School, Boston, MA, USA
14
Department of Medicine, University of North Carolina School of
Medicine, Chapel Hill, NC, USA
Diabetologia