diabetes research and clinical practice 1 4 3 (2 0 1 8) 1 0 1–11 2

Contents available at ScienceDirect

Diabetes Research
and Clinical Practice
journal homepage: www.elsevier.com/locat e/dia bre s

Review

2020 vision – An overview of prospects for diabetes

management and prevention in the next decade

Chih-Yuan Wang a,*, David L. Neil b, Philip Home c

a
Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
b
Scientific Development Department, Content Ed Net, Taipei, Taiwan
c
Institute for Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK

A R T I C L E I N F O A B S T R A C T

Article history: After a century of medical progress, people nowadays live longer with diabetes than ever
Received 2 March 2018 before. However, current preventative approaches, compounded in part by increased life-
Received in revised form expectancy, are failing to reduce the prevalence of diabetes. Cardiovascular sequelae
24 May 2018 account for many of the four million deaths annually attributable to diabetes. Evidence
Accepted 13 June 2018 indicates that certain glucose-lowering medications can improve vascular outcomes in
Available online 23 June 2018 some people with type 2 diabetes, which, together with better understanding of using
multiple therapies concurrently, offers opportunities for beneficial personalization of med-
ication regimens. However, further well-designed long-term studies are needed to evaluate
Keywords:
cardiovascular benefits and safety of new and older medications, particularly in users
Type 2 diabetes mellitus (T2DM)
typical of everyday diabetes care. Although there are numerous other promising advances
Prevalence
in pharmacotherapies and biotechnology, these will probably be unaffordable for most peo-
Management
ple with diabetes globally. Therefore, effective national public health approaches will be
Glucose-lowering medications
essential to reducing the incidence of diabetes and its associated burdens; these may entail
Prevention
politically controversial measures to change unhealthy lifestyle behaviours. Stakeholders
Future
could learn from past failures and emulate successes in other health-care initiatives.
Without early action at all levels, we face a future in which approaching one-quarter of
humans will have diabetes, with more than half afflicted during their lifetime.
Ó 2018 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-
NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Contents

1. A prediction . . . and a predicament . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102

2. Questions ongoing clinical trials can and cannot answer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
2.1. Cardiovascular safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
2.2. Choice and order of glucose-lowering medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103

* Corresponding author at: Department of Internal Medicine, National Taiwan University Hospital, College of Medicine, National
Taiwan University, 7 Chung-Shan South Rd., Taipei 10051, Taiwan.
E-mail address: cyw1965@ntu.edu.tw (C.-Y. Wang).
https://doi.org/10.1016/j.diabres.2018.06.007
0168-8227/Ó 2018 The Authors. Published by Elsevier B.V.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
102 diabetes research and clinical practice 1 4 3 ( 2 0 1 8 ) 1 0 1 –1 1 2

2.3. Diabetes prevention. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105

3. New management paradigms for the 2020s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
3.1. Beyond ‘treat-to-failure’ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
3.2. Optimizing combination therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
3.3. Insulins present and future. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
4. The nutritional nexus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
4.1. Partners in health crime . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
4.2. Pharmacological and surgical weight-loss . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
4.3. Influence of gut microbiota. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
5. Biotechnology beckons. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
5.1. Integrating the ‘omics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
5.2. Applications and opportunities. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
5.3. Cell therapy ventures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
6. Whither forecast . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
6.1. Turning Joslin’s tide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
Acknowledgements. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
Author contributions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
Role of funding source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109

1. A prediction . . . and a predicament
Before the 1920s, people diagnosed with diabetes succumbed
fast, often as juveniles [1]. Insulin promised resurrection, yet
even as Joslin hailed the first astounding ‘cures’, he cautioned
that an ominous tide of obesity-related chronic disease was
swelling [2]. Today, adults with type 2 diabetes (T2DM) out-
number those with type 1 diabetes (T1DM) nine to one, hun-
dreds of millions worldwide use glucose-lowering
medications, and the pandemic is overwhelming health-
care capacity [3–8]. Since 1980, successive estimates of the
global prevalence of diabetes have surpassed earlier projec-
tions (Fig. 1, Supplementary Table S1), and its prevalence
has not declined significantly in any country [7]. Although
prevalence may be stabilizing in some countries, the global
total may exceed 700 million by 2025, more than 10% of peo-
ple [7]; the increase is most rapid in Africa and largest in Asia
[6–8]. Estimated global health-care spending on diabetes has
more than tripled since 2003, with direct annual expenditure
currently estimated at USD825 million equivalent [4,7].
However, the health burden of diabetes is largely unknown –
as yet, ‘only’ four million deaths per year are attributable to
diabetes or its sequelae [3].
Supplementary data associated with this article can be
found, in the online version, at https://doi.org/10.1016/j.dia-
bres.2018.06.007.
Clearly, diabetes management must be substantially
improved, with both wider access to health-care and better
care delivery [5]. How will contemporary developments shape
the future therapeutic landscape, what impact might these
have in diminishing the associated cost and health burdens
– or in increasing them – and what issues may remain unre-
solved? International experts met in April 2016 to address this
agenda; this commentary focuses on the evolution of glucose-
lowering pharmacotherapy, potential applications of new and
emerging technologies, and their implications for clinical
practice in the 2020s. Our intention is to prospect the near-
future clinical landscape, and we do not cover farther-
distant technologies nor, inevitably, review each topic area
in detail. Neither do we seek to address the important but
essentially political issue that new technologies are usually
expensive, which raises a barrier to access by the majority
of people with diabetes, irrespective of their needs.
2. Questions ongoing clinical trials can and
cannot answer
2.1. Cardiovascular safety
Although most people with diabetes die from cardiovascular
(CV) sequelae, early studies were not large enough to evaluate
CV outcomes validly [9]; even the United Kingdom Prospective
Diabetes Study (UKPDS) was underpowered at its endpoint
[10], although longer-term follow-up showed reduced all-
cause and diabetes-related death, as well as myocardial
infarction for the sulfonylurea/insulin cohort [9,11]. Since
2008, when the United States (US) Food and Drug Administration
(FDA) mandated CV safety studies as a licensing precondition,
more CV outcomes trials (CVOTs) in T2DM have added to ear-
lier data from UKPDS [10–12] and thiazolidinedione studies
[13–15] (Table 1); results for dipeptidyl-peptidase-4 inhibitors
(DPP-4i) [16–18]; glucagon-like peptide-1 receptor agonists
(GLP-1RA) [19–22], sodium-glucose linked transporter-2
blockers (SGLT2b) [23,24], and insulins [25,26] have been
reported, with others anticipated in 2018–2020.
The most compelling evidence so far for CV benefits asso-
ciated with glucose-lowering has come from the LEADER [19]
and SUSTAIN-6 [20] studies (liraglutide, semaglutide) and
EMPA-REG-OUTCOME [23] and CANVAS [24] (empagliflozin,
canagliflozin). However, glucose lowering is unlikely to
account for any of the strong advantage for hospitalization
for heart failure (HF) or lesser effects on overall major CV out-
comes. The discordant results for exenatide may be real, or
due to the study design [22]. Chronic kidney disease (CKD) is
a major comorbidity of T2DM, culminating in the heavy bur-
den of end-stage renal failure. Both SGLT2b studies suggest
 diabetes research and clinical practice 1 4 3 ( 2 0 1 8 ) 1 0 1 –1 1 2 103

Fig. 1 – Contemporary, retrospective and projected estimates of global diabetes prevalence since 1980. IDF, International
Diabetes Federation; WHO, World Health Organization; NCD, non-communicable disease. For source references, see
Supplementary Table S1.

strong protection against renal disease progression [24,27],
and other studies in people with T2DM and CKD are under-
way. A current concern is that SGLT2b’s have been associated
with potentially life-threatening euglycemic diabetic ketoaci-
dosis [28]. Other unresolved issues include possible class or
drug-specific effects on bone metabolism, pancreatic inflam-
mation, and toe amputations.
Recent studies have also begun to redress the lack of data
on HF comorbid with T2DM, which increases a person’s
mortality risk ten-fold [29]. Current evidence suggests that
SGLT2b’s may be especially advantageous, presumably
secondary to their hypovolaemic effect, although metabolic
changes have been suggested [23,24]; in a large real-world
T2DM cohort, incidence of HF and mortality risk were
significantly lower among people newly initiated on
SGLT2b’s versus other glucose-lowering drugs [30]. Although
SAVOR-TIMI unexpectedly suggested that saxagliptin
worsens HF [16], an outcome that was neither a primary nor
secondary endpoint, and data for alogliptin are equivocal,
there is no evidence that sitagliptin or other glucose-
lowering medications, except thiazolidinediones, have
harmful effects; further data for linagliptin are expected in
2018. An earlier contraindication for metformin was revoked
[29]. Further long-term trials are needed for the many
glucose-lowering medications without data in users with HF.
Unfortunately, the imperative to demonstrate acceptable
CV risk as efficiently as possible means that CVOT cohorts
are often unrepresentative of people receiving ambulatory
diabetes care [9,18,21,23]; better-designed trials in more repre-
sentative populations (eg, unrestricted for prior morbidity or
age) and with longer follow-up and superiority as the out-
come are needed to find out whether benefits observed in
people with CV disease will extrapolate to those without.
Until then, the potential longer-term risks and benefits will
remain uncertain and there will be no answer to the question
of precisely how much glucose-lowering therapy with newer
agents reduces CV risk, and over what timeframe.
2.2. Choice and order of glucose-lowering medications
International guidelines generally recommend lifestyle
changes and starting metformin as monotherapy at diagnosis
or in the ensuing months, unless contraindicated or glycated
haemoglobin (HbA1c) 9.0% (75 mmol/mol) suggests first-line
dual therapy [31]. If HbA1c remains above the target level
after 3 months, other medications are added sequentially
 104
Table 1 – Studies evaluating cardiovascular outcomes of glucose-lowering medications.
Drug class Medication Study name/acronym Outcomes assessed Clinicaltrials.gov ID
[Reference]
Primary Other cardiovascular

Biguanide Metformin UKPDS (sub-study) Diabetes death/MI Stroke [12]

Sulfonylurea Sulfonylurea/insulin UKPDS (main study) Diabetes death/MI Stroke [10]
Thiazolidinedione Pioglitazone PROactive MI/stroke/ACS/ MACE and components NCT00174993 [13]

diabetes research and clinical practice

endovascular surgery
Pioglitazone TOSCA-IT Death/MI/Stroke/ Composite including HF NCT00700856 [14]
Revascularisation hospitalisation/endovascular
surgery/silent MI/UA
Rosiglitazone RECORD CV hospitalisation/death MACE, HF NCT00379769 [15]
Dipeptidyl- Saxagliptin SAVOR-TIMI-53 CV death/MI/stroke Hospitalisation for HF/UA/ NCT01107886 [16]
peptidase-4 revascularisation
inhibitor Sitagliptin TECOS Composite MACE HF hospitalisation NCT00790205 [17]
Alogliptin EXAMINE CV death/MI/stroke Revascularisation NCT00968708 [18]
Linagliptin CARMELINA CV death/MI/stroke UA hospitalisation NCT01897532
Linagliptin CAROLINA CV death/MI/stroke UA hospitalisation NCT01243424
Glucagon-like Liraglutide LEADER CV death/MI/stroke Revascularisation, NCT01179048 [19]
peptide-1 hospitalisation for HF/UA
receptor agonist Semaglutide SUSTAIN-6 CV death/MI/stroke NCT01720446 [20]
Lixisenatide ELIXA CV death/MI/UA Hospitalisation for HF/ NCT01147250 [21]
hospitalisation/stroke revascularisation
Albiglutide HARMONY CV death/MI/stroke Hospitalisation for HF/UA NCT02465515

1 4 3 ( 2 0 1 8 ) 1 0 1 –1 1 2
revascularisation
Dulaglutide REWIND CV death/MI/stroke Hospitalisation for HF/UA NCT01394952
Exenatide EXSCEL CV death/MI/stroke Hospitalisation for ACS/HF NCT01144338 [22]
Exenatide DUROS ITCA650 CV death/MI/UA/stroke NCT01455896
Sodium-glucose Empagliflozin EMPA REG OUTCOME CV death/MI/stroke UA/HF hospitalisation NCT01131676 [23]
linked Canagliflozin CANVAS CV death/MI/stroke NCT01032629 [24]
transporter-2 Dapagliflozin DECLARE-TIMI-58 CV death/MI/stroke/HF NCT01730534
inhibitor hospitalization
Ertugliflozin VERTIS CV CV death/MI/stroke HF hospitalisation NCT01986881
Sotagliflozin SCORED CV death/MI/stroke/HF Emergency treatment for HF NCT03315143
hospitalization
Insulins Glargine ORIGIN CV death/MI/stroke/HF NCT00069784 [25]
hospitalisation/
revascularisation
Degludec DEVOTE CV death/MI/stroke NCT01959529 [26]
MI, myocardial infarction; ACS, acute coronary syndrome; MACE, major adverse cardiovascular events; HF, heart failure; UA, unstable angina.
 diabetes research and clinical practice 1 4 3 ( 2 0 1 8 ) 1 0 1 –1 1 2 105

[32]; in the absence of comparative data, the choice currently
largely depends on local paradigms, resource issues, availabil-
ity, and personal circumstances.
In the UKPDS, rates of HbA1c decline were similar for
sulfonylurea, metformin, and insulin [10,12]. Except for
rosiglitazone, which in monotherapy was superior to met-
formin or particularly glibenclamide in delaying loss of
glycaemic control [33], and for which CV outcomes were the
same as metformin or sulfonylurea in dual therapy [15], few
other glucose-lowering therapies, besides insulins, have been
compared head-to-head. Accordingly, the Glycemia Reduc-
tion Approaches in Diabetes (GRADE) study is evaluating the
efficacy of metformin combined with sitagliptin, liraglutide,
insulin glargine, or glimepiride in people with T2DM charac-
teristic of those requiring dual therapy. GRADE should show
which partners for metformin are most effective and how
they differ in terms of hypoglycaemia, islet b-cell function,
weight gain, microvascular complications, and quality of life
[34]; however, the comparative effectiveness of SGLT2b’s will
remain unknown, and GRADE is not powered to assess CV
outcomes.
2.3. Diabetes prevention
Although more effective prevention is crucial to abating inci-
dent T2DM [5], it is unclear whether glucose-lowering and
anti-obesity medications have a role in supporting public
health measures. In the Diabetes Prevention Program
Outcomes Study, which followed people at high risk for
T2DM, metformin reduced the incidence of T2DM by 18%
compared to placebo over 15 years, while intensive
non-pharmacological intervention with healthy diet and
physical activity reduced the relative risk by 27%. As
expected, participants who did not develop T2DM had signif-
icantly lower risk of microvascular disease than those who
did, but there was no corresponding intervention benefit
[35,36]. Likewise, acarbose reduced the incidence of T2DM in
Chinese people with ischaemic heart disease and impaired
glucose tolerance, but not their risk of major CV events [37].
UK researchers have demonstrated the potential feasibility
of a study to compare CV outcomes between prolonged-
release metformin and placebo in non-diabetic people with
hyperglycaemia at high CV risk being managed in primary
care [38]. The Restoring Insulin Secretion (RISE) study is inves-
tigating whether obesity-reducing surgery, or glucose-
lowering with metformin alone or combined with insulin
glargine or liraglutide, can slow or reverse progressive islet
b-cell dysfunction in incipient T2DM [39]. RISE is also
intended to determine whether T2DM pathogenesis and pro-
gression are similar in adults and children. However, it will
remain uncertain whether or not interventions evaluated in
prevention studies can be applied in clinical practice.
3. New management paradigms for the 2020s
3.1. Beyond ‘treat-to-failure’
Hyperglycaemia involves multiple interacting metabolic pro-
cesses, including increased hepatic glucose production, defi-
cient insulin secretion and action, excess glucagon
secretion, and a diminished incretin effect, modulated by
increased lipolysis and abnormal neurotransmission, among
others [40]. Different pharmacotherapeutic classes target par-
ticular aspects of this nexus but none deteriorating islet b-cell
function, which starts before diabetes develops and continues
inexorably thereafter [41]; indeed, only thiazolidinediones
have evidence of any efficacy in this regard [33]. Among
1799 first-time metformin users who achieved HbA1c < 7.0%
(<53 mmol/mol), 42% had secondary failure within 2–5 years,
only 30% of whom were prescribed a second medication;
although failure to maintain target was less likely among
those using metformin within 3 months of diagnosis, the rate
was still 12% per year [42]. Until recently, metformin was typ-
ically partnered with a sulfonylurea, which are inexpensive;
however, the strong initial effect of these medications is lost
by 12 months, with progressive b-cell failure at a rate higher
than metformin thereafter [33,40].
There is a strong rationale for abandoning the conven-
tional ‘treat-to-failure’ approach in favour of a paradigm in
which drug combinations with complementary mechanisms
capable of addressing multiple underlying pathophysiological
defects and normalizing glucose levels with low risk of hypo-
glycaemia are begun earlier (Table 2) [31,40,43,44]. Such a reg-
imen is unproven, but might include agents that are insulin
sensitizing and anti-atherogenic (eg, metformin, thiazolidine-
dione), islet b-cell preserving (thiazolidinedione), and that

Table 2 – Desirable attributes of glucose-lowering medications.

 Lower blood glucose level effectively (at least as well as lifestyle intervention)
 Carry low risk of hypoglycaemia
 Do not result in weight gain
 Evidence for amelioration of microvascular and macrovascular risk
 Additional benefits on other cardiovascular outcomes, lipid profile, or preserving islet b-cell function
 Durable glucose-lowering effect/prevention of islet b-cell decline
 Well-tolerated, with minimal toxicity or adverse effects
 Safe in long-term use, with no need for safety monitoring
 Complementary to other glucose-lowering classes, or even synergistic
 Mechanism remedies underlying pathophysiological defects
 Priced comparably with established medications that are widely available
After Brannick B, Wynn A, Dagogo-Jack S. Prediabetes as a toxic environment for the initiation of microvascular and macrovascular compli-
cations. Exp Biol Med (Maywood) 2016;241(12): pp. 1323–1331, copyright Ó 2016 by Experimental Biology and Medicine. Adapted by Permission of
SAGE Publications, Ltd.
106 diabetes research and clinical practice
modulate caloric intake or loss (GLP-1RAs, SGLT2b’s) [31,40].
Successful outcomes of some GLP-1RA and SGLT2b CVOTs
[19,23,24], make these further candidates for early combina-
tion approaches.
3.2. Optimizing combination therapy
Although up-front combination therapy is often used and
successful in therapeutic areas such as cancer and infectious
disease, current mainstream T2DM guidelines do not endorse
this approach [31]. Besides avoiding unnecessary polyphar-
macy if monotherapy suffices, another barrier may be con-
cern about adverse effects – nearly all classes of oral
glucose-lowering medications cause significant problems,
ranging from gastrointestinal intolerance and weight gain,
through symptomatic hypoglycaemia, fractures, and genito-
urinary infection, to severe hypoglycaemia and lactic acidosis
[45]. Low-dose combination therapies have been suggested as
a pragmatic approach to minimizing side effects. For exam-
ple, the Canadian Normoglycemia Outcomes Evaluation
study, found that people with impaired glucose tolerance
who received half-maximal doses of metformin plus rosiglita-
zone had 26% lower absolute risk of developing T2DM versus
placebo [45]. Another rational option, widely available in fixed
combinations, would be metformin plus a DPP-4i, as the latter
are unusually well tolerated and achieve durable HbA1c
reduction [44]. Other possibly advantageous combinations
include a SGLT2b plus metformin or a DPP-4i, or a GLP-1RA
combined with either metformin and a thiazolidinedione
[46], or insulin [32]; however, there are many rational possibil-
ities [44].
3.3. Insulins present and future
Due to progressive islet b-cell failure [41], most people with
T2DM eventually need insulin therapy if they are to control
hyperglycaemia. A century of development has produced
truly long-acting insulins, some now with flat 24-hour profiles
[47,48]. Once-daily basal insulin thus enabled insulin therapy
to be started more timely [49], traditionally followed by add-
ing prandial insulin. However, fixed or variable ratio insulin/
GLP-1RA combinations that are highly efficacious, with less
hypoglycaemia or weight gain, are now entering routine
use, usually once-daily or even once-weekly [49,50]; these
are used when starting insulin, or often instead of adding
prandial insulin to basal insulin. Though expensive, these
approaches are rapidly becoming more widespread, with
meal-time insulin only introduced later. Weekly GLP-1RAs
are already proving commercially successful and weekly insu-
lins, though posing a bigger pharmaceutical challenge, are
anticipated, potentially enabling weekly combination
injection.
Diverse developments in pharmaceutical and injection
depot technologies are also enabling more physiological pran-
dial insulin profiles, with more rapid onset [49]. These
approaches are being supplemented with continuous glucose
monitoring, which is now making clinical inroads after 50
years of development, together with various insulin dose
advisor concepts, many based on smart phone technology,
although common standards are lacking. Some systems are
1 4 3 ( 2 0 1 8 ) 1 0 1 –1 1 2
linked to insulin pumps, in forms that include low-glucose
insulin suspend, dual insulin/glucagon delivery, and basal
only devices for T2DM, all moving towards full closed-loop
control. However, unresolved problems of intravenous sens-
ing and infusion, and the barriers imposed by time-lag, sub-
cutaneous sensing and insulin absorption, mean that
normoglycaemia remains unattainable [51].
Other products anticipated after 2020 include glucose-
responsive insulins [52], regenerative insulin secretion by
engineered self- or stem-cell-derived b-cells, and insulin-
linked single peptides including GLP-1RA and other
glucagon-related molecules. Equally or more problematic
are oral insulin delivery, which must overcome erratic absorp-
tion and poor bioavailability, and small-molecule insulin ana-
logue agents; these fail to match physiological insulin
profiles, and insulin analogues may send undesirable down-
stream cellular growth signals.
4. The nutritional nexus
4.1. Partners in health crime
Diabetes had been linked to obesity long before Joslin pub-
lished seminal epidemiological evidence 100 years ago [1,53].
Asians appear especially susceptible to the adverse effects
of calorie surplus, developing T2DM at a higher rate than sim-
ilarly heavy Europids, probably reflecting their tendency to
central and hepatic rather than peripheral adiposity. Besides
rapid socioeconomic development in Asia driving an obeso-
genic nutritional transition, metabolic genetic differences
probably make an important contribution as well [6].
Although many obese people have a cluster of metabolic
abnormalities that increase their risk of diabetes and CV dis-
ease, some are relatively ‘metabolically normal’ and may
therefore require less aggressive preventive interventions
than others [54]. New research is elucidating the pivotal role
of adipose tissue in mediating the beneficial effects of weight
loss and exercise, which are essential to non-pharmacologic
intervention. Changing body weight alters adipose tissue
gene expression; weight gain increases lipogenic capacity
(in ‘metabolically-normal obese’ people) [54], while lipid flux
pathways are up-regulated and lipid synthesis down-
regulated in step with weight loss [55]. Pre-clinical studies
are also revealing a previously unrecognized role for adipose
tissue in mediating the benefit of physical activity in improv-
ing glucose homeostasis, beyond known effects on muscle
[56].
Randomized studies have shown that low-carbohydrate
diets achieve more weight loss than low-fat diets [57], while
Mediterranean-style or high-protein diets are more effective
in controlling glycaemia and improving CV risk markers in
T2DM [58]. Very low calorie intake can even reverse key meta-
bolic abnormalities underlying T2DM within days, through
depleting pancreatic and hepatic lipid stores which are
strongly implicated in its aetiology [59,60]. In a large-scale
prospective UK study, structured weight management
supervised in routine primary care upon withdrawal of
glucose-lowering pharmacotherapy, achieved remission at
12 months in nearly half of people with T2DM diagnosed
within the past 6 years [61]. The results suggest that
 diabetes research and clinical practice
remission and its considerable associated benefits is a
realistic and potentially cost-effective health service
objective. Although calorie restriction progressively improves
insulin sensitivity, islet b-cell function and metabolic func-
tions in multiple organs [55], the cardioprotective effect
remains uncertain; in the Look AHEAD study, around 10 years
of intensive weight control mitigated individual CV risk
factors but did not significantly reduce CV morbidity or
mortality, perhaps reflecting poor longer-term adherence to
dietary change [62].
4.2. Pharmacological and surgical weight-loss
Since lifestyle modification alone seldom sustains weight
control over the long-term, additional medical intervention
appears desirable; however, there is an unmet need for better
options [63]. Though the US FDA has approved 15 anti-obesity
drugs since the 1940s, several were withdrawn due to adverse
effects. Until recently, orlistat, which is poorly-tolerated and
unsatisfactorily efficacious in promoting weight loss but has
been shown to reduce the incidence of T2DM, was the only
drug approved for long-term therapy [63,64]. Newer agents,
including phentermine/topiramate, lorcaserin, bupropion/
naltrexone and high-dose liraglutide, now offer alternatives
for suitable patients; however short-term efficacy is modest,
and long-term efficacy and safety data are awaited [63,64].
Semaglutide appears particularly efficacious [65]. Prospective
therapies include combination peptides, components includ-
ing GLP-1RAs, peptide YY, and glucagon receptor agonists,
and oxyntomodulin derivatives [66]. For now, bariatric surgery
is the most effective way to achieve clinically-meaningful
long-term weight loss; this can control glycaemia and
reverses diabetes in some people, potentially reducing CV
mortality [64,67], but is obviously not a feasible population-
level solution.
4.3. Influence of gut microbiota
Manipulating the gut microbiota offers a potentially non-
pharmacological, non-invasive intervention approach [68].
Recipients of faecal transplants from obese donors gain
weight [69], whereas intestinal microbiota transplants from
lean donors to people with metabolic syndrome improved
insulin sensitivity [70].
5. Biotechnology beckons
5.1. Integrating the ‘omics
‘Omics research has potential to drive future advances in pre-
cision medicine, in which molecular signatures can be
reverse-translated via preclinical and clinical studies to reveal
disease mechanisms responsive to new therapeutic targets.
For example, integrating genetics, epigenetics, and gene
expression profiling with metabolomics has unveiled the
ubiquitin proteasome system and endoplasmic reticulum
stress as mechanistic links between short-chain dicarboxyla-
cylcarnitine levels and CV disease [71]. Genome-wide
association studies identified a common single-nucleotide
1 4 3 ( 2 0 1 8 ) 1 0 1 –1 1 2 107
polymorphism in SLC30A8 associated with significantly
increased risk for developing T2DM. SLC30A8 encodes an islet
b-cell-specific zinc transporter involved in insulin secretion,
and subsequent high-throughput sequencing showed that
SLC30A8 loss of function mutations protect against T2DM,
suggesting that inhibiting this pathway may have therapeutic
potential [72].
Metabolomic profiling has confirmed that elevated levels
of branched-chain amino acids (BCAA) are implicated in insu-
lin resistance and strongly prognostic for developing T2DM
[73]. BCAA levels are influenced by multiple interacting fac-
tors, including diet, genotype, metabolic processing, and the
gut microbiome, and levels fall with weight loss [74,75]; con-
sequently, they are responsive to various therapeutic inter-
ventions, including gastric bypass surgery, certain
pharmacological agents (eg, sulfonylureas), and lifestyle
interventions [73–76]; in the Weight Loss Maintenance trial,
BCAAs and related metabolites were associated with
improved insulin resistance [74].
5.2. Applications and opportunities
More than 100 other genetic variants associated with the risk
of developing T2DM have been reported. Although most have
too little effect individually to enhance clinical risk assess-
ment [77], such markers can complement each other and
metabolomics to provide greater predictive accuracy than
conventional risk factors, especially in younger people (<50
years) [78]. Individual genetic risk analysis can also help in
discriminating T1DM from T2DM in young adults – an
increasing clinical need [79]. When it comes to targeted pre-
vention, high absolute individual risk, rather than relative
genetic risk, is most important, highlighting the need for
universal approaches [80]; nevertheless, ethnic-specific poly-
morphisms with much greater impact may help to target
pre-emptive intervention to susceptible individuals [81]. For
example, a TBC1D4 mutation increases the risk of T2DM
ten-fold in Greenland Inuit [82], and an HNF1A variant carried
by 2% of Mexicans increases their risk five-fold [83]. SLC16A11
mutations, which are also very common in Latin America,
increase the risk of early-onset T2DM and account for up to
20% of the increased risk in Mexico [84].
Genetic testing may also have a role in predicting who
might respond best to lifestyle or pharmacological interven-
tions; for example, the success of non-pharmacological
weight loss varies with polymorphism in the MC4R gene
[81], and different susceptibility variants cluster into aetiolog-
ical groups that correspond to primary effects on insulin sen-
sitivity, reduced insulin secretion and fasting hyperglycaemia,
and defective insulin processing [85]. Metformin monother-
apy fails to sustain glycaemic control in half of children and
adolescents with T2DM [86], partly due to intolerance but
likely due also to genetic determinants of poorer drug
response [87].
5.3. Cell therapy ventures
Progress continues apace in the elusive quest to restore
endogenous insulin secretion, notably in T1DM [88]. Though
advances in pancreatic tissue transplantation have made this
108 diabetes research and clinical practice
expedient for some people, this has inherent limitations of
shortage of donor tissue and the need for subsequent
immunosuppression [88,89]. Stem-cell engineering break-
throughs are realizing the promise of in vitro mass-
production of glucose-responsive, insulin-producing cells
from human pluripotent stem cells (hPSC) [90,91]. Function-
ally equivalent to islet b-cells, such cells reversed diabetes
in mice within 40 days [90]; others have since reported
longer-term survival and function in microencapsulation
devices implanted into immunocompetent mice [92]. Encap-
sulation materials are engineered to forfend immune rejec-
tion by excluding host cells, as well as confining
transformed cells with malignant potential, while allowing
ingress/egress of nutrients and cell products [88,89]. However,
it is currently uncertain how the cells will mature in situ, how
long they will survive, how many are needed for insulin-
independence, and how the body reacts to such devices. Pos-
sible solutions to preserving the functional integrity of hPSC-
derived implants include pre-vascularized devices, anti-
inflammatory and/or chemokine coatings, re-engineered
self-cells, and immunotherapy to induce immune tolerance
[88,89,93]. Following proof-of-concept [94], first-in-human tri-
als to evaluate the efficacy and safety of implanting encapsu-
lated hPSC-derived pancreatic endoderm progenitors into
adults with T1DM may provide preliminary answers
(https://clinicaltrials.gov/ID: NCT02239354, NCT02939118,
NCT03163511, NCT03162926).
6. Whither forecast
How will the diabetes therapy landscape look in the 2020s?
Improving vascular and safety outcomes will entail integrat-
ing pharmacological, biomechanical and behavioural
approaches; in particular, technologies proven to prevent
diabetes and vascular disease must be deployed diligently to
all who might benefit. Trends towards individualized and
precision medicine targeting underlying pathological
components of diabetes, should enable longer-term, more
physiological, glycaemic control, with fewer undesirable
effects – perhaps even reversal of T2DM. There will also be
continued growth of using existing therapies concurrently,
basal insulins, and glucose-lowering medications with benefi-
cial additional vascular effects, such as GLP-1RAs and
SGLT2b’s. Glycaemic targets will probably be better defined
and individualized, and evidence from large-scale long-term
clinical trials will continue to change guidelines. CVOTs over
the past decade have steadily raised the bar for assessing
CV safety, while positive findings from EMPA-REG-OUTCOME
[23], CANVAS [24] and LEADER [19] suggest that their respec-
tive medications are not just options but should be adopted
in clinical practice, particularly in groups representative of
those studied. Other studies widening the applicable popula-
tions are underway. However, there remains a major unmet
need to more rigorously evaluate the CV effects and wider
safety of all new medications, as well as other clinically-
relevant outcomes including microvascular complications,
preservation of islet b-cell function, improved metabolic pro-
file, cost effectiveness, and not least quality of life. The issue
of ketoacidosis associated with SGLT2b’s [28] (perhaps more
so with SGLT1/2b’s), needs further investigation, particularly
1 4 3 ( 2 0 1 8 ) 1 0 1 –1 1 2
in T1DM [95] – professional and patient education may, but
might not, lessen the risk of this potentially fatal complication.
6.1. Turning Joslin’s tide
Importantly, an unmet need for inexpensive but efficacious
drugs and lifestyle modification will persist; cutting-edge
pharmacotherapies, biotechnologies, and risk-assessment
techniques benefit only people with access to state-of-
the-art health-care services, and are likely to remain beyond
the reach of the majority of people with diabetes in
resource-poor countries who suffer the heaviest global
burden [5]. Accordingly, most people will remain reliant on
conventional glucose-lowering medications and those com-
ing off patent. Besides, medicine alone cannot turn Joslin’s
tide; it will be impossible to substantially reduce the
incidence of diabetes without public health initiatives that
cement enduring lifestyle-changes [5,7]. This inescapable
conclusion deserves much more thorough analysis beyond
the scope of this broad overview, particularly concerning the
socioeconomic and political forces driving the diabetes
epidemic.
Joslin, who deplored obesity, wrote in 1921, ‘‘. . .it is proper at
the present time, to devote attention not alone to treatment, but still
more . . . to prevention” [53]. His maxim is truer now than ever,
but how to achieve and fund this is still unclear. The appar-
ently obvious solution of changing unhealthy behaviour is a
difficult undertaking [96]. Although population-based
interventions have reduced hard outcomes over periods as
long as 40 years [97] and school-based anti-obesity
programmes have shown some success [98,99], escalating
incidence of T2DM globally attests to the failure of conven-
tional approaches, and better alternatives are clearly needed,
perhaps including taxing convenience foods and high-sugar
drinks [5]; however, emerging evidence suggests that this is
no panacea [100]. Although such measures can be politically
controversial, the approach has had some success for tobacco
and alcohol, while another relevant initiative involved
removing soft-drinks machines from schools. The battle-
ground is a human constitution hardwired to endure prehis-
toric privations and ill-adapted to cope with incessant
bounty, while adult habits seem programmed by childhood
experience. A subtler approach that considers obesity the
natural consequence of modern urban environments and
persuasive marketing rather than weak willpower, and pro-
motes incrementally healthier lifestyle choices, may be more
fruitful than admonitions to eat less [96].
Facing this immense challenge, what are the most press-
ing priorities? Low-hanging fruit appear to be school educa-
tion, and expanded access to existing diagnostic and
therapeutic modalities, which must be applied more assidu-
ously and effectively [5]. A key missing element is universal
implementation of pragmatic, cost-effective, awareness rais-
ing and prevention programs that can change unhealthy life-
style behaviours at the population level [5], for which there
are models [61,97,98] and without which rising prevalence
of diabetes cannot be reversed [5,7]. It is incumbent on stake-
holders to work together to emulate other successes, such as
with tobacco control and sun/skin safety, as well as to learn
from earlier failures. Without action at all levels, we face a
 diabetes research and clinical practice
foreseeable future in which approaching one quarter of
humankind may have diabetes, and half will suffer during
their lifetime – a 21st century scourge rivalling any in history. [4]
Acknowledgements
[5]
This review is based partly on an international diabetes
expert meeting, in April 2016, Philadelphia, USA. The authors
thank the faculty and other participants for their contribu- [6]
tions; especially, Zachary Bloomgarden MD, FACE, for critical
commentary on the first draft, Maike Sander MD, for helpful
[7]
feedback on the cell replacement therapy section, and Jose
C. Florez MD, PhD, for helpful feedback specific to the genetics
section.
[8]
Author contributions
CYW conceived the review format and content, and analysed
and interpreted source materials. PH and DLN supplied, anal- [9]
ysed and interpreted source materials. DLN wrote the manu-
script, which CYW and PH revised critically for important [10]
intellectual content; CYW, DLN, and PH approved the final
version submitted and take responsibility for its integrity
and accuracy.
Conflicts of interest [11]
Chih-Yuan Wang has received funding for educational activi-
[12]
ties from Merck.
David L. Neil is a medical editor employed at time of writ-
ing by Content Ed Net (Taiwan); his research and writing ser-
vices were funded by MSD Taiwan. [13]
Philip Home has received funding for his research, educa-
tional, and advisory activities from Antriabio, AstraZeneca,
Biocon, Boehringer Ingelheim, GlaxoSmithKline, Hanmi, Jans-
sen/Johnson & Johnson, Merck (MSD), Novo Nordisk, Roche
Diagnostics, and Sanofi. [14]
Role of funding source
This work was conceived by CYW and did not receive any
specific grant from funding agencies in the public, commer- [15]
cial, or not-for-profit sectors. MSD Taiwan funded medical
writing but played no further role in reviewing or amending
text drafts, nor the final decision to publish. Merck (MSD)
funded participants in the diabetes expert meeting (author
[16]
disclosures above).
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