Type 2 Diabetes The Lancet 2022

Seminar
Type 2 diabetes
Ehtasham Ahmad*, Soo Lim*, Roberta Lamptey, David R Webb, Melanie J Davies
Type 2 diabetes accounts for nearly 90% of the approximately 537 million cases of diabetes worldwide. The number Lancet 2022; 400: 1803–20
affected is increasing rapidly with alarming trends in children and young adults (up to age 40 years). Early detection Published Online
and proactive management are crucial for prevention and mitigation of microvascular and macrovascular complications November 1, 2022
https://doi.org/10.1016/
and mortality burden. Access to novel therapies improves person-centred outcomes beyond glycaemic control.
S0140-6736(22)01655-5
Precision medicine, including multiomics and pharmacogenomics, hold promise to enhance understanding of disease
*Contributed equally
heterogeneity, leading to targeted therapies. Technology might improve outcomes, but its potential is yet to be realised.
Diabetes Research Centre,
Despite advances, substantial barriers to changing the course of the epidemic remain. This Seminar offers a clinically University of Leicester and the
focused review of the recent developments in type 2 diabetes care including controversies and future directions. Leicester NIHR Biomedical
Research Centre, Leicester
Epidemiology and global trends in choices in lifestyle are non-existent. Affordability, General Hospital, Leicester, UK
(E Ahmad MBBS, D R Webb PhD,
type 2 diabetes availability, and accessibility profoundly affect not only Prof M J Davies MD);
Defined solely on the basis of persistently elevated blood meal patterns and fitness routines, but also food Department of Internal
glucose concentration, type 2 diabetes is increasingly preparation methods and portions consumed while eating. Medicine, Seoul National
University Bundang Hospital,
recognised as a complex, cardiorenal-metabolic disease A person’s next meal might not be guaranteed,9 and the
Seoul National University
entity driven by a chronic positive energy balance.1 Multiple so-called appropriate meal choice might be difficult to College of Medicine,
metabolic and homoeostatic disturbances develop over source. Consequently, management goals for type 2 Seongnam, South Korea
the course of the disease and are sustained over time. diabetes will need to adapt to the changing demography (Prof S Lim MD); Family
Medicine Department,
Perturbations in glucose and lipid metabolism have and better understanding of pathophysiology. Detailed
Korle Bu Teaching Hospital,
profound detrimental effects on vascular integrity and genotyping and phenotyping, individualised targets, weight Accra Ghana and Community
supply, leading to organ dysfunction and premature death. management, and maintaining a good quality of life, Health Department, University
The rising global incidence of type 2 diabetes is including mental wellbeing, might represent new goals of of Ghana Medical School,
Accra, Ghana
associated with a rise in obesity trends. Rapid economic care.10 However, a united, international response truly
(R Lamptey MB ChB)
development and urbanisation coupled with sedentary focused on improving global health inequalities in the
Correspondence to:
lifestyles and unhealthy eating patterns are believed to be delivery of diabetes care is needed to accomplish all these Prof Melanie J Davies, Diabetes
the main environmental factors fuelling this increase.2 management goals (appendix p 7).11 Research Centre, University of
About 537 million adults worldwide have diabetes, most Leicester and the Leicester NIHR
of whom have type 2 diabetes, and this number is expected Pathophysiology Biomedical Research Centre,
Leicester General Hospital,
to rise to 783 million by 2045.3 Globally, the proportion of The pathophysiology of type 2 diabetes is characterised by University of Leicester,
people living with undiagnosed diabetes is around 45%, insulin resistance and initial hyperinsulinaemia, followed Leicester LE5 4PW, UK
but this figure ranges from 54% in Africa to 24% by progressive decline in the capacity of pancreatic β cells [email protected]
in North America and the Caribbean regions.3 Additionally, to produce insulin. The variable mix of β-cell dysfunction See Online for appendix
about 352 million people have impaired fasting glucose or and insulin resistance ultimately underlies the complexity
impaired glucose tolerance,4 which can progress to of type 2 diabetes. Although at diagnosis 40–80% of β-cell
type 2 diabetes at a rate of 5–10% of people within this function is already lost,12,13 with good glycaemic control or
population per year.5 remission substantial functional β-cell mass can be
More than 80% of people with type 2 diabetes live in restored.14 Reactivation or recovery of existing β-cells or
low-income and middle-income countries.2 Although redifferentiation and regeneration from other pancreatic
Africa has the lowest prevalence (5·3%) relative to other cell lines might underpin this restoration.15 Consequently,
global regions, this continent is projected to have the
highest increase over the next 25 years.2
Although the number of new cases of type 2 diabetes Search strategy and selection criteria
increases rapidly after age 55 years, the rates of early-onset We searched the Cochrane Library, MEDLINE, and Embase for
type 2 diabetes (aged ≤40 years) are increasing and present manuscripts published in English only in peer-reviewed
new public health and societal challenges.6 Generally, journals between Jan 1, 2000, and Dec 31, 2021. We used the
type 2 diabetes is more common among marginalised search terms “type 2 diabetes” or “type 2 diabetes mellitus”.
groups in any society. Genetic and epigenetic changes We largely selected publications from 2019 onwards, but did
associated with persistent hyperglycaemia perpetuate not exclude commonly referenced and highly regarded older
disparities in the distribution and burden of the disease. publications. We also searched the reference lists of articles
Environmental factors contribute further to widening the identified by our broad search strategy and selected those we
gap. Natural and man-made disasters also negatively affect judged relevant. Our reference list was modified on the basis
diabetes care.7,8 of comments from coauthors and reviewers focusing on
The prevalence of type 2 diabetes is correlated with high-quality publications.
lifestyle choices, but for most people with type 2 diabetes,
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a β-cell-centric model, recognising abnormal β-cell guidelines advocate screening individuals at high risk,
function as a primary defect of type 2 diabetes, has been including people who are overweight or obese, ethnic
proposed.16 In 2009, DeFronzo proposed that incretin groups susceptible to type 2 diabetes at a younger age,
dysregulation, lipolysis, hyperglucagonaemia, increased or people with a strong family history of type 2 diabetes
glucose reabsorption in kidney, and central appetite and previous gestational diabetes (figure 2).
dysregulation have key roles in the pathophysiology of When suspected, the diagnosis of type 2 diabetes can
type 2 diabetes in addition to the traditional triumvirate of be made by analysis of plasma glucose concentrations or
muscle, liver, and β-cell interplay.17 This interplay was later glycated haemoglobin (HbA1c; table 1). Although type 2
extended to include defects in 11 interlocking pathways, diabetes is the most prevalent type of diabetes,
with β-cell dysfunction as the common denominator distinguishing it from other forms of diabetes, including
connecting the pathways.16 type 1 diabetes, monogenic diabetes or maturity-onset
In this Seminar, we combine all the pathophysiological diabetes of the young, or latent autoimmune diabetes in
factors contributing to hyperglycaemia: the deleterious adults (LADA), is not always straightforward (figure 2).
dozen (figure 1). This model incorporates dysbiosis in Taking time to review the history and clinical context is
gut microbiota, inflammation, immune dysregulation, extremely important for diagnosis and appropriate
and islet amyloid polypeptide (amylin) deposition in the management. For example, LADA and diabetes arising
pancreas.18 It has implications for management of from pancreatic disease (type 3) are occasionally
type 2 diabetes, with reprofiling of existing drugs to mistaken for type 2 diabetes, as these conditions usually
target the underlying pathophysiological defects and the present after 30 years of age. The presence of diabetes-
development of new drugs (figure 1). associated autoantibodies including glutamic acid
decarboxylase (GAD), normal BMI, and rapid
Screening and diagnosis progression to insulin requirement (usually after
Universal screening for diabetes is not recommended 6 months of diagnosis) can aid in diagnosis of LADA.23
as there is little evidence that this approach is cost- Ketosis-prone diabetes shares similar pathophysiology
effective or improves health outcomes.19,20 Consensus to type 2 diabetes but can present like type 1 diabetes; for
(7) Brain (8) Gastrointestinal tract (9) Inflammation

(3) Adipose Defects Defects
tissue • Impaired appetite Defects • ↑Chronic inflammation
regulation • ↓ Incretin effect
(4) Skeletal • ↑ Sympathetic tone Therapeutic options:
muscles • ↓ Dopamine activity Therapeutic options: • GLP-1 receptor agonist
• GLP-1 receptor agonist • SGLT2 inhibitor
Therapeutic options: • Anti-inflammatory agents
• GLP-1 receptor agonist • DPP-4 inhibitor
(5) Liver • Dopamine agonists
Defects
• ↑ Insulin resistance (10) Immune function
Therapeutic options: Defects
• Metformin • Immune dysregulation
• Thiazolidinedione Therapeutic options:
• GLP-1 receptor agonist and • GLP-1 receptor agonist
SGLT2 inhibitor* Hyperglycaemia • Immune modulators
• SGLT2 inhibitor
(12) Pancreatic amyIin (IAPP)

(11) Stomach or small intestine,
or both
Defects Defects
• IAPP deposition • Abnormal emptying
in pancreas (1) β cells (6) Kidney (2) α cells • Gut dysbiosis
Therapeutic options: • ↑ Glucose absorption
• Future therapeutic target Defects
Therapeutic options:
• ↓ Mass Defects
Defects • GLP-1 receptor agonist
• ↓ Function • ↑ Glucose reabsorption
• α cells including • DPP-4 inhibitor
Therapeutic options: including SGLT2
↑ glucagon • α-glucosidase
• GLP-1 receptor agonist hyperexpression
inhibitors
• Insulin • ↑ Inflammation and fibrosis Therapeutic options: • Amylin analogues
• Sulfonylurea Therapeutic options: • GLP-1 receptor agonist • Metformin
• Meglitinides • SGLT2 inhibitor • Amylin analogues
• DPP-4 inhibitor • Non-steroidal selective MRA • DPP-4 inhibitor
Figure 1: The deleterious dozen: 12 pathophysiological defects contributing to β-cell failure in type 2 diabetes with therapeutic options for individual
pathways
↑=increase. ↓=decrease. DPP-4=dipeptidyl peptidase 4. GLP-1=glucagon-like peptide-1. IAPP=islet amyloid polypeptide. MRA=mineralocorticoid receptor
antagonist. SGLT2=sodium-glucose cotransporter 2. *Not the primary mechanism of action.
1804 www.thelancet.com Vol 400 November 19, 2022

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Asymptomatic adults Hyperglycaemia symptoms* in childhood and adolescence
Diagnostic test
HbA1c ≥6·5%
Diagnostic Fasting plasma ≥7 mmol/L (126 mg/dL)
Screening test glucose
Diagnosis of diabetes
for diabetes 2 h OGTT ≥11·1 mmol/L (200 mg/dL)
Random blood ≥11·1 mmol/L (200 mg/dL) with
glucose hyperglycaemic symptoms* Differential diagnosis
Screening candidates† Type 2 diabetes LADA Type 1 diabetes MODY

(1) Adults with overweight or obesity Age >30 years >30 years Children and <25 years
(BMI ≥25 kg/m2 or ≥23 kg/m2 in some ethnic groups) adolescents
(2) Family history of diabetes Inheritance Polygenic Polygenic Polygenic Monogenic
(3) Ethnicities at high risk (eg, African American, Latino,
Native American, Asian, African, American, or Pacific Islander) BMI Overweight Mostly normal Mostly normal Mostly normal
(4) History of cardiovascular disease or hypertension or obese
(≥140/90 mm Hg or medications) Autoantibodies‡ Absent Detectable Detectable Absent
(5) Triglyceride >2·82 mmol/L (>250 mg/dL) or HDL-cholesterol
<0·90 mmol/L (<35 mg/dL), or both C-peptide Normal Low but Very low to Detectable
(6) Clinical conditions associated with insulin resistance: or elevated detectable undetectable
polycystic ovary syndrome, acanthosis nigricans, history of Diabetic Rare Rare Recognised Rare
gestational diabetes, and HIV infection ketoacidosis
(7) All other people aged ≥35 years Features Commonly Slowly progressive Presents with Strong family
asymptomatic β-cell destruction hyperglycaemic history
symptoms
Figure 2: Screening process for diabetes, its diagnostic criteria, and differential diagnosis
HDL=high-density lipoprotein. LADA=latent autoimmune diabetes in adults. MODY=maturity-onset diabetes of the young. OGTT=oral glucose tolerance test.
*Polyuria, polydipsia, polyphagia, or weight loss. †Modified from Standards of Medical Care in Diabetes—2022.21 ‡Glutamic acid decarboxylase, islet tyrosine
phosphatase 2, and zinc transporter-8.
example, with increased risk of diabetic ketoacidosis.24 HbA1c*(%) Fasting 2 h glucose Random
Unlike LADA, this condition is not associated with GAD plasma in oral blood
anti
bodies and occurs most commonly in men with glucose glucose glucose
(mmol/L) tolerance (mmol/L)
overweight.25 This type is often seen in African test
populations who require insulin during acute illnesses (mmol/L)
and hospital admissions. However, ketosis-prone Diabetes ≥6·5 ≥7 ≥11·1 ≥11·1 with
diabetes can be managed with diet or oral glucose- symptoms
lowering therapies under most circumstances.25 If Prediabetes, 6–6·4 6·1–6·9 7·8–11 ··
diagnostic uncertainty persists, the condition should not range (5·7–6·4†) (impaired (impaired
be labelled as either type 1 diabetes or type 2 diabetes fasting glucose
glucose; tolerance)
until diagnosis is confirmed, while safely managing 5·6–6·9†)
glycaemic control. No diabetes <6 (<5·7†) ≤6 <7·8 ··
HbA1c=glycated haemoglobin. *In individuals without symptoms, HbA1c should be
Subtypes of type 2 diabetes repeated. HbA1c alone should not be used for diagnosis in children or young adults
In clinical practice, the diagnosis of type 2 diabetes is (<18 years old), pregnant women, people with short duration of symptoms
focused on specific phenotypic characteristics, such as (<2 months), or in people with certain haematological disorders (eg, anaemia or
haemoglobinopathies) causing rapid red blood cell turnover. †Stated in some
BMI, or is made once other types of diabetes have been guidelines, including American Diabetes Association.22
excluded. Use of precision medicine models, including
biogenetics, might aid in diagnosis and management of Table 1: Diagnosis of diabetes
subtypes of type 2 diabetes.
A Swedish model analysed data from a cohort of more
than 20 000 people from Scania County with newly characteristics, disease progression rates, and clinical
diagnosed diabetes. The model identified five subtypes outcomes (panel). The frequency of different subtypes
using clinical variables on the basis of the understanding varies across populations. Mild obesity-related diabetes
that diabetes develops when insulin secretion does not and mild age-related diabetes have been identified as the
meet the demands of insulin resistance.26 The variables main cluster in European populations and severe
included age of onset, BMI, HbA1c, GAD antibody, β-cell insulin-deficient diabetes (SIDD) has been identified as
function (homoeostasis model assessment [HOMA] for the predominant cluster in Asian populations, which
β-cell function; HOMA2-B), and insulin resistance tend to develop diabetes at a younger age and lower BMI
(HOMA2-IR). The novel subtypes have different clinical than do Europeans.26–28 Some subtypes, especially those

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impact in reducing the risk of future complications. By

Panel: Characteristics of diabetes subtypes contrast, intensification of glucose-lowering therapy at a
Type 1 diabetes or latent autoimmune diabetes in adults later stage in people with long duration of type 2 diabetes
Severe autoimmune diabetes (known as SAID) might not be beneficial38–40 and, in fact, might result in
• Positive glutamic acid decarboxylase (GAD) antibody worse outcomes.39 Benefits of glucose-lowering therapies
• Early onset persisted for years after the conclusion of the initial trial
• Low BMI period in UKPDS, despite loss of earlier glycaemic
• Low insulin secretion between-group differences, an occurrence termed the
• High glycated haemoglobin (HbA1c) legacy effect.36
• Early requirement for insulin Because of the multifactorial nature of type 2 diabetes,
• High prevalence of retinopathy other modifiable risk factors, like hypertension and
dyslipidaemia, should be addressed with a holistic
Type 2 diabetes approach, and not just glycaemic control, to reduce risk
Severe insulin-deficient diabetes (known as SIDD) of long-term complications. The Steno-2 study41 showed
• Negative GAD antibody but other features like SAID that multifactorial risk reduction targeting glycaemic,
• Low insulin secretion blood pressure, and lipid control in those with pre-
• High HbA1c existing microalbuminuria reduced both microvascular
• Early requirement for insulin and macrovascular complications.
• High prevalence of retinopathy and nephropathy
Severe insulin-resistant diabetes (known as SIRD) Prevention and delay of type 2 diabetes
• Obesity Proactive management at an early stage in individuals at
• Insulin resistance high risk is key to delaying or preventing type 2 diabetes.
• Late onset Considerable evidence shows that type 2 diabetes can be
• Increased risk of kidney disease and fatty liver prevented, or its onset delayed, through lifestyle inter
Mild obesity-related diabetes (known as MOD) ventions (calorie-restricted diets and exercise) particularly
• Obesity targeting weight loss or by use of pharmacotherapy,
• Lack of insulin resistance including metformin, pioglitazone, and liraglutide.42–45
• Early onset Community-based cluster phenotyping might aid in
identifying individuals at increased risk for type 2 diabetes
Mild age-related diabetes (known as MARD) and allow for efficient prevention strategies.46
• Late onset Unfortunately, long-term effectiveness and adherence to
• Low risk of complications all these interventions remain challenging,47,48 particularly
in low-income and middle-income countries.49 There is an
predom inant in Asian populations like SIDD, are increasing emphasis in advanced health-care systems on
associated with high risk of complications.26 the implementation of effective strategies for preventing
Other approaches to phenotyping and characterising type 2 diabetes through promotion of healthier lifestyle
subtypes of type 2 diabetes have also been proposed,29,30 and working with food manufacturers and retailers to
but further research is need to help clarify the best encourage healthy eating at national levels.50 Risk
methods to identify different subtypes of type 2 diabetes. assessment and then management of people at high risk
(fasting plasma glucose of 5·5–6·9 mmol/L or HbA1c of
Long-term complications of type 2 diabetes 6·0–6·4%) are the two key components of this strategy.
Type 2 diabetes is associated with increased risk of both Individuals who are overweight, with a BMI of 25 kg/m²
microvascular (ie, retinopathy, neuropathy, and nephro or more (≥23 kg/m² in some ethnic groups), are encour
pathy) and macrovascular (ie, ischemic heart disease, aged to lose weight through diet, exercise, and pharma
cerebrovascular disease, and peripheral vascular disease) cotherapies. Use of modern technology, including use of
complications. Long duration of diabetes, suboptimal wearable devices, might aid in delivering prevention
glycaemic control, increased glycaemic variability, male programmes.51,52 A systematic review assessed the
sex, underlying comorbidities, and pre-existing compli effectiveness of different technology-driven programmes
cations such as albuminuria or subclinical atherosclerosis to prevent type 2 diabetes.53 Digital features in these
are all associated with increased risk of microvascular programmes comprised of diet and weight tracking,
and macrovascular complications in people with activity monitors, online coaching, social media, remin
type 2 diabetes.31–33 These complications of diabetes can ders, and gamification. The review found that these
impose substantial socioeconomic burden and affect technology-driven programmes to be effective in both the
quality of life.34 The UK Prospective Diabetes Study short-term (≤6 months) and long-term (≥12 months).
(UKPDS)35 and several subsequent studies36,37 have shown Gestational diabetes is an established risk factor for
that achieving intensive glycaemic control, especially developing type 2 diabetes. A meta-analysis has shown
early intervention, could have a clinically significant that future risk of type 2 diabetes is almost ten times

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higher in women with previous gestational diabetes than of 15% or more can induce diabetes remission in a large
in the healthy control group,54 highlighting the need for proportion of people with type 2 diabetes (HbA1c to
effective prevention strategies during pregnancy and <6·5% for at least 3 months without any glucose-
post partum. Lifestyle interventions and metformin have lowering therapies).65,66 A key component of short-term
been trialled with variable success,55–57 and the blended diabetes remission is achieving adequate weight loss
approaches including lifestyle and medications might be through use of restricted calorie intake in the form of
more useful to the needs and time restrictions of either a low energy diet (800–1200 calories per day) or
pregnant women. However, challenges remain for very low energy diets (<800 calories per day).65,67 However,
the successful implementation of prevention strategies, long-term adherence to such diets is challenging and
including person engagement, use of new technologies, many people regain weight.68
assessment of weight loss interventions, development of A balanced diet is a core component of lifestyle
risk models, and embracing of omics to help with management in type 2 diabetes. Medical nutrition therapy
individualised care plans to accelerate understanding of delivered by dietitians is associated with improved
gestational diabetes.58 glycaemic control across diverse ethnic groups.69 Nutri
tional recommendations should be individualised,
Glycaemic management ongoing, and delivered by expert health-care providers.
The consensus guidelines by the American Diabetes Self-management education should be specific to a
Association (ADA) and the European Association for the person’s needs and culturally sensitive.70,71
Study of Diabetes (EASD) recommend a target HbA1c Low carbohydrate and low-glycaemic index diets,
of 7% or less for most adults with sufficient life comprising mainly of non-starchy vegetables, whole
expectancy for long-term benefits, particularly micro grains, and pulses, are advocated for prevention and
vascular benefits.59,60 Lower targets should only be aimed management of type 2 diabetes.70 Evidence exploring the
at otherwise stable people with type 2 diabetes if these effect of low-glycaemic index diets, such as Mediterranean
targets can be achieved safely without hypoglycaemia or diets, shows that this diet is associated with improve
adverse effects of the therapies. The ADA and the EASD ments in HbA1c and bodyweight.72–74 Calorie restriction is
consensus59,60 stress the need for a person-centred holistic important for reduction in bodyweight and metabolic risk
approach to achieving glycaemic targets including weight factors.75
reduction, control of cardiovascular risk factors, and Interest is increasing in exploring the effect of
cardiorenal protection. This shift from a glucocentric ketogenic diets and intermittent fasting on health
model to a more holistic approach aims to empower outcomes of people with type 2 diabetes. Ketogenic
people living with diabetes. The consensus also stresses diets consist of 90% of total daily calorie intake from fat
the need for diabetes self-management education. Such and only 10% from proteins and carbohydrates,76
programmes are considered an integral part of routine whereas intermittent fasting is an eating pattern
care for type 2 diabetes.61 characterised by periods of negligible energy intake
The 2022 ADA and EASD consensus report59,60 alternating with periods of ad-libitum feeding.77 A meta-
emphasises the need for management of multiple analysis showed that the ketogenic diets were associated
comorbidities to reduce the burden of complications and with improvement in glycaemic control in the short-
improve quality of life as important goals of care. In term only.78 A decline in compliance was proposed as
addition, remission of type 2 diabetes should be a the primary reason for this. Similarly, a review of RCTs
treatment goal for those newly diagnosed or with a short comparing intermittent fasting to continuous energy-
duration of type 2 diabetes. restricted diet for people with type 2 diabetes did not
find any difference in glycaemic control between the
Lifestyle management two groups.79 There were also safety concerns including
Lifestyle management is considered first-line treatment hypoglycaemia and hyperglycaemia with intermittent
in the management of type 2 diabetes. Several studies fasting. In summary, the full potential of these dietary
have confirmed that intensive lifestyle intervention, approaches for type 2 diabetes is yet to be explored, and
especially when accompanied by clinically significant it is important to take a person-centred approach that is
weight loss, improves glycaemic control.62,63 beneficial and sustainable for that individual.
Obesity is linked to multiple comorbidities including Exercise should be part of routine management of
type 2 diabetes. More than 80% of people with type 2 diabetes due to the diverse cardiometabolic benefits
type 2 diabetes are classified as overweight or obese.64 beyond glycaemic control. These include improved
Consequently, targeting weight loss is an effective means insulin sensitivity and reduced visceral fat content.80,81 A
of reducing the metabolic burden of type 2 diabetes. prospective intervention study showed that habitually
Sustained weight loss of 5–10% can delay progression active individuals who decreased their physical activity for
from a prediabetes state to diabetes.42 Studies have shown 2 weeks accrued abdominal and liver fat and developed
that weight loss of at least 5% is required for beneficial adverse metabolic features including insulin resistance
effects on glycaemic control, and greater weight loss and dyslipidaemia.82 By contrast, randomised controlled

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trials (RCTs) for diabetes prevention42,83,84 have shown that placebo. However, adverse effects of pioglitazone, such
moderate-to-vigorous physical activity (eg, brisk walking as fluid retention, weight gain, heart failure, and
or swimming) has proven effective in the management of decreased bone mineral density, should be considered
hyperglycaemia and cardiometabolic risk. when prescribing.
Regular engagement in exercise (both aerobic and Since the mid-2000s, dipeptidyl peptidase 4 (DPP-4)
resistance) elicits adaptations that can lead to improve inhibitors have been widely used because of their safety
ments in clinical outcomes like diabetes prevention, including low risk of hypoglycaemia, good tolerability,
reductions in abdominal and visceral fat, and mental wide availability, and convenient dosing. However, their
wellbeing and a substantially lower cardiovascular and glucose-lowering efficacy is only modest and exerts
overall mortality risk.85,86 The benefits of exercise are neutral effect on weight.
especially prominent for people currently doing less than Both SGLT2 inhibitors and GLP-1 receptor agonists
30 min of purposeful activity including work-related or have shown cardiorenal benefits in trials with weight loss
recreational activity per week.87 Breaking up prolonged and low risk of hypoglycaemia. International guidelines
sitting time with short regular bouts of slow walking and now recommend early use of these agents even before
simple resistance exercises (eg, calf raises and squats) metformin in patients with established or at high risk of
has been shown to improve glucose metabolism.85 Smart cardiovascular and renal diseases irrespective of baseline
watches or physical activity trackers with step counters HbA1c.97,98 SGLT2 inhibitors are also now included in
are effective in supporting behaviour change through the WHO list of essential medications along with
enabling goal setting and feedback.88 metformin, sulfonylureas, and insulin.99 Noteworthy
The most successful glycaemic outcomes were seen adverse effects of these agents include genital infection
with exercise programmes that were multifactorial, (SGLT2 inhibitors), gastrointestinal side-effects (GLP-1
including programmes that were structured, flexible, receptor agonists), and increase in heart rate (GLP-1
individually tailored, supervised with behavioural receptor agonists).
support, culturally appropriate, and made use of digital Treatment intensification beyond metformin should be
technology.88–91 Exercise should be combined with dietary guided by presence of established or high-risk of
support for maximum benefits.92 cardiorenal comorbidities, including heart failure and
chronic kidney disease, weight issues, and risk of
Drug therapies hypoglycaemia.59,60 The GRADE trial100 assessed the
In many guidelines, metformin is considered first- relative effectiveness of the four common second-line
line glucose-lowering therapy for management of glucose-lowering therapies after metformin, namely
type 2 diabetes.59,60,93 Reasons for this recommendation glimepiride, sitagliptin, liraglutide, and basal insulin
include widespread availability, low cost, ease of glargine. The results show that after a mean follow-up of
administration, good tolerability, low risk of hypogly 5 years, all four medications, when added to metformin,
caemia, weight neutrality, combination formulations, reduced HbA1c concentrations. However, glargine and
and importantly decades of experience with clinical liraglutide were significantly more effective in achieving
effectiveness.94 However, sodium–glucose cotransporter and maintaining target HbA1c concentrations of <7%. We
2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) have scarce evidence for combined use of both SGLT2
receptor agonists, with or without metformin, are inhibitors and GLP-1 receptor agonists with early results
appropriate initial therapy for individuals with showing additive glycaemic and metabolic benefits.101–103
established or who are at high risk of atherosclerotic As these medications target different pathways in the
cardiovascular disease, heart failure, or chronic kidney deleterious dozen, preference should possibly be given to
disease.59,60,93 combinations of these agents to produce additive or
Sulfonylurea and meglitinides have good glucose- synergistic effects that ultimately reduce risk of micro
lowering efficacy and are less expensive but they have vascular and macrovascular complications and improve
unfavourable effects such as hypoglycaemia and weight cardiometabolic and renal outcomes.104 However, dedi
gain. These agents might be recommended when cost cated RCTs are required to confirm these beneficial
and availability matters. Of note, glyburide or glipizide, effects. In the VERIFY trial,105 an initial combination
which have high affinity for mitochondrial KATP channels, therapy of metformin and vildagliptin provided greater
have shown increased risk of major adverse cardio and more durable long-term benefits than metformin
vascular events (MACE) compared with gliclazide or monotherapy in people with newly diagnosed type 2
glimepiride, which have lower affinity for KATP.95 diabetes. Use of fixed-dose combinations can also
Thiazolidinediones have durable glucose-lowering facilitate improved medication-taking behaviour.106
properties and improve insulin resistance with low risk Tirzepatide, a novel dual glucagon-like peptide-1
of hypoglycaemia. The PROactive Study96 exploring use (GLP-1) and glucose-dependent insulinotropic polypep
of pioglitazone for secondary prevention of macrovascular tide (GIP) analogue, has been approved by the US Food
events in people with type 2 diabetes showed reduction and Drug Authority (FDA) and European Medicines
in composite macrovascular outcomes compared with Agency for management of type 2 diabetes. Across the

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SURPASS phase 3 programme107–111 versus placebo and production,117 suggesting that some GLP-1 receptor
active comparators, including semaglutide, tirzepatide agonists have vasculoprotective properties, which might
has shown superior dose-dependent reductions in be the main mechanism of their beneficial effect on stroke
HbA1c (2–2·5%) and weight (11–13%), which is expected prevention. A cardiovascular outcome trial of tirzepatide
to further change the landscape of type 2 diabetes is also ongoing (SURPASS-CVOT; NCT04255433).
management. SGLT2 inhibitor therapy is effective in reducing
Insulin therapy (both basal and bolus) remains an hospitalisation for heart failure and progression of
important part of glycaemic management of type 2 chronic kidney disease in patients with type 2 diabetes.118
diabetes, especially in people who are struggling to meet Some large trials showed a reduction in hospitalisation
glycaemic targets. The main advantage of insulin over for heart failure and renal complications by more than
other glucose-lowering therapies is that it lowers glucose 30% with SGLT2 inhibitor therapy (appendix p 6). The
in a dose-dependent manner to almost any glycaemic reduction in these outcomes occurred within 6 months,
target; however, it comes with the disadvantage of weight and these reductions were also seen in people without
gain, risk of hypoglycaemia, and frequent glucose type 2 diabetes, which suggests that the cardiovascular
monitoring.60 Use of basal insulin is the preferred and renal benefits driven by SGLT2 inhibitors might be
approach to initiating insulin therapy in people with induced through its haemodynamic effects rather than
type 2 diabetes. These can be combined with GLP-1 glucose-lowering effects.119
receptor agonists to reduce the risk of hypoglycaemia Because of the beneficial effects of GLP-1 receptor
and weight gain.59,60 Fixed-ratio combinations of GLP-1 agonists and SGLT2 inhibitor therapies beyond glycaemic
receptor agonists and basal insulin give the option of management,120,121 guidelines now recommend early
convenience with fewer injections, increased efficacy, addition of these agents in people with established
and reduced risk of side-effects.59,60 A comprehensive cardiorenal disease or at high risk of atherosclerotic
approach to insulin therapy is provided in the ADA and cardiovascular disease, heart failure, or chronic kidney
EASD report for management of hyperglycaemia.59,60 disease.59,60,122
Details of the oral and injectable glucose-lowering
therapies including commonly prescribed basal and Management beyond glycaemic control
bolus insulins are provided in tables 2 and 3. Obesity management
Type 2 diabetes and obesity are interconnected,
Large cardiovascular and renal outcomes trials heterogeneous diseases that share many patho
The FDA requires all glucose-lowering therapies in physiological mechanisms including ectopic adiposity,
development to undergo RCTs for cardiovascular out insulin resistance, inflammation, and β-cell dysfunction.66
comes to confirm their cardiovascular safety and to However, much remains unknown about the relation
exclude risk of MACE. Cardiovascular outcome trials of ship between obesity and type 2 diabetes, including the
DPP-4 inhibitors, such as alogliptin, sitagliptin, and fundamental pathophysiological mechanism to explain
linagliptin, have shown a neutral effect on MACE how overnutrition and chronic adipose tissue accumu
outcomes, with the exception of saxagliptin, which lation predispose to insulin resistance, β-cell dysfunction,
increased the risk of hospital admission for heart failure.112 and ultimately type 2 diabetes. Not everyone classed as
Among the nine cardiovascular outcome trials of GLP-1 overweight or obese will develop type 2 diabetes;123
receptor agonists, six trials of liraglutide (Novo Nordisk, similarly, people with a so-called healthy weight can be
Bagsvaerd, Denmark), both injectable and oral diagnosed with type 2 diabetes, suggesting that other
semaglutide (Novo Nordisk), albiglutide (GlaxoSmithKline, factors have a role in pathogenesis. There is also little
Brentford, UK), dulaglutide (Eli Lilly, Indianapolis, IN, evidence that weight loss, per se, improves patient-
USA), and efpeglenatide (Hanmi Pharmaceutical, Seoul, relevant outcomes or premature death from cardiovascular
South Korea) have shown superiority in MACE.113 In the disease in people with type 2 diabetes.62,124
cardiovascular outcome trials with SGLT2 inhibitors, em Recent advances add to our understanding of the
pagliflozin, canagliflozin, dapagliflozin, and sotagliflozin biological mechanisms underpinning this relationship
have shown superiority in MACE, but ertugliflozin has and might provide important insight into future clinical
not.114 A forest plot showing the composite MACE out applications. Hereditability of obesity and type 2 diabetes
comes for GLP-1 receptor agonists and SGLT2 inhibitors is reportedly in the range of 30–70%, suggesting
and further details about the individual trials of these substantial genetic influence in disease susceptibility.125,126
novel agents are in the appendix (pp 2–5, 8–11). Awareness of inherited risk through polygenic scoring
GLP-1 receptor agonists, particularly dulaglutide and could allow earlier identification of individuals at high
semaglutide, showed better results in stroke prevention risk, and provide targeted management.127
than other glucose-lowering therapies.115 GLP-1 receptor With better understanding of biological mechanisms,
agonists have antioxidant and neuroprotective effects pharmacotherapies targeting pathways common to both
through upregulating vascular endothelial growth factor obesity and type 2 diabetes are improving in efficacy.
production116 and reducing pro-inflammatory cytokine Liraglutide 3·0 mg once daily128 and semaglutide 2·4 mg

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Medications Primary mechanism of Advantages Common side-effects or Additional notes

action disadvantages
Biguanide Metformin Decrease hepatic glucose Long-term safety and efficacy Gastrointestinal symptoms, Contraindicated if eGFR is <30 mL/min
production and output, data, no hypoglycaemia, lactic acidosis (rare), per 1·73m²; gastrointestinal side-effects
insulin sensitiser weight neutral or loss, low and vitamin B12 deficiency can be reduced with gradual dose
cost, and can be combined titration or using slow-release
safely with most other formulation
glucose-lowering therapies
Sulfonylurea Glibenclamide (also known Stimulate release of insulin Extensive experience, widely Risk of hypoglycaemia, Gliclazide and glipizide are associated
as glyburide), glipizide, from β cells of pancreas available, low cost, weight gain, with less risk of hypoglycaemia than are
gliclazide, and glimepiride (insulin secretagogues) and effective glucose- and no cardiovascular older generation of sulfonylureas like
lowering properties benefits glibenclamide; glyburide or glipizide that
has high affinity for mitochondrial KATP
channel showed increased risk of
cardiovascular events compared with
gliclazide or glimepiride with low affinity
Thiazolidinedione Pioglitazone, lobeglitazone, Insulin sensitiser No hypoglycaemia, low cost, Weight gain, fluid retention, Rosiglitazone is rarely used now due to
(PPAR-γ agonist) and rosiglitazone widely available, and effective heart failure, and increased increased risk of adverse cardiovascular
in fatty liver disease risk of fractures outcomes
Meglitinide Repaglinide, nateglinide, Short-acting insulin Shorter duration of action, Hypoglycaemia and weight Because of quick onset, can be used as an
and mitiglinide secretagogues less hypoglycaemia than gain option in people who need meal-related
sulfonylureas, and flexible blood glucose control like fasting
dosing patients or shift workers
α-glucosidase Acarbose, voglibose, Delays digestion Low hypoglycaemia, decrease Gastrointestinal side-effects Non-systemic mechanism of action
inhibitor and miglitol and absorption of glucose post-prandial rise in blood like diarrhoea and flatulence
from the gastrointestinal glucose, low cost,
tract and cardiovascular safety
DPP-4 inhibitor Sitagliptin, vildagliptin, Increase insulin secretion No hypoglycaemia, weight Angioedema, acute No dose adjustment is needed in people
(gliptin) saxagliptin, linagliptin, and decrease glucagon neutral, good tolerability, and pancreatitis, and increased with renal impairment for linagliptin,
alogliptin, gemigliptin, secretion simple dose scheduling risk of heart failure with gemigliptin, teneligliptin, and evogliptin
teneligliptin, anagliptin, and saxagliptin
evogliptin
SGLT2 inhibitor Canagliflozin, dapagliflozin, Increase urinary excretion of No hypoglycaemia, weight Genital tract infection, risk of Dapagliflozin and empagliflozin have
(gliflozin) empagliflozin, ertugliflozin, glucose via kidneys reduction, heart failure dehydration, euglycaemic proven heart failure and CKD benefits
ipragliflozin, and benefits, CKD benefits ketoacidosis, Fournier’s even in people without type 2 diabetes;
sotagliflozin including albuminuria, reduce gangrene, and fracture and dapagliflozin is approved for use in CKD
blood pressure, and decrease amputation (canagliflozin in with eGFR ≥15 mL/min per 1·73 m²;
major adverse cardiovascular CANVAS trial) canagliflozin approved for use in CKD
events in cardiovascular with eGFR ≥30 mL/min per 1·73 m²
outcome trials
GLP-1 receptor agonist Exenatide lixisenatide, Increase insulin secretion No hypoglycaemia, weight Gastrointestinal side-effects, Lixisenatide is short acting; albiglutide is
albiglutide, liraglutide, and reduce glucagon reduction, and cardiovascular acute pancreatitis, withdrawn; semaglutide, dulaglutide,
semaglutide, dulaglutide, secretion, reduce gastric benefits (except lixisenatide) and contraindicated if efpeglenatide, and tirzepatide are weekly
efpeglenatide, and emptying, and promote medullary carcinoma of injections; semaglutide is available in oral
tirzepatide satiety mainly by binding to thyroid formulation; higher doses of liraglutide
receptors in the 3 mg daily and semaglutide 2·4 mg
hypothalamus and weekly are approved for obesity
hindbrain management; tirzepatide has been
approved for the treatment of adults
with type 2 diabetes (May, 2022)
and is the first commercially licensed dual
GLP-1 and GIP agonist
Fixed-dose Lixisenatide plus insulin Combined benefit of Less weight gain than insulin High cost, less flexibility in Can be considered a good alternate in
combination of GLP-1 glargine, liraglutide plus GLP-1 receptor agonist and therapy alone dosing, and risk of people who prefer fewer injections than
receptor agonist and insulin degludec basal insulin therapy hypoglycaemia separate injections
long-acting insulin
CKD=chronic kidney disease. DPP-4=dipeptidyl peptidase-4. eGFR=estimated glomerular filtration rate. GIP=glucose-dependent insulinotropic polypeptide. GLP-1=glucagon-like peptide-1. KATP, ATP-sensitive
potassium channel. PPAR-γ=peroxisome proliferator-activated receptor-γ. SGLT2=sodium-glucose cotransporter-2.
Table 2: Non-insulin, glucose-lowering therapies (oral and injectable) routinely used in the management of type 2 diabetes
once weekly129 have been approved by both FDA and without type 2 diabetes (−15·0% with 5 mg weekly
National Institute for Health and Care Excellence for doses, −19·5% with 10 mg doses, and −20·9% with 15 mg
chronic weight management in people with obesity. doses compared with −3·1% for placebo). Metabolic
Tirzepatide130 has shown significant weight loss efficacy surgery is the most effective means of achieving the
with all doses at 72 weeks in people with obesity but amount of sustained weight loss required to affect

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Names of insulin in the class Peak onset (h) Duration of Timing with relation Additional notes
action (h) to meals
Ultra rapid acting Faster acting insulin aspart (Fiasp; 1–2 4–6 Can be taken at the Allows flexibility in relation
(bolus insulins) Novo Nordisk, Bagsvaerd, start of meal or within to meals
Denmark) and ultra-rapid lispro 20 min of starting a
insulin (Lyumjev; Eli Lilly, meal
Indianapolis, IN, USA)
Rapid acting Aspart, lispro (U100, U200), 1–3 2–5 5–15 min before meal These insulin formulations
(bolus insulins) and glulisine are used to provide cover for
post-prandial rise in blood
glucose
Short acting Human regular (U100, U500) 1–5 5–9 15–30 min before meal Also used as subcutaneous
infusions in diabetic
ketoacidosis or
hyperglycaemic
hyperosmolar state
management
Intermediate acting Human Neutral Protamine 2–12 12–24 Usually used as basal Cloudy insulin preparation,
(basal insulin) Hagedorn insulin once or twice most other formulations
daily are clear
Long acting Degludec (U100, U200), detemir, Mostly peakless 16–42 Usually once or twice An advantage is they are
(basal insulins) and glargine (U100, U300) insulins, except daily usually once daily injections;
including biosimilar insulins detemir (6–14) weekly insulin preparations
(Icodec and basal insulin Fc)
are in the pipeline
Premixed Varying proportions of short- 1–4 12–24 10–30 min before Mostly preferred for people
acting or rapid-acting and meals depending upon who have a fixed lifestyle
intermediate-acting insulins formulation with meals twice daily
(25:75, 30:70, and 50:50
formulations are commercially
available)
Insulins work by increasing uptake of glucose in the target organs, mainly skeletal muscles. Dose of the insulins can be adjusted to the glycaemic target and all carry the risk of
hypoglycaemia and weight gain. U=concentration of insulin formulation in units (eg, U100 means 100 units per mL of insulin solution).
Table 3: Insulin formulations commonly used in treatment of type 2 diabetes
long-term outcomes. It is an invasive procedure and large muscle mass,135 is a feature of type 2 diabetes and
associated with complications including nutritional one of the main reasons for decline in physical function.
deficiencies and post-prandial hypoglycaemia. The The pathogenesis of sarcopenic obesity includes ageing,
procedure is an important addition to pharmacotherapy physical inactivity, malnutrition, low-grade inflammation,
and lifestyle intervention options and is the right approach insulin resistance, and hormonal changes,135 which are
in some patients.131 also common risk factors for type 2 diabetes.
Interventions like multicomponent exercise, which
Physical dysfunction and frailty in people with improve muscle function, could be used to improve this
type 2 diabetes condition and quality of life in people with
Type 2 diabetes increases biological ageing and leads to type 2 diabetes.136,137
early-onset frailty, consequently leading to impaired The precise effect of different glucose-lowering
physical function and reduced quality of life.132 Data from therapies on physical function and frailty is unknown.
the Chronotype of Patients with Type 2 Diabetes and Novel agents, SGLT2 inhibitors, and GLP-1 receptor
Effect on Glycaemic Control cross-sectional study133 agonists not only induce weight loss but exert pleiotropic
showed that nearly a third of people with type 2 diabetes metabolic effects, which could mean an improvement in
have some impairment of physical function. Risk of frailty physical function. However, 20–50% of total weight loss
and decline in physical function are strongly associated achieved by the use of these agents consists of lean body
with obesity, poor glycaemic control, longer duration of mass,138 which could adversely affect some of the potential
diabetes, and comorbidities like hypertension.134 benefits realised. Hence, there is a need for dedicated
Assessment of frailty and physical function in trials to explore the exact effect of these therapies,
management of type 2 diabetes is rarely undertaken in including combination therapies on physical function.132
clinical practice and there is a need to develop reliable The implications of glucose-lowering therapies should
point-of-care tools for assessment of these variables. also be considered when prescribing for a frail, older
Sarcopenic obesity, characterised by low functional population, including risk of hypoglycaemia, glycaemic
capacity of muscles in the presence of adiposity despite targets, and complexity of regimen.139

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Sleep behaviours cognitive decline in people with type 2 diabetes.170,171 Further

Type 2 diabetes is associated with poor sleep hygiene, studies are, however, needed to understand these
including insomnia.140 Poor sleep quality, such as short relationships.
sleep duration, sleep fragmentation, and variability, is
associated with increased risk of type 2 diabetes and Emerging populations in diabetes management
obesity.141–143 Both duration and timing of sleep Early-onset type 2 diabetes
(chronotypes) can have a major impact on the risk of The incidence and prevalence of type 2 diabetes in young
type 2 diabetes,144 with evening chronotypes (ie, go to bed people (aged 40 years or younger) is rising globally. Rates
late and get up late) at a higher risk of type 2 diabetes than vary widely depending upon the age, sex, and ethnicity of
are morning chronotypes (ie, early to bed and early to the study population and geography, resulting in an
rise).145 This effect is primarily driven by clustering of incidence range of 0–330 cases per 100 000 person-years
unhealthy behaviours—probably sedentary lifestyle, and a prevalence rate of 0–5300 cases per 100 000 children
higher BMI, and hypertension. Poor sleep patterns are and adolescents.172 Early-onset type 2 diabetes represents a
also associated with impaired quality of life.146,147 Non- more aggressive metabolic phenotype,173 and is associated
pharmacological therapies, such as structured sleep with increased insulin resistance, early β-cell failure, and
education programmes, behavioural therapy, and exercise, earlier onset of complications.174,175 One study showed that
can improve sleep hygiene in people with type 2 nearly 60% of individuals with early-onset type 2 diabetes
diabetes.147–151 have at least one complication by early adulthood.176
Obstructive sleep apnoea frequently coexists in people Furthermore, complication rates are high in people from
with type 2 diabetes and contributes to poor sleep minority ethnic groups and individuals with lower
quality.152 It is recognised as a risk factor for type 2 diabetes income.177 Few treatment options are explored for young
and obesity,153,154 and nearly 50% of people with type 2 people with type 2 diabetes because of limited long-term
diabetes have obstructive sleep apnoea.155 Consequently, it safety data.174 Novel treatment approaches and innovative
is important to screen for obstructive sleep apnoea with study designs are needed to address these concerns as
validated questionnaires.156 Use of continuous positive currently only few trials have assessed the safety and
airway pressure has been found to improve insulin efficacy of glucose-lowering therapies in people younger
resistance in people without diabetes and might lead to a than 40 years of age.174,178,179 ADA and EASD59,60 both now
trend in decrease in insulin resistance in people with recommend early combination therapy in young people
diabetes.157 As weight loss improves obstructive sleep (aged <40 years) with type 2 diabetes.
apnoea, the use of glucose-lowering therapies associated
with weight loss is also expected to improve it. SGLT2 Ethnicity, diversity, cultural, and religious
inhibitors have been shown to reduce the incidence of considerations
obstructive sleep apnoea.158,159 However, as weight loss The risk and burden of vascular complications in
with SGLT2 inhibitors is only modest, other factors, type 2 diabetes is underestimated in women.180,181
including decrease in cardiac preload and beneficial UK studies have consistently shown that women are less
effects on re spiratory dynamics, might also be likely to meet quality targets for risk factor control than are
responsible.159 Similarly, liraglutide therapy showed men.181–183 Women are also under-represented in cardio
significant improvement in the apnoea–hypopnea vascular outcome trials assessing the safety of glucose-
index.160 lowering therapies.184 Similarly, health research often does
not understand and address the needs of minority ethnic
Mental wellbeing and depression groups,185 even though these groups present with higher
Like many chronic medical conditions, type 2 diabetes is metabolic risk even at lower BMI with earlier-onset of
strongly linked to depression. Almost one in four people type 2 diabetes and rapid progression to diabetes-related
with type 2 diabetes experience depression at some point.161 complications.186,187 Thus an aggressive approach to not
This increased risk is related to female sex, socioeconomic only early diagnosis and management is needed in people
status, complications, and metabolic control including from minority ethnic groups but it is equally important to
obesity.162,163 If left untreated, depression can have a major ensure their inclusion in clinical research through robust
detrimental impact on both physical and mental wellbeing, designs.
including cognitive function and self-management of Cultural and religious views must be taken into
diabetes.164–166 Moreover, people with type 2 diabetes and consideration when making management decisions
depression are at increased risk of cardiovascular mortality (eg, allowing flexibility during Ramadan). Ensuring safe
and morbidity.167 Timely recognition and therapy, either in fasting can be challenging for several reasons: increased
the form of psychotherapy, group therapy, lifestyle risk of hypoglycaemia during the fasting hours,
intervention, or pharmacotherapy, are crucial to reducing hyperglycaemia after the fast, alterations in physical
the growing burden of depression in people with activity, changes in sleeping patterns, and socioeconomic
type 2 diabetes.168,169 There is evidence that use of GLP-1 and cultural differences.188 To reduce risk of complications
receptor agonist therapy is associated with slowing of during Ramadan, treatment goals for Ramadan should

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be mutually agreed and use of novel glucose-lowering supply (glucose and free fatty acids) and ketone body
therapies considered well in advance during the pre- metabolism; and (4) changes in microbiota (mainly GLP-1
Ramadan counselling.189 receptor agonist). Tirzepatide has also shown significant
reductions in liver fat content compared with insulin
COVID-19 pandemic and the effect on people with degludec in people with type 2 diabetes and a fatty liver
type 2 diabetes index of at least 60 in the SURPASS-3 study.109
The COVID-19 pandemic has adversely affected global Substantial evidence also supports the beneficial effects
health-care systems, causing disruptions in health-care of thiazolidinediones for the alleviation or mitigation of
delivery services and reduced frequency of contact with fatty liver disorders. In an RCT involving people with
health-care providers.190 It has also altered the social biopsy-proven non-alcoholic steatohepatitis (NASH or
environment toward unhealthy lifestyles such as decrease MAFLD), pioglitazone 45 mg daily for 6 months signifi
in physical activity and increase in unhealthy food cantly improved insulin sensitivity, hepatic steatosis,
consumption,191 which have influenced cardiometabolic ballooning necrosis, and inflammation.208 Another RCT
factors in a negative way.192 showed that more than half of patients with NASH and
People with type 2 diabetes, especially with obesity and glucose dysregulation had a significant reduction in fatty
cardiorenal comorbidities, are at high risk of severe liver activity score and histological improvement with
infection, high morbidity, and mortality.193 Several patho 18-month pioglitazone treatment.209 However, only a few
physiological mechanisms underlie this relationship,194 licensed medications are approved for MAFLD.210
including effects on glucose dysregulation, inflammation,
and activation of the renin–angio tensin–aldosterone Challenges and future directions of
system.194,195 Hyperglycaemia also affects immune func type 2 diabetes management
tion; conversely, a dysregulated immunological status is Clinical inertia
linked to diabetic complications, potentially explaining Clinical or therapeutic inertia is defined as health-care
the poor prognosis of patients with diabetes and providers not initiating, intensifying, or deintensifying
COVID-19 (appendix p 12).196,197 therapy when indicated. Despite encouragement to
In terms of the prescription of glucose-lowering consider early addition of novel agents in people with
therapies during the pandemic, a large observational elevated risk of cardiorenal disease, irrespective of
study, found no specific associations between the use of glycaemic control, the uptake of these agents remains
specific glucose-lowering therapies and COVID-19- generally low, especially at the primary or community
related mortality.198 Although use of SGLT2 inhibitors is care level.211 A global survey of 1677 health-care providers
usually discouraged in severely ill people, in the DARE-19 showed that 67% of the respondents were aware of the
trial,199 dapagliflozin therapy was well tolerated in published cardiovascular outcome trial data for novel
hospitalised patients with COVID-19. Taken together, glucose-lowering therapies, and 81·6% agreed that early
there is no clear indication to change glucose-lowering intensification is associated with clinical benefits; how
therapies in patients with COVID-19. ever, 46·1% would reserve these therapies for late stage
only.212 Similarly, risk of overtreatment with conventional
Metabolic dysfunction-associated fatty liver disease older agents, particularly sulfonylureas, which increase
(MAFLD) risk of hypoglycaemia, remains a concern.213
MAFLD is a phenotype of cardiometabolic syndrome and Clinical inertia is a multifactorial problem with issues at
is fundamentally linked to cardiovascular and hepatic the level of the prescribers, patients, and health-care
outcomes.200 The term MAFLD stresses a causal systems, including reduced frequency of clinical consult
relationship between impaired glucose metabolism and ations, higher costs, and medications availability issues.214
the initiation and progression of fatty liver disease.200–202 The solution is also multifactorial, involving multi
Therefore, it is reasonable to explore the potential disciplinary care approaches through patient-focused
therapeutic efficacy of SGLT2 inhibitors and GLP-1 interventions. A 2021 meta-analysis showed that the most
receptor agonists, as they reduce bodyweight in addition effective approaches to mitigating clinical inertia are those
to improving glycaemic control.203 Preliminary evidence involving non-physician providers such as nurses and
from clinical trials shows that these therapies can reduce pharmacists in partnership with health-care providers,
intrahepatic triacylglycerol accumulation and prevent supported by appropriate guidelines and collaborative
progression of hepatic fibrosis.204,205 Because neither work.215
SGLT2 nor GLP-1 receptors are expressed in the liver,
these agents have indirect mechanisms interfering Use of technology in management of type 2 diabetes
with the pathophysiology of MAFLD, including:206,207 Technology offers benefits extending beyond glucose
(1) contribution of weight loss and associated improve management, including remote monitoring and patient
ments in insulin sensitivity; (2) adipokine-mediated and empowerment. There is a growing interest in use of
cytokine-mediated anti-inflammatory, antifibrotic, and telehealth, including virtual consultations,216 which has
antioxidant effects; (3) alterations in hepatic substrate the potential to improve health services and patient

Seminar
satisfaction. Use of wearable technology, like physical metabolomics, and pharmacogenomics, into the precision
activity monitors and calorie counting apps, can provide medicine model of type 2 diabetes.229 Also, large scale
insight into the lifestyle behaviours.217,218 studies are needed to show the full potential and clinical
Use of continuous glucose monitoring systems, benefit of such approaches. The future role of precision
including flash glucose monitoring (FGM) and medicine in diabetes management is also acknowledged
automated insulin delivery devices, is mostly restricted to by the ADA, and the Precision Medicine in Diabetes
type 1 diabetes. However, because of the emerging Initiative was launched by the ADA in 2018, in partnership
evidence, this technology will probably expand to with the EASD.10
type 2 diabetes. A study in people with type 2 diabetes Targeting the key therapeutic pathways and organs,
using insulin showed that use of FGM was associated such as the brain, kidneys, and particularly the gastro
with significant reduction in HbA1c along with improve intestinal system, which has an important role in glucose
ment in treatment satisfaction and perceived frequency regulation, could be possible.230 Artificial intelligence
of hypoglycaemia.219 The REPLACE study220 assessed the might also aid in precise repurposing or reprofiling of
use of FGM as a replacement for self-monitoring of therapies in management of type 2 diabetes, by matching
blood glucose in people with type 2 diabetes and showed patients to their optimal drug combinations with tech
a significant reduction in HbA1c for young participants niques like large-scale prediction models.
(<65 years of age) with improved treatment satisfaction. Several agents that mimic the action of gut hormones
There is an increasing advocacy for use of FGM in people and thus regulate appetite and weight are in
with type 2 diabetes requiring intensive insulin therapy.221 development. In this regard, dual agonists, including
The use of continuous subcutaneous insulin infusion or combinations of GLP-1 receptor agonist and GIP or
insulin pump therapy is not yet advocated in people with triple agonist such as GLP-1 receptor agonist–GIP–
type 2 diabetes and only little evidence is available.222,223 glucagon, and long-acting amylin derivatives are all in
Combining continuous glucose monitoring systems with different development phases with promising early
continuous subcutaneous insulin infusion, also known as results and are likely to have key roles in the near future.
closed-loop systems or an artificial pancreas, has been In healthy volunteers, a GLP-1–GIP–glucagon triple
proposed as a viable long-term solution for people with agonist (SAR441255; Sanofi, Bridgewater, NJ, USA)
type 1 diabetes.224 Again, there are scarce data available for improved glycaemic control with good tolerability.231 The
these interventions in people with type 2 diabetes because results show that integrating glucagon receptor agonism
of different pathophysiological mechanisms and availa might be able to induce greater weight loss and better
bility of alternate non-insulin therapies. glycaemic control. In a 2021 RCT, treatment with
cagrilintide, a once-weekly amylin analogue, led to
Precision medicine and future therapeutic options significant reductions in bodyweight in people with
As a multifactorial heterogeneous disease, the develop overweight and obesity.232 Based on these findings,
ment of type 2 diabetes involves a confluence of various combinations such as GLP-1–GIP (NCT04153929),
susceptible genetic and predisposing environmental GLP-1–amylin derivative (NCT04982575, NCT05394519,
factors. With advances in genome-wide association and NCT04940078), or GLP-1–GIP–glucagon receptor
studies (GWAS), around 400 genetic variants associated agonist (NCT03744182) are under clinical trials for
with type 2 diabetes have been identified.225,226 Many of obesity management and glucose control.
these variants also have strong genetic correlation with Oral and novel insulins (also called smart insulins),
cardiometabolic traits such as obesity, hypertrigly which have shown promising results in the trials, are also
ceridaemia, coronary artery disease, unhealthy sleeping expected to become available in the near future.233 An RCT
behaviours, and depression.227 However, many are low- comparing a weekly insulin preparation (icodec) to glargine
frequency, rare variants and their contribution to overall in people with type 2 diabetes showed similar efficacy and
disease risk and burden is not fully understood. safety, including risk of hypoglycaemia between the two
GWAS could aid in developing precision medicine preparations.234 Similarly, basal insulin Fc is another novel,
models in type 2 diabetes, in which an individual’s own once-weekly insulin in development that combines Fc, a
genetic data could aid in prevention, diagnosis, and fusion protein, with human immunoglobulin G,235 and in
development of targeted therapies. Using GWAS, a large early trials showed lower risk of hypoglycaemia than
UK biobank study has identified 202 independent genetic insulin degludec with similar glycaemic efficacy.236
variants associated with higher waist-to-hip ratio.228 The Contributors
study found that hip-specific polygenic scores were All authors were involved in writing and revision, at all stages of
specifically associated with lower gluteofemoral and waist- manuscript preparation. EA and SL did most of the work in the final
shaping of the draft, including figures and tables. All authors have seen
specific polygenic scores with higher abdominal fat. and approved the final text.
However, to implement precision medicine in
Declaration of interests
type 2 diabetes, not only a better understanding of EA has received fellowship funding from AstraZeneca. SL has been a
genomics is required, but it will be imperative to integrate member on advisory boards or has consulted with Merck
other types of omics, including epigenomics, proteomics, Sharp & Dohme, and NovoNordisk. He has received grant support from

Seminar
AstraZeneca, Merck Sharp & Dohme, and Astellas. He has also served on 17 Defronzo RA. Banting lecture. From the triumvirate to the ominous
the speakers’ bureau of AstraZeneca, Boehringer Ingelheim, octet: a new paradigm for the treatment of type 2 diabetes mellitus.
Eli Lilly & Co, Merck Sharp & Dohme, Chong Kun Dang Pharmaceutical, Diabetes 2009; 58: 773–95.
and Novo Nordisk. RL has received a research grant from Novo Nordisk. 18 Gupta D, Leahy JL. Islet amyloid and type 2 diabetes:
She has also received funds for serving on an advisory board for Sanofi overproduction or inadequate clearance and detoxification?
and consultancy fees from Sanofi, AstraZeneca, Novo Nordisk, J Clin Invest 2014; 124: 3292–94.
and Boehringer Ingelheim. DRW has received honoraria as a speaker for 19 Jonas DE, Crotty K, Yun JDY, et al. Screening for prediabetes and
AstraZeneca, Sanofi-Aventis, and Lilly, and received research funding type 2 diabetes: updated evidence report and systematic review for
support from Novo Nordisk. MJD has acted as consultant, advisory board the US preventive services task force. JAMA 2021; 326: 744–60.
member, and speaker for Boehringer Ingelheim, Lilly, Novo Nordisk, and 20 Peer N, Balakrishna Y, Durao S. Screening for type 2 diabetes
Sanofi; an advisory board member and speaker for AstraZeneca; mellitus. Cochrane Database Syst Rev 2020; 5: CD005266.
an advisory board member for Janssen, Lexicon, Pfizer, and ShouTi 21 Draznin B, Aroda VR, Bakris G, et al. 9. Pharmacologic approaches
Pharma; and as a speaker for Napp Pharmaceuticals, Novartis, and to glycemic treatment: standards of medical care in diabetes—2022.
Diabetes Care 2022; 45 (suppl 1): S17–38.
Takeda Pharmaceuticals International. She has received grants in support
of investigator and investigator-initiated trials from Novo Nordisk, 22 American Diabetes Association. 2. Classification and diagnosis of
diabetes: standards of medical care in diabetes—2021. Diabetes Care
Sanofi-Aventis, Lilly, Boehringer Ingelheim, AstraZeneca, and Janssen.
2021; 44 (suppl 1): S15–33.
Acknowledgments 23 Buzzetti R, Tuomi T, Mauricio D, et al. Management of latent
The authors would like to also acknowledge Mike Bonar (Creative autoimmune diabetes in adults: a consensus statement from an
Director) and Charlie Franklin (Design Assistant) from the Leicester international expert panel. Diabetes 2020; 69: 2037–47.
Diabetes Centre, Leicester, UK, who provided considerable support in 24 Waddankeri SS, Swaraj Waddankeri M,
drafting and amending the figures. This paper was supported by the Gurushantappa Mangshetty B. Clinical and biochemical
National Institute for Health Research (NIHR) Leicester Biomedical characteristics and treatment outcomes of ketosis-prone diabetes:
Research Centre, and the NIHR Leicester Clinical Research Facility. the remission prone diabetes. Int J Endocrinol Metab 2021;
19: e106799.
The views expressed are those of the authors and not necessarily those of
the National Health Service, the NIHR, or the Department of Health. 25 Lebovitz HE, Banerji MA. Ketosis-prone diabetes (flatbush
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(7) Brain (8) Gastrointestinal tract (9) Inflammation

(12) Pancreatic amyIin (IAPP)

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Asymptomatic adults Hyperglycaemia symptoms* in childhood and adolescence

Screening candidates† Type 2 diabetes LADA Type 1 diabetes MODY

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impact in reducing the risk of future complications. By

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Medications Primary mechanism of Advantages Common side-effects or Additional notes

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Table 3: Insulin formulations commonly used in treatment of type 2 diabetes

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Sleep behaviours cognitive decline in people with type 2 diabetes.170,171 Further

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