Article
Latent autoimmune diabetes in adults (LADA):
What do primary care professionals need
to know?
Sarah Davies
Latent autoimmune diabetes in adults (LADA) is a subtype of diabetes which often falls
between types 1 and 2, with an estimated prevalence ranging between 2% and 12%
of all people with diabetes. LADA can be difficult to diagnose, particularly in primary
care, where access to tests such as autoantibodies may be limited. This article reviews
the essentials of diagnosing and managing LADA, in accordance with recent guidance
from the American Diabetes Association.
W
hen healthcare professionals consider
the classification of diabetes, we
are all aware of type 1 and type 2.
However, in real-life clinical practice, the divide
may not be so binary, and there are many cases
where the diagnosis is less clear. In such cases, it
may be easier to think about whether a person is
insulin-deficient, insulin-resistant or both, and to
tailor investigations and treatments accordingly,
in order to improve outcomes for the individual
(Prasad and Groop, 2019).
Latent autoimmune diabetes in adults (LADA) is
a subtype of diabetes which often falls in between
types 1 and 2. LADA is essentially a slowly
progressing form of autoimmune diabetes which
has immunological markers of type 1 diabetes but
which does not necessarily require insulin treatment
at diagnosis.
Following the recent publication of a useful
Consensus Statement by the American Diabetes
Association (ADA) on the management of LADA
(Buzzetti et al, 2020), the present review aims to
focus on what healthcare professionals need to know
about this condition in primary care.
Diagnosing LADA
The prevalence of LADA is estimated to be between
2% and 12% of all people with diabetes (Naik
Journal of Diabetes Nursing Volume 25 No 3 2021
Citation: Davies S (2021) Latent
autoimmune diabetes in adults
(LADA): What do primary care
professionals need to know? Journal
of Diabetes Nursing 25: JDN191
Article points
1. Latent autoimmune diabetes
in adults (LADA) is a
slowly progressing form of
and Palmer, 2003). This is higher than one may autoimmune diabetes with
immunological markers of
have expected and a good reminder that we are all
type 1 diabetes but which
likely to have people with LADA under our care. does not necessarily require
The prevalence varies considerably depending insulin treatment at diagnosis.
on ethnicity, with the highest rates in people of 2. LADA is typically associated
with age 30–50 years, absence
Northern European origin.
of metabolic syndrome
It is interesting to note that diagnosis of LADA and the presence of other
is much less common in primary than secondary autoimmune conditions.
care (Buzzetti et al, 2020). This is not surprising 3. Guidance from the American
as people with more complex diabetes, and Diabetes Association
recommends managing LADA
often those on insulin, will be in secondary care. either with insulin or with
However, in practice, and certainly in the author’s a modified type 2 diabetes
experience, it will often be the case that a person treatment strategy, depending
on C-peptide levels.
is initially diagnosed with type 2 diabetes but that
the autoimmunity progresses and, at some stage,
the person becomes insulinopenic and develops Key words
- Clinical guidelines
the autoimmune-mediated, insulin-requiring
- Diagnosis
condition more characteristic of type 1 diabetes. - Latent autoimmune diabetes
The primary concern is that the person is at risk in adults (LADA)
of diabetic ketoacidosis (DKA) when they become
insulinopenic, and so it is highly important that
healthcare professionals can recognise this condition
in primary care (Davis and Davis, 2020).
The current key diagnostic criteria of LADA are
as follows:
Author
l Adult age of onset (>30 years).
Sarah Davies is GP Partner,
l Presence of pancreatic islet cell autoantibodies Woodlands Medical
(e.g. anti-GAD antibodies). Centre, Cardiff.
1
Latent autoimmune diabetes in adults (LADA): What do primary care professionals need to know?
Read more
online
Late-onset type 1
diabetes: More common
than you think? A
GPnotebook Shortcut
A handy guide to the different
classifications of diabetes to
help readers establish the
right diagnosis.
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23: JDN102
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2
l No requirement of insulin for at least 6 months
after diagnosis.
These criteria, however, are certainly not finite
and there is much heterogeneity between the clinical
presentation and course of LADA from person to
person (Pozzilli and Pieralice, 2018).
When might we suspect LADA in
primary care?
Diagnosing LADA can be very challenging,
particularly in the primary care setting, where access
to tests such as autoantibodies is likely to be limited.
In ACTION LADA, a multicentre European study
that evaluated over 6000 people with adult-onset
diabetes within 5 years of their diagnosis, there
were no significantly different clinical phenotypes
between people with LADA and those with type 2
diabetes (Hawa et al, 2013). The only way to be
certain is to check for pancreatic autoantibodies
in the blood. There are, however, some clues and
broad characteristics that may guide primary care
professionals as to when to consider LADA.
1. Age 30–50 years
We tend to consider LADA in people over the age
of 30 years simply because below this age type  1
diabetes is more likely, and in LADA we are
specifically considering diabetes of adult onset.
There is no absolute upper age cut-off for LADA,
but studies show that generally the condition is
more common when diabetes is diagnosed under the
age of 50 years (Buzzetti et al, 2020).
In the UK Prospective Diabetes Study, the
presence of autoantibodies in people diagnosed with
type 2 diabetes was 34% in those aged 25–34 years
compared to 7% in those aged 55–65 years (Turner
et al, 1997). Therefore, it makes sense to consider
LADA particularly in people aged 30–50 years, but
of course the heterogeneity of this condition means
that it can be seen outside of this range as well.
2. Absence of metabolic syndrome
Metabolic syndrome is the combination of central
obesity, hyperlipidaemia, hypertension and insulin
resistance. People with LADA are more likely to
have metabolic syndrome than people with type 1
diabetes, but less likely than those with antibody-
negative type 2 diabetes (Hawa et al, 2013).
In clinical practice, a person diagnosed with
type  2 diabetes who has a normal BMI with no
features of metabolic syndrome is a good clue for the
possible presence of autoantibodies and, potentially,
a LADA diagnosis. Of course, this is not always
true, and some cases may be indistinguishable from
type 2 diabetes with metabolic syndrome (Andersen
et al, 2010).
3. Presence of other autoimmune conditions
Positive pancreatic autoantibodies are strongly
associated with other autoimmune diseases,
particularly thyroid disease (Zampetti et al 2012).
There is also an association with coeliac disease
(Xiang et al, 2019). A personal or family history of
other autoimmune disease is another useful clue
when considering LADA.
Screening for LADA
In view of the relatively high prevalence seen in
studies (up to 12%), it can be argued that there is
value in screening all adults with a new diagnosis
of diabetes for autoantibodies. Knowing that
someone is antibody-positive will alert clinicians to
the possibility of a more rapid progression towards
insulin and affect our monitoring and treatment
choices (Hawa et al, 2013).
In the ADA Consensus Statement, the panel
concluded that general screening for autoantibodies
should be used in newly diagnosed, non-insulin-
requiring diabetes, and that the one-off cost
associated with this test would be justified (Buzzetti
et al, 2020). They recommended testing for
anti-GAD antibodies, which are the most sensitive
marker of LADA and most widely used across the
world (Hawa et al, 2013).
This is a controversial but fascinating
recommendation. NICE (2015) guidance does
not recommend routine use of autoantibodies at
diagnosis and only advises using this test when
type 1 diabetes is suspected but atypical, such as
in people with a BMI of ≥25 kg/m2, age ≥50 years,
slow evolution of hyperglycaemia or a long
prodrome. The ADA, however, advises its use across
all cases of newly diagnosed diabetes where insulin
is not required, which would include everyone
diagnosed with type 2 diabetes. Obviously this is
a very large number of people, with associated cost
and practical considerations. This is an interesting
Journal of Diabetes Nursing Volume 25 No 3 2021
 Latent autoimmune diabetes in adults (LADA): What do primary care professionals need to know?
area for debate and we need more research to assess
the effectiveness of such a strategy. In the UK, the
current strategy is opportunistic identification
of LADA using the clues we have discussed on a
case-by-base basis.
Management of LADA
People with a diagnosis of LADA are likely to be
under secondary care management. There have
been no specific guidelines for the management of
LADA until now. The ADA Consensus Statement
discusses the options in detail and emphasises that
management needs to be individualised (Buzzetti et
al, 2020).
The statement recommends a key role for the
use of C-peptide testing in monitoring LADA
and deciding on treatment choices. C-peptide is
a by-product of the production of insulin by the
pancreas. It can be used in LADA to monitor
the degree of beta-cell function, and treatment
can be matched accordingly using variations of
type  2 diabetes treatment. If the C-peptide level is
<0.3  nmol/L, insulin is required. At levels above
this, treatment can be matched to the individual,
with frequent monitoring of C-peptide levels (every
6 months or if glycaemic control worsens).
In terms of treatment choices, if C-peptide
levels are maintained, the advised algorithm is
similar to the ADA/EASD Consensus Report
on managing type 2 diabetes (Buse et al,
2020), except it avoids the use of sulfonylureas
altogether, as a more rapid deterioration in beta-
cell function due to direct stimulation by this
drug class cannot be excluded. This advice is
summarised in Figure 1 (overleaf ).
Case study
Colin is a 46-year-old man with type 2 diabetes,
diagnosed 8 months ago, as well as hypothyroidism.
He is currently taking levothyroxine 100  µg and
metformin 1 g twice daily. His BMI is 22 kg/m2.
Colin presents feeling generally unwell, with
fatigue for several weeks. He also complains of some
osmotic-type symptoms over the last week, with
increased urination and thirst. Possible slight weight
loss of 1–2 kg. No change in bowel habit. He is
eating and drinking normally, with no vomiting.
Full blood count, urea and electrolytes, and liver
function tests are all normal, but his HbA1c has
Journal of Diabetes Nursing Volume 25 No 3 2021
risen from 61 mmol/mol (7.7%) 3 months ago to
105  mmol/mol (11.8%) now. Colin has continued
taking his medications throughout.
What do you think?
Type 2 diabetes diagnosed at age 46 years, no
metabolic syndrome, history of autoimmune
disease. Sudden deterioration in HbA1c, some
osmotic symptoms. We need to exclude DKA.
What do you do?
Examine and assess:
l Random blood glucose: 21 mmol/L.
l Blood ketones: 0.2 mmol/L (normal <0.6 mmol/L).
l All observations normal.
What do you do now?
Having excluded DKA, the case is discussed with
the diabetes team urgently. Blood tests are arranged
for pancreatic autoantibodies (anti-GAD), that
day if possible, and with careful safety-netting in
the meantime; Colin will require admission if he
develops any symptoms or signs of DKA, such as
vomiting, abdominal pain or inability to maintain
hydration. Home glucose and ketone monitoring is
arranged, and Colin will be seen by the specialist
team in urgent clinic that week.
Results
Anti-GAD antibodies were found to be positive,
and Colin was diagnosed with LADA. He was
commenced on insulin urgently by the specialist
diabetes team.
He is now feeling much better, his blood glucose
is improving and his HbA1c is coming down.
Conclusions
LADA is a slowly evolving form of autoimmune
diabetes. It is important to be aware of this type
of diabetes in primary care so that it can be
identified early in order to avoid the development
of DKA.
It is impossible to diagnose LADA without
checking blood autoantibody levels, but there
are a number of clues to look for. It is more likely
in people between the age of 30 and 50 years,
in those with a diagnosis of type 2 diabetes but
without metabolic syndrome, and in those with
other autoimmune diseases such as thyroid disease.
Diabetes Volume 69, October 2020
Management of Latent Autoimmune Diabetes in Adults: A
Consensus Statement From an International Expert Panel
Raffaella Buzzetti,1 Tiinamaija Tuomi,2,3 Didac Mauricio,4 Massimo Pietropaolo,5 Zhiguang Zhou,6
Paolo Pozzilli,7,8 and Richard David Leslie8
Diabetes 2020;69:2037–2047 | https://doi.org/10.2337/dbi20-0017
A substantial proportion of patients with adult-onset
diabetes share features of both type 1 diabetes (T1D)
and type 2 diabetes (T2D). These individuals, at diagno-
sis, clinically resemble T2D patients by not requiring
insulin treatment, yet they have immunogenetic markers
associated with T1D. Such a slowly evolving form of
autoimmune diabetes, described as latent autoimmune
diabetes of adults (LADA), accounts for 2–12% of all patients
with adult-onset diabetes, though they show consider-
able variability according to their demographics and
mode of ascertainment. While therapeutic strategies
aim for metabolic control and preservation of residual
insulin secretory capacity, endotype heterogeneity within
LADA implies a personalized approach to treatment.
Faced with a paucity of large-scale clinical trials in LADA,
an expert panel reviewed data and delineated one ther-
apeutic approach. Building on the 2020 American Diabetes
Association (ADA)/European Association for the Study of
Diabetes (EASD) consensus for T2D and heterogeneity
within autoimmune diabetes, we propose “deviations”
for LADA from those guidelines. Within LADA, C-peptide
values, proxy for b-cell function, drive therapeutic deci-
sions. Three broad categories of random C-peptide levels
were introduced by the panel: 1) C-peptide levels <0.3
nmol/L: a multiple-insulin regimen recommended as for
T1D; 2) C-peptide values ‡0.3 and £0.7 nmol/L: defined by
the panel as a “gray area” in which a modified ADA/EASD
1Department of Experimental Medicine, Sapienza University of Rome, Rome,
Italy
2Division of Endocrinology, Abdominal Center, Helsinki University Hospital,
Institute for Molecular Medicine Finland FIMM and Research Program for
Clinical and Molecular Metabolism, University of Helsinki, and Folkhälsan
Research Center, Helsinki, Finland
3Lund University Diabetes Center, University of Lund, Malmo, Sweden
4Department of Endocrinology & Nutrition, CIBERDEM, Hospital de la Santa Creu
i Sant Pau & Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau),
Autonomous University of Barcelona, Barcelona, Spain
5Division of Endocrinology, Diabetes and Metabolism, Diabetes Research
Center, Baylor College of Medicine, Houston, TX
6Department of Metabolism and Endocrinology, The Second Xiangya Hospital,
Central South University and Key Laboratory of Diabetes Immunology, Central
The ADA Consensus Statement
on managing LADA is
available here.
2037
algorithm for T2D is recommended; consider insulin in
combination with other therapies to modulate b-cell
failure and limit diabetic complications; 3) C-peptide
values >0.7 nmol/L: suggests a modified ADA/EASD
algorithm as for T2D but allowing for the potentially
progressive nature of LADA by monitoring C-peptide
PERSPECTIVES IN DIABETES
to adjust treatment. The panel concluded by advising
general screening for LADA in newly diagnosed non–
insulin-requiring diabetes and, importantly, that large
randomized clinical trials are warranted.
Both type 1 diabetes (T1D) and type 2 diabetes (T2D) are
complex heterogeneous diseases with a highly variable
clinical course given that not all patients fit into the
current binary classification. A substantial subgroup of
patients, mostly with onset in adulthood, share several
characteristics of both T1D and T2D as described over
30 years ago (1–3). These patients are considered to have
a slowly progressive form of autoimmune diabetes with
serum immune markers of T1D but not requiring insulin at
diagnosis. Such patients identified as having latent auto-
immune diabetes of adults (LADA) account for 2–12% of
all patients with diabetes, with considerable variability
according to ethnicity, type of autoantibody used for
screening (most often autoantibody against glutamic acid
South University, Ministry of Education, National Clinical Research Center for
Metabolic Diseases, Changsha, Hunan, China
7Unit of Endocrinology and Diabetes, Department of Medicine, Campus Bio-
Medico University, Rome, Italy
8Blizard Institute, Barts and The London School of Medicine and Dentistry,
University of London, London, U.K.
Corresponding authors: Paolo Pozzilli, p.pozzilli@unicampus.it, and Richard David
Leslie, r.d.g.leslie@qmul.ac.uk
Received 22 April 2020 and accepted 9 July 2020
© 2020 by the American Diabetes Association. Readers may use this article as
long as the work is properly cited, the use is educational and not for profit, and the
work is not altered. More information is available at https://www.diabetesjournals
.org/content/license.
3
Latent autoimmune diabetes in adults (LADA): What do primary care professionals need to know?

A typical history often includes a person with the merits of screening for LADA in all people
type 2 diabetes in whom there is sudden worsening diagnosed with diabetes, but this is not currently
of glycaemic control. There is a debate around advocated in the UK. n

<0.3 nmol/L C-peptide level ≥0.3 and ≤0.7 nmol/L

Insulin Use metformin and reassess every 6 months

(basal and/or prandial) Avoid use of sulfonylureas
Apply ADA/EASD guidelines (Buse et al, 2020)

Indicators of high-risk or Without high-risk or

established ASCVD, HF or CKD established ASCVD, HF or CKD

ASCVD HF or CKD DPP-4i GLP-1 RA SGLT2i* TZD

predominates predominates

If HbA1c above target

GLP-1 RA with proven SGLT2i with proven
CV benefit CV benefit
OR OR Basal Basal
DPP-4i
SGLT2i with proven CV SGLT2i with proven CV insulin insulin
benefit if eGFR adequate and benefit if eGFR adequate and Basal insulin OR
OR OR
BMI >27 kg/m2. Consider BMI >27 kg/m2. Consider OR GLP-1 RA
GLP-1 RA GLP-1 RA
potential insulin requirement potential insulin requirement OR
SGLT2i
and risk of future deterioration and risk of future deterioration OR OR
and ketoacidosis and ketoacidosis SGLT2i
SGLT2i DPP-4i
OR OR (if SGLT2i not tolerated
Basal insulin in combination or contraindicated)
with GLP-1 RA or SGLT2i if GLP-1 RA with proven
HbA1c >75 mmol/mol (9.0%) CV benefit
If HbA1c above target

Basal–bolus insulin
If HbA1c above target

Basal–bolus insulin Follow ADA/EASD

guideline, but avoid
sulfonylureas

Figure 1. American Diabetes Association consensus advice on glycaemic management in people with latent autoimmune diabetes in adults (Buzzetti et al, 2020).
*Increased risk of diabetic ketoacidosis, especially in people with BMI ≤27 kg/m2.
ADA/EASD=American Diabetes Association/European Association for the Study of Diabetes; ASCVD=atherosclerotic cardiovascular disease;
CKD=chronic kidney disease; CV=cardiovascular; DPP-4i=dipeptidyl peptidase-4 inhibitor; eGFR=estimated glomerular filtration rate; GLP-1
RA=glucagon-like peptide-1 receptor agonist; HF=heart failure; SGLT2i=sodium–glucose cotransporter 2 inhibitor; TZD=thiazolidinedione.

4 Journal of Diabetes Nursing Volume 25 No 3 2021

 Latent autoimmune diabetes in adults (LADA): What do primary care professionals need to know?
Andersen MK, Lundgren V, Turunen JA et al (2010) Latent
autoimmune diabetes in adults differs genetically from classical
type 1 diabetes diagnosed after the age of 35 years. Diabetes
Care 33: 2062–4
Buse JB, Wexler DJ, Tsapas A et al (2020) 2019 Update to:
management of hyperglycemia in type 2 diabetes, 2018. A
Consensus Report by the American Diabetes Association (ADA)
and the European Association for the Study of Diabetes (EASD).
Diabetes Care 43: 487–93
Buzzetti R, Tuomi T, Mauricio D et al (2020) Management of latent
autoimmune diabetes in adults: a consensus statement from an
international expert panel. Diabetes 69: 2037–47
Davis TME, Davis W (2020) Incidence and associates of diabetic
ketoacidosis in a community-based cohort: the Fremantle
Diabetes Study Phase II. BMJ Open Diabetes Res Care 8:
e000983
Hawa MI, Kolb H, Schloot N et al; Action LADA consortium (2013)
Adult-onset autoimmune diabetes in Europe is prevalent with
a broad clinical phenotype: Action LADA 7. Diabetes Care 36:
908–13
Naik RG, Palmer JP (2003) Latent autoimmune diabetes in adults
(LADA). Rev Endocr Metab Disord 4: 233–41
Journal of Diabetes Nursing Volume 25 No 3 2021
NICE (2015) Type 1 diabetes in adults: diagnosis and management “It is important to be
[NG17]. Updated December 2020. NICE, London. Available at:
www.nice.org.uk/guidance/ng17 (accessed 06.04.21) aware of this type of
Pozzilli P, Pieralice S (2018) Latent autoimmune diabetes in adults:
current status and new horizons. Endocrinol Metab (Seoul) 33: diabetes in primary
147–59
Prasad RB, Groop L (2019) Precision medicine in type 2 diabetes. care so that it can
J Intern Med 285: 40–8
Turner R, Stratton I, Horton V et al (1997) UKPDS 25: be identified early
autoantibodies to islet-cell cytoplasm and glutamic acid
decarboxylase for prediction of insulin requirement in type 2 in order to avoid the
diabetes. UK Prospective Diabetes Study Group. Lancet 350:
1288–93 development of diabetic
Xiang Y, Huang G, Zhu Y et al; China National Diabetes and
Metabolic Disorders Study Group (2019) Identification of ketoacidosis.”
autoimmune type 1 diabetes and multiple organ-specific
autoantibodies in adult-onset non-insulin-requiring diabetes
in China: a population-based multicentre nationwide survey.
Diabetes Obes Metab 21: 893–902
Zampetti S, Capizzi M, Spoletini M et al; NIRAD Study Group
(2012) GADA titer-related risk for organ-specific autoimmunity
in LADA subjects subdivided according to gender (NIRAD
study 6). J Clin Endocrinol Metab 97: 3759–65
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