Received: 4 June 2024 Revised: 9 August 2024 Accepted: 20 August 2024

DOI: 10.1111/dom.15921

SPECIAL ISSUE ARTICLE

Continuous ketone monitoring: Exciting implications for

clinical practice

Yee Wen Kong MBBS 1 | Dale Morrison PhD 1 | Jean C. Lu MBBS 1,2 |
1,2,3 1,2,4,5
Melissa H. Lee PhD | Alicia J. Jenkins MD | David N. O'Neal MD 1,2,3,4

1
Department of Medicine, University of
Melbourne, Melbourne, Victoria, Australia Abstract
2
Department of Diabetes and Endocrinology, Diabetic ketoacidosis (DKA) is a life-threatening complication usually affecting people
St. Vincent's Hospital, Fitzroy, Victoria,
Australia
with type 1 diabetes (T1D) and, less commonly, people with type 2 diabetes. Early
3
Werribee Mercy Hospital, Werribee, Victoria, identification of ketosis is a cornerstone in DKA prevention and management. Cur-
Australia rent methods for ketone measurement by people with diabetes include capillary
4
Australian Centre for Accelerating Diabetes
Innovations, Melbourne, Victoria, Australia
blood or urine testing. These approaches have limitations, including the need to carry
5
Baker Heart and Diabetes Institute, testing strips that have a limited shelf life and a requirement for the user to initiate a
Melbourne, Victoria, Australia test. Recent studies have shown the feasibility of continuous ketone monitoring
Correspondence (CKM) via interstitial fluid with a sensor inserted subcutaneously employing an enzy-
David N. O'Neal, Department of Medicine, matic electrochemical reaction. Ketone readings can be updated every 5 minutes. In
St. Vincent's Hospital Melbourne, University of
Melbourne, Fitzroy, 3065, VIC, Australia. the future, one would expect that commercialized devices will incorporate alarms
Email: [email protected] linked with standardized thresholds and trend arrows. Ideally, to minimize the burden
on users, CKM functionality should be integrated with other devices used to imple-
ment glucose management, including continuous glucose monitors and insulin pumps.
We suggest CKM provision to all at risk of DKA and recommend that the devices
should be worn continuously. Those who may particularly benefit are individuals who
have T1D, are pregnant, on medications such as sodium-glucose linked transporter
(SGLT) inhibitors that increase DKA, people with recurrent DKA, those with T1D
undertaking high intensity exercise, are socially or geographically isolated, or those
on low carbohydrate diets. The provision of ketone profiles will provide important
clinical insights that have previously been unavailable to people living with diabetes
and their healthcare professionals.

KEYWORDS
clinical physiology, continuous glucose monitoring, glycaemic control, type 1 diabetes

1 | I N T RO DU CT I O N and less commonly in people with type 2 diabetes (T2D). It is usually

defined as a metabolic state in which the individual has either a glu-
Diabetic ketoacidosis (DKA) is a major acute life-threatening compli- cose concentration of more than 11.1 mmol/L (> 200 mg/dL) at pre-
cation of diabetes, mostly seen in people with type 1 diabetes (T1D) sentation, or has been previously diagnosed with diabetes; they must

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any
medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Diabetes Obes Metab. 2024;1–12. wileyonlinelibrary.com/journal/dom 1

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2 KONG ET AL.

have a plasma β-hydroxybutyrate concentration of 3.0 mmol/L or billion in 2003 to $5.1 billion in 2014.7 DKA therefore remains of sig-
higher, or urine ketones of more than 2+ on a standard urine ketone nificant clinical relevance, and this review will focus on the potential
test-stick; and a pH less than 7.3 or a serum bicarbonate of less than of continuous ketone monitors (CKMs) to minimize DKA risk. We also
15.0 mmol/L.1 Blood glucose levels may not always be elevated in recognize that ketoacidosis may occur in the absence of diabetes,
DKA, a state referred to as euglycaemic ketoacidosis.2 such as with starvation,8 low carbohydrate or ketogenic diets,9 heavy
DKA results from a relative or absolute deficiency in circulating alcohol intake10 and pregnancy.11 For the purposes of this paper,
insulin associated with elevated glucagon. These, in turn, promote the however, we will restrict our focus to the potential benefits of CKMs
uncontrolled release of free fatty acids that are converted to ketone for people living with diabetes.
bodies, resulting in an anion gap acidosis. Acetoacetate, the primary
ketone body, is then converted enzymatically to β-hydroxybutyrate,
the predominant circulating ketone body, and non-enzymatically to 2 | C U R R E N T A P P R O A C H E S T O T HE
acetone, which is exhaled3 (Figure 1). The reduced peripheral uptake P RE V E N T I O N , RE C O G NI T I O N A N D
of glucose and increased endogenous glucose production results in MANAGEMENT OF DKA
marked hyperglycaemia and dehydration. The metabolic acidosis,
hypovolaemia, electrolyte disturbance and hyperosmolar state stimu- The standard management of established DKA has been extensively
late a counter-regulatory hormone response increasing insulin resis- documented in international guidelines.4,12,13 The principles are vol-
tance and ketogenesis, further exacerbating the metabolic ume replacement, the correction of electrolyte abnormalities, provi-
disturbance, resulting in a downward spiral. If left unaddressed this sion of insulin and addressing precipitating factors, all of which should
culminates in altered consciousness, cardiovascular collapse, coma occur in a hospital environment in which the patient is closely moni-
and death.4 tored.4 Patients with DKA may range from early presenters who are
Contributing factors to the development of DKA include the late mildly unwell and have rapid reversal of their metabolic disturbances
recognition of new-onset T1D, poor adherence to insulin therapy, to late presenters who are severely unwell with marked
severe catabolic stressors such as sepsis and myocardial infarction, disturbances in acid–base balance, volume status and electrolyte
recreational drug use (e.g. amphetamines and cocaine), therapies abnormalities requiring admission to an intensive care unit. Generally,
(e.g. steroids, some antipsychotic agents, sympathomimetic agents, or early presentation with a milder metabolic derangement is associated
sodium-glucose linked transporter inhibitors [SGLTinh]).4 with lower mortality, faster recovery and lower socioeconomic
Although data collected in the United States and Australia prior costs.14
to the coronavirus disease 2019 (COVID-19) pandemic suggest that The first step in the prevention and management of DKA is rec-
DKA-associated mortality is stable or falling, conversely, the incidence ognition of the impending or established condition with a ketone mea-
of DKA is increasing.5,6 This increased incidence has implications surement. The measurement of ketones requires that the person
regarding healthcare costs. For example, in the United States, aggre- recognizes that they are at an increased risk of DKA and to proac-
gate DKA-related charges adjusted for inflation increased from $2.2 tively initiate a test to confirm the presence of elevated ketones.

F I G U R E 1 An overview of
ketone body metabolism
(adapted from3)
 14631326, 0, Downloaded from https://dom-pubs.pericles-prod.literatumonline.com/doi/10.1111/dom.15921 by Readcube (Labtiva Inc.), Wiley Online Library on [04/10/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
KONG ET AL. 3

Symptoms such as nausea, vomiting and thirst occur late, and hyper- 12 months, and testing is painful and involves blood exposure. As with
glycaemia, which is not invariably present, may not always prompt the urine ketone measurements, interfering substances may impact
person to check their ketone levels. Current available options test for specificity.26
the presence of ketones in urine and blood samples.

2.3 | Real-world experience with current ketone

2.1 | Urine testing for ketones testing options

Urine testing for ketones is a method that has been available for a Although there is evidence that continuous glucose monitor (CGM)
long time; it is relatively inexpensive and painless, does not require provision has resulted in a reduction in DKA,27 this is probably
the user to carry a meter and involves minimal technical skill to imple- because insulin has been administered to address elevated glucose
ment. However, many patients prefer to avoid doing urine tests. The levels rather than any specific action to determine the presence or
colour-coded, strip-based test uses a nitroprusside reaction, which absence of ketosis. Indeed, while CGM provision has improved gly-
provides a semiquantitative measure of acetoacetate and with some caemia, DKA has not yet been abolished.27 The real-world experience
15
brands acetone. The test represents an average of ketones excreted highlights many of the limitations of blood ketone testing. An audit of
in the urine since the last void, which may delay recognition of 205 adults (38 on insulin pumps) attending our T1D outpatient service
impending DKA or its resolution. Importantly with treatment, the cir- revealed that 31% did not have in-date ketone testing strips at home
culating pool of β-hydroxybutyrate is oxidized to acetoacetate, which and only a minority were carrying these with them.28 A survey of
may cause urine ketone readings to rise, while blood 2995 people with T1D in the United States found that 32% had no
β-hydroxybutyrate concentrations are falling. The paradoxical increase urine or blood ketone testing materials at home, with only 21% check-
in urinary acetoacetate gives the false impression that the condition is ing ketones when nauseated or vomiting and only 18% possessing a
not improving. In addition, acetoacetate accounts for approximately blood ketone meter.29 A report in Switzerland of 333 respondents
only 20% of circulating ketone bodies, impacting the sensitivity of revealed that 64% did not test for ketones at all.30 These data support
urine testing. False positive results can result from highly pigmented the need for alternative approaches to ketone testing that minimize
urine and interfering substances, including levodopa and drugs that the burden on the person with diabetes and increase their ability to
are present in the blood and/or excreted in the urine as free- recognize current or impending DKA.
15,16
sulphydryl compounds. Finally, it requires the person to recognize
an increased risk of DKA to then initiate testing. This may be difficult
because of oliguria from dehydration and acute renal failure or in the 3 | B R E A T H - B A S E D K ET O N E T E S T I N G
absence of a private environment where a urine sample may be
obtained. Although not widely available clinically, ketones can also be measured
by breath testing. The predominant ketone measured is acetone,
which is volatile and exhaled.31 Advantages include the painless
2.2 | Blood testing for ketones assessment of ketone levels and no necessity for blood exposure or
urine collection. Additionally, changes in acetone are dynamic and
Current best practice in Australia advises that ketone levels should be may provide an early signal of change in a person's metabolic state.
checked on finger-prick capillary blood using a handheld meter and Conversely, breath ketone meters are expensive, the test needs to be
ketone testing strips.17 Blood ketone testing measures β-hydroxybu- user-initiated and the person is required to carry an additional device.
3
tyrate, which constitutes the major circulating ketone body. There is A proof-of-concept study evaluating a breath ketone analyser
no clear consensus in the literature as to thresholds of blood ketone (Ketonix, Varberg, Sweden) in 10 adults and nine children with T1D
levels that should be considered as significantly elevated. In general, concluded that the device could be used to rule out ketosis in adults,
levels below 1.0-1.5 mmol/L are considered to exclude DKA, while but not in children.32 However, in general, there is a lack of an evi-
those above 2.5-3.0 mmol/L suggest the diagnosis or the level at dence base for the accuracy and dynamic range of these devices for
which an urgent medical review should be obtained.18–24 those with T1D because they have generally been developed
Blood testing for ketones has a greater sensitivity and specificity for those pursuing ketogenic diets instead of for medical use.
for DKA than does urine testing.25 A blood sample is usually readily
available, and because it provides a measurement quickly it minimizes
delays in diagnosis. Although ketone meters may vary in their accu- 4 | T H E I D E A L K E T O N E M O NI T O R
racy depending on their manufacturer, these devices generally repre-
sent a mature technology and many combine blood glucose and To address the limitations associated with current approaches to
ketone testing, which means that a person is not required to carry an ketone testing we propose the following: (i) an ideal ketone testing
additional device. Conversely, ketone meters and their blood strips device would measure ketones over a relevant dynamic range
are expensive, ketone strips have a short shelf-life of typically (we suggest 0-10 mmol/L) with automated alerts that would not
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4 KONG ET AL.

require the user to initiate a measurement; (ii) measurements would in vivo studies. We include an illustrative example in Figure 2 using a
need to be precise, particularly at the lower end of the measured streptozotocin-induced rat model in conjunction with a prototype
range, so as not to result in a significant number of false alerts leading ketone sensor (PercuSense, Valencia, CA). Abbott (Alameda, CA) have
to alarm fatigue; (iii) the display should not be noticeable unless published the first-in-human data regarding interstitial fluid measure-
required; and (iv) the technology should be integrated with the user's ments made by their dedicated ketone sensor. The Abbott CKM has
usual glucose-management system so that they are not required to 14-day durability and 2.1% signal change, requiring a single retrospec-
carry an additional device. For example, ketone levels and trend infor- tive calibration with 82.4% of data pairs within 0.225 mM/20% and
mation could be displayed on a smartphone or insulin pump screen. 91.4% of data pairs within 0.3 mM/30%.34 However, given that most
Ideally, discomfort, as well as psychological, financial and physical bur- healthy people living with diabetes have ketone levels of less than
dens imposed upon the user, should be minimized. At the same time, 0.6 mmol/L almost all of the time, calibration by the user (as was
the device needs to be reliable and durable (Table 1). A further level required with early versions of the CGM) will be problematic. There-
of refinement, although not essential, could include instructions fore, from a practical perspective, commercially available devices will
regarding the most appropriate response to the information provided. probably be factory calibrated.
Urine, blood and breath ketone testing do not meet these criteria and There are no published data regarding interfering substances with
therefore other approaches need to be explored. CKMs and further research is required. Given that a similar approach
is employed in interstitial and blood ketone testing, it may be inferred
that CKMs could be subject to similar interferences as blood ketone
5 | I N T ER S T I TI A L F L U I D KE TO N E testing, for example, ascorbate.26 Similarly, there are limited data
MEASUREMENTS regarding the lag between blood and interstitial ketone levels. One
would expect that the ketone body, with a smaller molar mass than
The continuous interstitial measurement of ketones has the potential glucose, would more readily diffuse into the interstitial space with
to address many of the limitations associated with urine, capillary minimum lag in the setting of rapidly changing ketone levels, as sup-
blood and breath testing. Ketones can be quantified in interstitial fluid ported by observations made in our unpublished animal studies
using a similar conceptual approach as that taken with CGMs by (Figure 2). However, further research is required to conform this.
employing an enzymatic reaction. A sensing element is inserted sub- Further development of the device is aimed at developing a sys-
cutaneously that utilizes the enzyme β-hydroxybutyrate dehydroge- tem that will combine continuous glucose and ketone monitoring
nase (βHBDH). These devices detect the concentration of capabilities as a single platform. A CKM would therefore address
β-hydroxybutyrate, a ketone body that is highly associated with the many of the shortcomings associated with blood ketone testing using
onset of DKA. βHBDH belongs to the family of oxidoreductase a handheld meter.
enzymes that requires the availability of a co-factor, nicotinamide ade-
nine dinucleotide (NAD+), to catalyse the oxidation of βHB to acetoa-
cetate and NADH. NADH is, in turn, oxidized at the electrode surface 6 | DI SPL A YI NG CKM I N FO R MATIO N
to generate a current proportional to the concentration of βHB
(Figure 1).33 The CKM display should consider burden, by minimizing the num-
Ketone bodies, like glucose, are hydrophilic. They have a molar ber of devices and screens needed and the risk of information over-
mass of 104 g/mol, which is less than that of glucose (180 g/mol), and load. Ideally, CKM information would be integrated as part of the
therefore should readily enter the interstitial space, as confirmed by same device screen providing the glucose readings. We suggest
that if the ketone levels are below 0.6 mmol/L then a numerical
value need not be provided, and a simple green light could be dis-
TABLE 1 Desirable characteristics of ketone testing technologies.
played indicating that the ketone sensor is functioning, and that the
• Accurate at lower end of range levels are not a matter of concern. Above this level, numerical
• Relevant dynamic range (0-10 mmol/L) values indicating ketone levels should be displayed; these could be
• Does not require user to initiate check colour-coded to reflect rising clinical urgency as they increase.
• Provides trend information and alarms Because ketone-level fluctuations are not as rapid as those of glu-
• Reliable (low failure rate) cose, the display could be updated every 5-15 minutes. Trend

• Durable (similar life to other analyte sensors [7-14 days]) arrows would be useful, indicating the rate and direction of change
in ketone levels. We suggest a horizontal arrow if ketone levels are
• Minimally intrusive unless required
changing at less than 0.25 mmol/L/h, a single up or down arrow if
• Single insertion multianalyte platform/insulin cannula
ketone levels are increasing or decreasing between 0.25 and
• Signal integrated with other technologies (e.g. AID)
0.5 mmol/L/h, and two trend arrows if levels are changing at more
• Factory-calibrated
than 0.5 mmol/L/h. Alarms could be linked to specific ketone
• Cost-effective
thresholds or a high rate of change. We suggest thresholds for
Abbreviation: AID, automated insulin delivery. alarms at 1.0 or 1.5 mmol/L and rate-of-change alarms at more
 14631326, 0, Downloaded from https://dom-pubs.pericles-prod.literatumonline.com/doi/10.1111/dom.15921 by Readcube (Labtiva Inc.), Wiley Online Library on [04/10/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
KONG ET AL. 5

F I G U R E 2 Prototype PercuSense (Valencia, CA) CKM tested in a rat model with streptozotocin-induced DKA followed by insulin rescue. Blue
dots = raw CKM data. Solid blue line = filtered data. Green dots = reference capillary blood ketone measurements (Abbott Freestyle Precision
Neo meter). CKM, continuous ketone monitor; DKA, diabetic ketoacidosis.

F I G U R E 3 Proposed display
of continuous ketone data on the
same screen as continuous
glucose data in an ambulatory
setting. The screen on the left
shows a glucose level of
6.3 mmol/L, which is stable, and a
ketone level of less than
0.6 mmol/L where no values or
trend arrows are displayed. The
screen on the right shows a
glucose level of 11.3 mmol/L that
is trending downward and ketone
levels of 1.3 mmol/L, which are
also trending downward.

than 0.5 mmol/L/h. Finally, the CKM display could also provide a addition, we suggest displaying a bar graph with the percentage of
graph with a trace analogous to that of a CGM35 (Figure 3). time spent with ketones less than 1.0 mmol/L (green), 1.0-1.5 mmol/L
We also propose that the ketone and glucose data are able to be (yellow), 1.6-3.0 mmol/L (orange) and more than 3.0 mmol/L (red).
concurrently uploaded to a web-based platform, processed by soft- CKM use would be reflected in % time that the ketone sensor was
ware and integrated as part of a single report. This report could incor- used (Figure 4). The provision of ketone profiles in free-living people
porate a profile across the 24-hour cycle with the average percentage with diabetes will provide important previously unavailable insights
of time spent in various ketone ranges according to the time of day. In into the natural history of ketone levels in health and illness.
 14631326, 0, Downloaded from https://dom-pubs.pericles-prod.literatumonline.com/doi/10.1111/dom.15921 by Readcube (Labtiva Inc.), Wiley Online Library on [04/10/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
6 KONG ET AL.

F I G U R E 4 Proposed example of 14 days of continuous ketone data that have been uploaded and processed. The upper panel shows a bar
graph displaying time spent in acceptable (< 1.0 mmol/L), elevated (1.0-1.5 mmol/L), high (1.6-3.0 mmol/L) and very high ranges (> 3.0 mmol/L).
The lower panel displays a proposed ambulatory ketone profile report profiling 14 days of data according to the time of day. CKM, continuous
ketone monitor.

7 | RESPONDING TO CKM INFORMATION Indeed, these minor elevations in ketones may provide part of the
protective effect of SGLTinh therapies.41 Therefore, we suggest that
The rationale behind the use of a CKM in an ambulatory setting would responses to CKM data should be initiated early at ketone levels of
be to pre-empt DKA rather than to recognize and manage the fully either 1.0 or 1.5 mmol/L, as levels below these thresholds effectively
established condition. In support of this approach, Song et al.36 exclude DKA.18–24 Conversely, ketone levels of more than
reported that maximum fasted blood ketone levels of 0.8 mmol/L or 3.0 mmol/L are consistent with a diagnosis of DKA.18–24 Levels
higher, as determined by point-of-care testing, predicted future DKA. between 1.5 and 3.0 mmol/L represent an intermediate ‘transition
It should also be noted that in the EASE,37 DEPICT38,39 and TAN- zone’ providing a window of opportunity to avert DKA. It should be
DEM40 studies, levels of up to 0.8-1.0 mmol/L were not uncommon. noted that until these CKM devices are approved for non-adjunctive
 14631326, 0, Downloaded from https://dom-pubs.pericles-prod.literatumonline.com/doi/10.1111/dom.15921 by Readcube (Labtiva Inc.), Wiley Online Library on [04/10/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
KONG ET AL. 7

TABLE 2 Proposed responses to continuous ketone monitor thresholds.

Acceptable Elevated High Very high

Ketone (mmol/ < 1.0 1.0-1.5 1.6-3.0 > 3.0
L)
Response • No action • No action • Check insulin delivery • Check insulin delivery/change set
• (Correct high • Observe trends • If missed insulin dose • If missed insulin dose
glucose) • (Correct high administer now administer now
glucose) • Consider hydration • Correct high glucose with
• Review in 2 h • Correct high glucose (eat) pen (eat)
• Review in 1 h • Seek medical help
• Observe trends • Hydrate now
• Review in 1 h

Note: The colours in the table correspond to the colours in Figures 3 and 4 relating the ketone ranges, urgency, and suggested responses to the proposed
display of ketone data in real time and post-upload for retrospective review.

use, confirmation with a finger-prick ketone measurement would be T A B L E 3 Those with T1D at increased risk of DKA who may
recommended. particularly benefit from a CKM.
In addition, there may be subgroups (e.g. low carbohydrate diet, • Pregnant women
low basal insulin dose, female sex, low body mass index [BMI], preg-
• Individuals with recurrent DKA
nancy, the use of ketogenic medications such as SGLTinh, constitutive
• Taking medications that increase the risk of DKA
β-hydroxybutyrate levels close to 1.0 mmol/L, and use of an insulin
• On very low carbohydrate diets
pump) and situations (e.g. acute illness, fasting for religious reasons or
• High intensity exercise
procedures) where an individual is at greater risk of DKA and alert
• Socially and geographically isolated
thresholds may need to be customized accordingly. However, any
proposed customized response thresholds need to be formally tested • Fasting for procedures

and the optimum settings for alerts have yet to be determined. • Hospitalized/acutely unwell

The use of trend arrow information adds a further dimension, pro- Abbreviations: CKM, continuous ketone monitor; DKA, diabetic
viding an opportunity for early intervention with predictive alarms. For ketoacidosis; T1D, type 1 diabetes.
example, a single arrow indicating an increase in ketone levels of 0.25 to
0.5 mmol/L/h could mean that a response initiated at a threshold of those on insulin pumps and multiple daily injections are listed in Table 2.
1.5 mmol/L would provide a 2-hour window for intervention before a However, an evidence base providing details of the optimum responses
level of 2.0-2.5 mmol/L was reached, thus ensuring a greater element of to minimize the risk of DKA is urgently needed.
safety and particularly relevant to those at an increased risk of DKA.
However, this would entail the cost of a greater number of alarms and
raise the possibility that carbohydrate eaten may not necessarily have 8 | C K M s : WH O M A Y BE N E F I T M O S T ?
been required. As is the case with thresholds, any proposed responses to
trend arrows will need to be formally tested. One could argue that all people with T1D, diabetes secondary to pan-
Should an alert inform a person that ketosis is developing, we rec- creatic insufficiency (Type 3c), and those with cystic fibrosis-related
ommend that a response algorithm based on a modification of the STICH diabetes who have a low C-peptide level may benefit from a ketone
(STop, Inject, Carbohydrate and Hydrate) protocol be followed to pre- sensor. The rationale for those with T2D is less compelling, although a
empt DKA risk.42 The key steps involved in this protocol include case could be made for those treated with ketone-promoting medica-
(i) verifying ketosis and identifying conditions that cause ketosis; tions such as SGLTinh and certain classes of antipsychotic agents. The
(ii) STopping the SGLTinh, Injecting bolus insulin, consuming 30 g of Car- need for a CKM may be unpredictable (e.g. acute illness, and insulin
bohydrate and Hydrating; (iii) monitoring ketone levels every 1-2 hours; pump failure), but the consequences of DKA are catastrophic. There-
and (iv) seeking medical care (such as presenting to the emergency fore, we suggest that a CKM should be worn continuously. However,
department if ketones persist at > 2.5 mmol/L) if ketosis does not resource availability may determine the prioritization of allocation to
resolve or if symptoms of DKA appear, such as abdominal pain, nausea those with T1D who are at an increased risk of DKA (Table 3).
and vomiting. At any elevated CKM level, before taking any further
action, it is recommended that the individual checks their ketones with a
capillary blood reading using a blood ketone meter. Conversely, should a 8.1 | Pregnancy in women with T1D
person experience any symptoms of ketosis despite the CKM indicating
normal levels, then confirmation with a blood ketone measurement is Pregnancy promotes ketosis, with predisposing factors including the
strongly recommended. Examples of potential response algorithms for increased insulin resistance with pregnancy-associated hormones and
 14631326, 0, Downloaded from https://dom-pubs.pericles-prod.literatumonline.com/doi/10.1111/dom.15921 by Readcube (Labtiva Inc.), Wiley Online Library on [04/10/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
8 KONG ET AL.

the increase in maternal metabolic rate.43 Factors that may precipitate 3.8%, respectively, vs. 0.2%).53 The mechanism remains unclear,
DKA in pregnancy include hyperemesis, infection and the physiologi- although contributing factors may relate to a reduction in insulin dose,
cal stress of labour, as well as the use of steroids and β-mimetics.44
a carbohydrate deficit, and increased glucagon release leading to
While maternal mortality is rare with DKA complicating pregnancy, upregulation of lipolysis and ketogenesis. Therefore, to date, SGLTinh
foetal mortality ranges from 10% to 35%.45,46 Emphasis should there- have in general failed to receive approval in the United States
fore be focused on DKA prevention, and a CKM could facilitate early (US Food and Drug Administration) and Australia (Therapeutic Goods
recognition and prompt pre-emptive measures being taken to reverse Administration) for use to control glucose levels in people with T1D.55
the ketotic state. In addition, although the European Medicines Agency initially
approved sotagliflozin and dapagliflozin as an adjunct to insulin ther-
apy in adults with T1D with a BMI of more than 27 kg/m2, in
8.2 | Those with a history of recurrent DKA November 2021 this was withdrawn because of an unacceptable risk
of DKA.55
A range of factors may contribute to episodes of recurrent DKA. SGLTinh therapy may be viable in people with T1D if an interven-
These include adolescence, younger age of T1D onset, poor baseline tion is able to shift the risk–benefit balance in favour of benefit; for
glycaemic control, psychological factors including depression and dia- example, if the risk of DKA could be monitored and addressed. Guide-
betes distress or burnout, financial deprivation and substance abuse.47 lines aimed at minimizing DKA risk with these agents have focused on
Those with more than five DKA admissions have a marked increase in the avoidance of alcohol and low carbohydrate diets, and the avoid-
long-term mortality.48 Interventions in those individuals presenting ance of extreme physical activity, and with cessation of any precipitat-
with recurrent DKA should primarily address underlying educational ing medications while ill or fasting for surgical procedures. In addition,
needs and behavioural factors that have resulted in repeated presen- early recognition of impending DKA enabling the implementation of
tations. However, the use of a CKM may provide a useful adjunct to pre-emptive measures, such as SGLTinh cessation, administration
warn the person of an impending metabolic derangement, providing of an insulin bolus, eating carbohydrate and hydration, may favourably
them with an opportunity to act to avoid further episodes of DKA. alter the risk–benefit balance.

8.3 | Medications that increase the risk of DKA 8.4 | People with T1D on a very low
carbohydrate diet
Therapeutic agents affecting carbohydrate metabolism, such as corti-
costeroids, thiazides, sympathomimetic agents, pentamidine, antipsy- Low (< 130 g/d) and very low (< 20-50 g/d) carbohydrate diets have
chotic agents and SGLTinh, may increase the risk of DKA.49 While the been embarked upon by some individuals with T1D for weight loss,
therapeutic actions provided by each of these agents may potentially and as a way of improving their glucose levels. The benefits and safety
be lifesaving, they come at an increased risk of DKA, with SGLTinh as of minimizing carbohydrate intake remains open to debate.56 Carbo-
the exemplar. hydrate reduction is accompanied by an increase in fat and protein
SGLTinh may play a key role in the prevention and management intake to maintain caloric intake and daily insulin doses are reduced
of the cardiovascular-kidney-metabolic syndrome because this class accordingly. Ketosis is a risk with these diets, and we would suggest
of agent has multiple benefits, including improved glucose levels that a high degree of vigilance is maintained upon embarking on these
(reducing HbA1c and glycaemic variability without increasing severe diets, particularly during the early stages. A CKM would provide
or total hypoglycaemia); reducing heart failure; improving weight con- increased visibility of excursions in ketone levels and the daily carbo-
trol; reducing cardiovascular mortality; and providing renoprotection hydrate intake could be adjusted accordingly to determine the mini-
in people with diabetes, thereby addressing some of the fundamental mum carbohydrate intake that does not incur unacceptable levels of
issues contributing to the syndrome.39,50 Although most available data ketosis.
pertain to people with T2D, these agents also have the potential to
substantially improve glucose control and weight, and reduce the
development of complications in those with T1D.51 8.5 | High intensity exercise
Despite these potential benefits in people with T1D, the use of
SGLTinh as adjunctive therapy to insulin has generally been associ- High intensity exercise elicits a robust counter-regulatory response
ated with a significantly increased risk of DKA, which may occur with- and, particularly in the fasting state, may be associated with an
out hyperglycaemia. Data from studies of selective SGLT2 inhibition increase in ketone levels following exercise that may coincide with a
and a dual SGLT2/1 inhibition as adjuncts to insulin in T1D showed a reduction in glucose.57,58 A reduction in insulin dose may be maladap-
higher incidence of DKA with these agents versus placebo.52–54 For tive. For example, automated insulin delivery (AID) algorithms use glu-
example, a pooled European analysis reported that over 52 weeks of cose levels as their primary input and do not consider ketone levels.
treatment, the incidence of adjudicated DKA was numerically higher The postexercise fall in glucose levels would result in a reduction in
with sotagliflozin 200 or 400 mg/day than with placebo (2.9% and insulin delivery following exercise, at the potential risk of a further
 14631326, 0, Downloaded from https://dom-pubs.pericles-prod.literatumonline.com/doi/10.1111/dom.15921 by Readcube (Labtiva Inc.), Wiley Online Library on [04/10/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
KONG ET AL. 9

increase in ketone levels. A more appropriate response under these be provided with a CKM. These inpatients could include those with a
circumstances would be for the AID system to signal the need for the history of T1D or T2D who are on SGLTinh and are critically unwell, or
59
individual to ingest carbohydrate. Ketone levels are not routinely have been fasting for prolonged periods, or treated with high dose ste-
measured following exercise, particularly if glucose levels are falling. A roids, or have an eating disorder, or are in isolation rooms.65
CKM could provide an appropriate alert. It should be noted that the CKMs used in a hospital would need a
more dynamic range, because of the higher ketone levels in those
who are unwell and the requirement to track those with DKA estab-
8.6 | Geographically and socially isolated people lished. This in contrast to devices used in an ambulatory setting, which
with T1D would primarily be used for the early detection of ketosis, following
which it would be expected that patients would present themselves at
Those individuals with T1D who are socially and geographically iso- hospital once DKA was established. In addition, these devices need to
lated are not necessarily at an increased risk of DKA. However, once display a robust performance under conditions where the patient may
DKA occurs, limited social supports and access to medical care may be severely dehydrated or acidotic and in a hospital environment
delay treatment, which could adversely impact morbidity and mortal- where they may be receiving multiple medications. The capacity for
60
ity. An early alert of impending DKA may allow the person to alter healthcare professionals to readily follow the CKM and its alerts are
their trajectory towards metabolic decompensation. In support of this key to the implementation of this technology.
we note that DKA-related mortality in a large United States-based For those who wish to read further on the subject, please refer to
cohort of people during the COVID-19 pandemic was several orders the review by Jaromy et al.65
of magnitude higher than that observed prepandemic, even in those
without a co-existent COVID-19 infection.61 Although the details
were not documented, delays in presentation may have been a signifi- 11 | C O N CL U S I O N S
cant contributing factor.62
Incorporating a CKM into the routine care of people living with T1D
will represent a significant step in the evolution of technology to bet-
9 | T H E C K M A S A D I A G N O S T I C TO O L ter address the needs of those living with the condition. To date, the
continuous monitoring of physiological analytes in the management of
The initial diagnosis of T1D versus T2D versus latent autoimmune dia- diabetes has understandably been glucose-centric given that the cir-
betes in adults (LADA) is usually based upon the patient's clinical pre- culating levels of this analyte may be subject to rapid changes of sub-
sentation in conjunction with blood ketone measurements, antibody stantial magnitude with major adverse consequences should they
testing and C-peptide levels, with therapies using insulin or oral exceed a narrow physiological range. By reducing the burden of care
agents started based on the assessment outcome. When screening for while simultaneously enhancing situational awareness, particularly if
ketosis, a single point-of-care blood test would be more economical this can be achieved with minimal incremental cost, we suggest that
than inserting a CKM. Therefore, at the time of initial presentation the continuous measurement of ketones represents a logical progres-
and diagnosis, the main use of the CKM, which uniquely tracks ketone sion of current management that will increase safety as part of self-
levels over time, would not be so much to make the diagnosis but to monitoring by people living with T1D.
determine a response to therapy. However, a more substantial role Feasibility has been shown, although there is still much that
for the CKM could be envisaged in tracking the evolution of the rapid remains to be determined. This includes optimization in the way
decline in beta-cell function during the honeymoon period (usually ketone data are displayed, thresholds at which alerts occur, the pro-
63
1-2 years) in those diagnosed with T1D/LADA. By contrast, the cessing of uploaded information, and minimization of cost and physi-
decline in beta-cell function in those with T2D is usually much more cal burden to the user. The latter may be achieved by combining
gradual (5%-10% per year)64 and manifests with hyperglycaemia that ketone sensing with the measurement of other analytes as part of a
is refractory to non-insulin therapy prior to any issues with ketosis. single platform and integration of CKM data into AID systems, which
We therefore suggest that a CKM may be useful in tracking the pro- represent the current standard of care.66
gression of beta-cell failure with autoimmune diabetes. However, we recognize that the CKM represents a very new
technology, and while there are sound theoretical reasons why these
devices may be of significant benefit to people living with diabetes, an
10 | CKMs IN HOSPITAL evidence base is lacking that includes responses to ketone levels and
the thresholds at which these are initiated. We advocate strongly for
In-hospital use of a CKM may be beneficial in some scenarios. Examples further research, which is required to determine the optimum user
of this include patients presenting to the emergency department and responses to CKM information and the impact of CKM use on DKA
those admitted to hospital for tracking responses to therapy, helping hospitalizations. We agree that trials with DKA as an endpoint may
guide transition out of an intensive care unit through to discharge. represent a challenge because of low incidence rates. We could use
Those at an increased risk of DKA during their inpatient stay could also CKM time spent above 1.5 and 3.0 mmol/L as surrogate endpoints, or
 14631326, 0, Downloaded from https://dom-pubs.pericles-prod.literatumonline.com/doi/10.1111/dom.15921 by Readcube (Labtiva Inc.), Wiley Online Library on [04/10/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
10 KONG ET AL.

alternatively study high-risk groups such as those treated with 2. Nasa P, Chaudhary S, Shrivastava PK, Singh A. Euglycemic diabetic
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As with an airbag in an automobile, we anticipate that standards
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