Skip to main content
Journal of Diabetes Science and Technology logoLink to Journal of Diabetes Science and Technology
. 2021 Apr 9;15(4):775–780. doi: 10.1177/19322968211009860

Continuous Ketone Monitoring: A New Paradigm for Physiologic Monitoring

Jennifer Y Zhang 1, Trisha Shang 1, Suneil K Koliwad 2, David C Klonoff 3,
PMCID: PMC8258504  PMID: 33834884

Abstract

In this issue of JDST, Alva and colleagues present for the first time, development of a continuous ketone monitor (CKM) tested both in vitro and in humans. Their sensor measured betahydroxybutyrate (BHB) in interstitial fluid (ISF). The sensor was based on wired enzyme electrochemistry technology using BHB dehydrogenase. The sensor required only a single retrospective calibration without a need for further adjustments over 14 days. The device produced a linear response over the 0-8 mM range with good accuracy. This novel CKM could provide a new dimension of useful automatically collected information for managing diabetes. Passively collected ISF ketone information would be useful for predicting and managing ketoacidosis in patients with type 1 diabetes, as well as other states of abnormal ketonemia. Although additional studies of this CKM will be required to assess performance in intended patient populations and prospective factory calibration will be required to support real time measurements, this novel monitor has the potential to greatly improve outcomes for people with diabetes. In the future, a CKM might be integrated with a continuous glucose monitor in the same sensor platform.

Keywords: acetoacetate, beta-hydroxybutyrate, ketone, monitor, sensor

Introduction

The global market for wearable sensors is growing at a rate of almost 20% per year.1 Indeed, wearable sensors are emerging as a key element in the digital health revolution, which comprises the use of sensors, smartphones, and software with which to collect and store massive streams of important physiological data. Wearable sensors permit these data to be monitored continuously and automatically, and enable information regarding the levels of metabolic analytes indicative of specific physiological processes to be transmitted to healthcare professionals both in real time and asynchronously. In this way, wearable sensors permit precision medicine management of patients by supporting diagnosis, prognosis, treatment, and prevention.2

The Benefits of Wearables

Diabetes is increasingly being managed with the uses of wearable devices. The most widely used of these devices is the continuous glucose monitor (CGM).3 CGM use has exploded in the past few years, going from being rarely used to now achieving record global sales of 1.6 billion dollars in the fourth quarter of 2020.4 This rapid adoption is due to improved technology, a progressively greater understanding of its benefits thanks to experience and research, and a consequent increase in the rates of insurance reimbursement for CGM prescriptions.

Other wearable devices besides CGMs are also being used for patients with various cardiovascular, neurologic, podiatric, and gastrointestinal conditions, some of whom also have diabetes. Soon, data from these other types of wearable devices will be routinely fused with CGM data. Moreover, this could occur through the ongoing advancement of a multi-sensor platform technology, using artificial intelligence in order to generate a highly integrated and thus much more complete metabolic picture for the wearer than can be provided by monitoring glucose concentrations alone. Other types of wearable sensors besides biochemical sensors that are currently available for monitoring people include biophysical (eg, vital signs), bioelectrical (eg, electrocardiogram or electroencephalogram), behavioral (eg, exercise or eating), and environmental (eg, geolocation or ambient pollution) devices. But how about sensors capable of continuously monitoring biochemical substances other than glucose? There is increasing interest in identifying additional analyte or hormonal inputs, especially if they can be measured continuously with a wearable device, besides glucose to improve glycemic control.5

Benefits of Spot Ketone Testing of Blood and Urine

Blood ketones are an important analyte for any patient with type 1 diabetes (T1D) patient and some with type 2 diabetes (T2D) as a means to prevent and reverse diabetic ketoacidosis (DKA). Table 1 presents a list of blood ketone monitors that are currently on the market in the United States (US) and whether they are cleared by the U.S. Food and Drug Administration (FDA). These monitors were identified through searches of the phrase “blood ketone monitor” on both Google and Amazon. Regulatory status was identified through a search of the blood ketone monitor website when available and a search of the FDA 510(k) database.6 If no information about regulatory clearance was found from these 2 sources, then a search of the blood ketone monitor name combined with the word “FDA” was queried on Google. If no information showed up after this last search, then we indicated that the monitor was not cleared by the FDA.

Table 1.

A list of Blood Ketone Monitors that are currently on the market in the United States and whether they are cleared by the FDA.

Blood Ketone Monitor Blood Ketone Monitor Manufacturer Manufacturer Location Regulatory Status—Cleared by the FDA?
Bruno MD67 Bruno MD Boca Raton, FL Yes8
CareSens N Plus Bluetooth Blood Diabetes Monitoring Kit9 i-SENS Torrance, CA Yes8
CareTouch Blood Ketone Monitoring System10 Taidoc Technology Corporation Brooklyn, NY Yes11
FORA 6 Bluetooth Blood Ketone Meter and Glucose Monitor12 ForaCare Moorpark, CA Yes13
KetoBM14 KetoBM Sheridan, WY No15
KetoCoach Blood Ketone Test Meter16 KetoCoach Minneapolis, MN Yes17
Keto-Doc Advanced Ketone Blood Meter Testing Kit18 Ketodoc Los Angeles, CA No13
Keto-Mojo19 Keto Mojo Napa, CA Yes20
KetoSens Blood Ketone Monitoring Kit21 i-SENS Torrance, CA Yes22
KetoTrak Blood Ketone Monitoring System23 ACON Laboratories San Diego, CA No13
Kiss My Keto Ketone Blood Meter Kit24 Kiss My Keto Los Angeles, CA No13
Nova Max Plus25 Nova Diabetes Care Billerica, MA Yes26
Precision Xtra Blood Glucose & Ketone Monitoring27 Abbott Diabetes Care Alameda, CA Yes28

Three ketone bodies are present in pathologic amounts during DKA: acetoacetate (AcAc), beta-hydroxybutyrate (BHB), and acetone. Acetone forms from spontaneous decarboxylation of AcAc, is exhaled as a gas, and causes the breath of a person in DKA to have a fruity odor. Measuring blood BHB (and to a lesser extent urine AcAc testing) is associated with fewer hospitalizations and lower healthcare costs.29 Increased amounts of ketones are formed in the blood of diabetes in the absolute (T1D) or occasionally relative (T2D) absence of insulin combined with increased release of counter-regulatory hormones including glucagon. These hormone imbalances together lead to breakdown of stored triglyceride into fatty acids and conversion of the fatty acids by the liver into ketone bodies, which lower the blood pH and can cause severe organ damage or death.30

Insulin therapy to reverse DKA results in a decline in the BHB concentration long before the AcAc concentration falls. In DKA, the ratio of BHB:AcAc concentration in the blood rises from a normal ratio of 1:1 up to 10:1 or more.31 With improvement in DKA, BHB is converted to AcAc. Determining blood BHB concentrations is thus the best way to follow the development and resolution of DKA. Currently, blood tests for ketones measure BHB and urine tests measure AcAc, which is a lagging indicator of improvement or worsening. If BHB levels in the blood are falling and urinary AcAc levels are rising, then the patient is usually improving and may not require ongoing high doses of insulin as their ketones are already clearing.32 Point-of-care blood ketone tests allow an individual with diabetes at risk for DKA to test themselves for elevated blood BHB concentrations if they have symptoms of impending DKA, if their blood glucose concentrations are rising rapidly, or if they have run out of insulin. Based on the blood ketone and blood glucose concentrations, sick day nomograms can instruct the patient on how to adjust their insulin regimen.32 A commonly used rule for interpreting blood ketone levels is that normal levels of BHB can be defined as <0.6 mM, ketosis can be defined as levels of 0.6-1.5 mM, hyperketonemia can be defined as levels of 1.5-3.0 mM, and ketoacidosis can be defined as levels in excess of 3.0 mM.33 However, strip-based point-of-care ketone monitors can only offer, at best, a snapshot that reflects ketonemia during a specific point in time, but may provide little additional information regarding the dynamic process that may be leading a patient towards DKA.34 Given how onerous it is for patients with diabetes to measure the levels of biochemical analytes using traditional fingerstick monitors frequently enough to give them critical insights, there may be in addition to CGMs a clear benefit to having the ability to continuously and passively measure the levels of ketones in the blood.

A Continuous Ketone Monitor

In this issue of JDST, Alva and colleagues report on the feasibility of continuous ketone monitoring in subcutaneous tissue using a continuous ketone sensor. To our knowledge, this is the first report of a continuous ketone monitor (CKM) tested in humans. The sensor used wired enzyme electrochemistry technology similar to that in a continuous glucose monitor and was based on BHB dehydrogenase chemistry. The CKM required a retrospective calibration process and functioned for 14 days on 12 human volunteers with a linear response over the 0-8 mM range in an in vitro study that preceded the human study. The operational stability of the sensor was good, with a 2.1% signal change over 14 days. The testing range for the human studies was 0-5.1 mM, with a median value of 0.6 mM. None of the 12 volunteers were either using an SGLT2 inhibitor (the significance of this is discussed below) or were in a state of DKA. One had T1D and 11 did not have diabetes. All were on a low carbohydrate diet. 87% of the measured CKM values were below 1.5 mmol, which is a range more consistent with starvation ketosis than DKA. For the comparison to point-of-care capillary blood ketone levels that the CKM was tracking, the reported accuracy was defined by the investigators in this study as either the absolute difference from a blood ketone <1.5 mM or the percentage difference for a blood ketone of ≥1.5 mM. The accuracy results for their in vivo tests for reference ketone concentrations <1.5 mM, were an overall mean absolute difference of 0.129 mM with 83.4% of points within ±0.225 mM and 91.7% within ±0.3 mM. The accuracy results for reference ketone concentrations ≥1.5 mM were 76.0% within 20% and 89.7% within 30%.

The study authors rightly pointed out that demonstration of feasibility of a ketone sensor is a significant step towards a product that can monitor ketones in people for lifestyle and medical management. However they also recognized that more work is necessary to evaluate their sensor in 4 areas.

First, the monitor was not tested in a setting when anybody was expected to have dynamically changing blood glucose or ketone levels. This is an important ongoing need, given that the risk of DKA rises markedly when ketone levels climb in the context of simultaneously rising or already elevated blood glucose concentrations.35 Information from an eventual threshold elevated blood ketone alarm combined with trend arrows from a CKM might turn out to be more clinically useful than a discrete value from a blood ketone test. At this point, we do not know the fidelity of the ketone sensor described by Alva and colleagues in risky settings. Future assessments of this technology will need to include situations that are potentially predictive of performance during impending DKA, such as prolonged fasting or fasting combined with exercise. Such future testing scenarios will also validate the dynamic range over which this CKM technology retains clinical-grade accuracy. Second, the authors utilized point-of-care fingerstick measurements in a paired protocol to provide a reference dataset for accuracy. However, future studies would benefit from including venous plasma measurements as a reference matrix more representative of a gold-standard. This too will be essential before the technology can be relied on for providing actionable data under urgent circumstances such as those associated with emerging DKA. Third, commercialization will ultimately require prospective factory calibration, and CKM devices having undergone such pre-calibration are yet to be validated. Fourth, and perhaps most importantly, this novel CKM technology needs to be tested in volunteers hospitalized with frank DKA, and the data compared not only against parallel venous BHB data, but also against urinary AcAc data both in the context of DKA onset and insulin initiation, but also during the process of DKA resolution and transition to subcutaneous insulin and oral food consumption. However, despite the need for these future studies, which will certainly be exciting to follow, this first human study by Alva and colleagues suggests that an inserted 14-day CKM, similar to a CGM, represents a device that is both technologically feasible and highly promising as an achievable tool for precision diabetes management.

Additional Benefits of Continuous Ketone Monitoring

Additional issues are intriguing to consider prior to implementation of CKM technology in the clinical sphere. As Alva, et al. mention, the sensor mechanism involved in the CKM they tested is based on technology analogous to that currently used for CGMs. Given this description, they state it may be feasible for both a CKM and a CGM to be housed in one physical sensor device. This would be a very useful engineering achievement with respect to patient convenience, desirability, and consequent utilization. Right now, at least in the setting of T1D, patients often wear both an insulin pump and a separate CGM.36 It might be inconvenient, if not tedious, to add a separate CKM to these 2 devices and thus ask an individual with T1D to constantly wear 3 separate devices. Combining the CGM and CKM into a single wearable device would avoid this issue and make incorporation of CKMs into widespread clinical use much more likely. As is the case with most new microdevice technologies, increasing miniaturization is the norm and therefore it is reasonable to consider a future that includes combined CGM/CKM devices.37

Another issue will be to determine which patients with diabetes would most benefit from wearing a CKM all the time. Patients with frequent hospitalization for DKA would potentially benefit from wearing a CKM. A large-scale trial of CKM effectiveness would logically include monitoring a large population of patients with T1D who have experienced multiple bouts of DKA in the 2 years prior to study enrollment in order to see if the rate of such bouts is reduced over a defined period of time by wearing a CKM. If so, then such patients might be uniformly recommended to wear a CKM going forward. Beyond this high-risk group, however, there are other groups of people with diabetes who might also benefit from wearing a CKM. These include people with meal insecurity, including for example homeless individuals with T1D. Given the multiple impediments to achieving optimal glycemic control and hemoglobin A1c goals for homeless people with T1D, management often revolves around a harm reduction model in which the primary goal is to prevent DKA.38 In this setting, making sure such patients wear a CKM may make logical sense. Additional use cases may include patients with T2D who have substantial beta cell failure but poor insulin adherence39 and those with so-called “ketosis-prone” type 2 diabetes.40 The technology could be beneficial in a setting of sick-day management for those with T1D.32 Dedicated trials will be warranted in order to demonstrate clear benefit in these scenarios, particularly given the hurdles that currently exist with respect to reimbursement for devices that benefit patients with diabetes by Medicare, Medicaid, and private insurance. For example, reimbursement for CGM prescriptions is complex and highly inconsistent across specific patient demographics, most notably medically vulnerable segments of the population with high rates of diabetes.41 Given this, one of the most challenging aspects to widespread CKM use may well be access to the technology in the first place.

Sodium glucose co-transporter 2 inhibitor (SGLT2I) therapy has emerged as a mainstay for patients with T2D, in particular because of potential ancillary benefits, beyond glucose lowering, to the heart and kidneys. SGLT2I therapy has been reported to double circulating plasma ketone levels.2 Euglycemic DKA has been reported in some patients with T2D who are using SGLT2Is, often in a setting of decreased insulin production, a missed dose of insulin, acute illness, or heavy alcohol intake.42 People with T2D using such drugs should be prepared to check blood ketone levels in the event of illness, especially because they might not be alerted to impending DKA by elevated glucose concentrations. Having a CKM that can capture ketone trends passively and warn the wearer when necessary could be highly useful for certain people taking SGLT2Is.

Finally, there are potential uses for individuals beyond simply reducing the rates of DKA among those with diabetes. For example, people are increasingly favoring very low-carbohydrate diets intended to produce mild to moderate chronic ketonemia as a means to gain metabolic health benefits.43 Apart from lowering blood glucose, such diets are effective in producing weight loss, and the accompanying mild ketosis has been linked to beneficial neuro-cognitive, myocardial, and renal effects, among others.44 However, adherence to so-called “ketogenic diets” is not easy, and starting and stopping such diets (yo-yo dieting) is common.45 Moreover, overdoing a ketogenic diet, particularly in the setting of diabetes, could hasten the onset of DKA.44 Thus, it would be highly advantageous for someone attempting such a diet to know their progress in achieving the desired state of ketosis, and to what extent specific meals might help or hinder this effort. Wearing a CKM could be a real boon to such individuals. Similarly, diets involving periodic fasting and time-restricted feeding are also becoming more popular,43 and these diets too are thought to exert at least some of their beneficial effects through the induction of ketosis. CKM usage might therefore increase adherence and effectiveness of such dietary strategies as well.

With all of these potential benefits, both within and potentially outside the realm of DKA prevention and management, a future that includes a wearable environment containing CKMs would be quite welcome. There remain several challenges, including some technological, some related to validation of clinical effectiveness, and yet others pertaining to the payer landscape of a given healthcare system. But despite these challenges, CKMs have the potential to enrich the idea of comprehensive self-monitoring. As this idea continues to expand with an ever increasing array of new devices, people with diabetes and those looking to optimize their metabolic health in general will have a highly precise and comprehensive set of unobtrusive tools to reach their goals.

Acknowledgments

We thank Annamarie Sucher-Jones for her expert editorial assistance.

Footnotes

Abbreviations: AcAc, acetoacetate; BHB, beta-hydroxybutyrate; CGM, continuous glucose monitor; CKM, continuous ketone monitor; DKA, diabetic ketoacidosis; FDA, United States Food and Drug Administration; SGLT2I, sodium-glucose cotransporter-2 inhibitor; T1D, type 1 diabetes; T2D, type 2 diabetes; US, United States.

Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: JYZ and TS have nothing of interest to disclose. SKK receives grant support from the UCSF Nutrition and Obesity Research Center (NIH P30 DK098722) and is an advisor to Yes Health, Suggestic, and Signos. DCK is a consultant to EOFlow, Fractyl, Lifecare, Novo Nordisk, Roche, Samsung, and Thirdwayv.

Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.

References


Articles from Journal of Diabetes Science and Technology are provided here courtesy of Diabetes Technology Society

RESOURCES