Automated Bolus Calculators and Connected Insulin Pens: A Smart Combination for Multiple Daily Injection Insulin Therapy

Abstract

Although automated bolus calculators (ABCs) have become a mainstay in insulin pump therapy, they have not achieved similar levels of adoption by persons with diabetes (PWD) using multiple daily injections of insulin (MDI). Only a small number of blood glucose meters (BGMs) have incorporated ABC functionality and the proliferation of unregulated ABC smartphone apps raised safety concerns and eventually led to Food and Drug Administration (FDA)–mandated regulatory oversight for these types of apps. With the recent introduction of smartphone-connected insulin pens, manufacturer-supported companion ABC apps may offer an ideal solution for PWD and health care professionals that reduces errors of mental math when calculating bolus insulin dosing, increases the quality of diabetes data reporting, and improves glycemic outcomes.

Introduction

The landscape of diabetes management has transformed in the past century. Since its discovery in 1921, insulin has undergone significant innovation, including the development of newer formulations that have improved the quality and safety of insulin administration.^1-5 Increasingly, decision support tools are available to providers and persons with diabetes (PWD) to improve care and simplify self-care behaviors. Unfortunately, limited health numeracy is common in PWD and is associated with treatment errors such as misinterpreting glucose meter readings, miscalculating carbohydrate intake, and medication dosing errors. Many PWD experience a perceived lack of self-efficacy often leading to performing fewer self-care behaviors and suboptimal glycemic outcomes. ⁶ In this context, automated bolus calculators (ABCs) that help determine insulin doses may be associated with an improvement in diabetes management.^7-10 In this article, we review the use of ABCs in the outpatient setting for people using multiple daily injections of insulin (MDI) and discuss the potential benefits of integrating ABCs with connected insulin pens.

A Brief History of ABCs

Automated bolus calculators were first introduced as a feature integrated into insulin pumps.^3,8 Components of bolus calculators generally include target glucose level, current glucose level, insulin-to-carbohydrate ratio, number of grams of carbohydrates, insulin sensitivity (correction) factor, active insulin on board (IOB), and duration of insulin action.^11,12 The first insulin pump to incorporate this feature was the Cozmo (Deltec, St. Paul, Minnesota) in 2002; shortly thereafter, the first MiniMed insulin pump (Medtronic Diabetes, Northridge, California) with a “Bolus Wizard” was released.^11-13 The ABC feature proved quite useful for pump users and saw widespread adoption, to the point where all insulin pumps currently sold in the United States include the ability to calculate bolus doses, although recommended doses between pumps can vary slightly due to manufacturer differences in the calculation method and incorporation of the pharmacokinetics of IOB.^13-16

Outside of insulin pump therapy, ABC adoption has been less pervasive in diabetes technology for users of MDI. The FreeStyle InsuLinx (Abbott, Alameda, California) was the first blood glucose meter with ABC to receive CE (Conformitè Europëenne) mark in the European Union in 2011. The first and only glucose meter in the United States to include a stand-alone bolus calculator on the meter itself is the Accu-Chek Aviva Expert (Roche, Basel, Switzerland), which received Food and Drug Administration (FDA) approval in 2014. The Accu-Chek Aviva Connect meter later became the first glucose meter to have its own software bolus calculator in the form of a companion smartphone app.

In 2018, Eiland et al identified a total of six bolus calculator mobile phone apps that had received FDA approval in the United States or CE mark in the European Union. ¹⁷ Three were official companion apps for hardware, two of which were available in the United States. The first was the previously mentioned companion app that paired with the Accu-Chek Aviva Connect meter, and the other companion app paired with the InPen connected insulin pen (Medtronic Diabetes, Northridge, California). The final three smartphone apps were software-only and none of the three is available in the United States.

A Brief History of Connected Insulin Pens

With respect to insulin pen technology, the HumaPen Memoir (Lilly Diabetes, Indianapolis, Indiana) in 2007 became the first insulin pen with a memory function, primarily storing date and time of previous insulin doses. ¹⁸ In 2010, Novo Nordisk similarly released the NovoPen Echo (Novo Nordisk, Bagsværd, Denmark), which kept record of the most recent insulin dose. Since that time, insulin pen caps that display historical dosing information on the pen cap and transmit data have also become available. ¹⁸

With the popularization of smartphones, Bluetooth, and near-field connectivity, ¹⁸ insulin pens were released that are able to pair wirelessly with smartphones. One such connected insulin pen is the InPen, the first FDA-cleared insulin pen with a bolus calculator in the form of a companion smartphone app. The InPen’s smartphone app included several features typically found only in insulin pumps: an insulin ABC that incorporates active IOB, data integration with continuous glucose monitors (CGMs), and a detailed automated insulin dosing record. ¹⁹ Such technology may be an option for PWD who require bolus insulin and who are not on insulin pump therapy. ²⁰ After its initial release, the InPen later received FDA clearance for additional bolus calculation modes: (1) fixed dosing, where a static dose is recommended for each meal, and (2) meal estimation, where the dose is based on estimated meal size (small, medium, and large).

In 2021, a second connected insulin pen option for MDI users, the Bigfoot Unity system (Bigfoot Biomedical, Milpitas, California), received 510(k) FDA clearance. ²¹ This system utilizes a connected insulin pen cap that features a simplified ABC. Similar to the meal estimation option for the InPen, the Bigfoot Unity ABC suggests a mealtime dose based on estimated meal size: small, medium, or large. The corresponding doses for each meal size are preprogrammed by the PWD and health care professional. The ABC can add an additional correction dose to lower blood glucose if needed.

Safety Concerns With Stand-Alone ABC Smartphone Apps

With the introduction of smartphones and downloadable apps, a growing number of stand-alone bolus calculator smartphone apps began to emerge, raising concern for their safety and clinical efficacy.^22,23 Such apps were not integrated with medical devices and were often created by smaller, independent software developers. One study reported that among 46 bolus calculation apps studied, 42 (91%) did not validate numeric entries, meaning that an errant extra digit or misplaced decimal point could lead to extreme dose suggestions. ²⁴ Given the narrow therapeutic window of insulin, such insulin dosing errors could potentially lead to harmful hyperglycemia or hypoglycemia.

The FDA thus hosted a public hearing in November 2014 to discuss the risks and benefits of bolus calculator apps and issued guidance in 2015 (updated in 2019) requiring regulatory oversight be applied to mobile applications that meet the definition of a medical device, specifically apps that “use patient-specific parameters and calculate dosage or create a dosage plan.” ²⁵

Hirsch et al described the importance of large trials to demonstrate safety and efficacy of ABC apps, the need to establish effective regulatory oversight, and the necessity of adequate training for PWD. ²⁶ Specifically, Parkin et al outlined the following best practices for HCP’s when introducing a patient to ABCs: (1) determine PWD competency in utilizing multiple daily injection therapy and self-management skills (eg, carbohydrate counting/calorie counting, sick day management, and hypoglycemia treatment), (2) assess the appropriateness of each PWD’s basal dose and key insulin parameters during exercise and changing health status (eg, physical activity, illness, menstruation), (3) utilize structured self-monitoring of blood glucose with PWD, and (4) monitor for safe use (eg, override frequency of boluses). ²⁷

The American Diabetes Association technology guidelines (in Standards of Medical Care - 2021) recommend that PWD interested in bolus calculators should be encouraged to use FDA-approved systems to ensure safety in dosing recommendations. ²⁸

ABCs Are Ideally Suited for Connected Insulin Pens

Although ABCs have become a key component of insulin pump therapy, users of MDI have had limited options in ABCs. As previously discussed, only a few options for glucose meter–based ABCs exist and no FDA-approved stand-alone smartphone ABC apps are on the market in the United States. Thankfully, connected insulin pens might prove to be a natural complement to ABCs for several reasons.

Manufacturer Infrastructure

With the updated 2019 FDA Guidance defining ABCs in mobile apps as a medical, regulatory approval is integral for the long-term success of ABC smartphone apps. Unfortunately, stand-alone smartphone app developers are often independent publishers or small software startups that lack the financial resources and necessary experience to earn regulatory approval, as listed in Table 1. On the contrary, for connected insulin pen manufacturers, navigating the arduous process of FDA approval is a prerequisite to creating a medical device company and any associated ABC smartphone app could easily be included in this endeavor.

Table 1.

Comparison of Different ABC Categories.

	Insulin pump with ABC	Stand-alone ABC smartphone apps	Connected glucose meter with ABC	Connected insulin pen with ABC
Examples	Tandem T:Slim X2 Insulet Omnipod Dash, Medtronic 770G	RapidCalc Diabetes:M	Accu-Chek Aviva Expert, a Accu-Chek Aviva Connect a	InPen, Bigfoot Unity
Insulin dosing method	CSII	MDI	MDI	MDI
Long-term support	Yes	Limited b	Yes	Yes
Regulatory oversight	Required	Limited Enforcement c	Required	Required
Source of revenue	Hardware Sales	App Store Pricing	Hardware Sales	Hardware Sales
Insulin dosing history	Automated	Manual	Manual	Automated

Abbreviations: ABC, automated bolus calculator; CSII, continuous subcutaneous insulin infusion; FDA, Food and Drug Administration; MDI, multiple daily injection.

^aNo longer available for sale in the United States.

^bSmartphone-only apps are often built by independent developers, leading to apps often being abandoned or removed from the App Store.

^cDespite FDA guidelines categorizing ABC apps as meeting the definition of a medical device, they can still be found unregulated on App Stores.

Furthermore, any successful product or company requires a revenue stream and ABC smartphone apps are no exception. While stand-alone apps can generate limited revenue through App Stores by charging an initial download cost and/or subscription fee, a connected pen manufacturer has a much clearer path to profitability by bundling the smartphone app with a high margin physical good (ie, the insulin pen itself). Furthermore, medical devices like connected insulin pens are covered by many insurance plans, which helps subsidize the cost of their companion ABC apps.

Another significant infrastructure advantage that connected insulin pen manufacturers have over independent software developers is longevity and customer support. Over time, smartphone apps require constant software updates to provide bug fixes, ensure compatibility with new operating systems and smartphone releases, and improve functionality and usability. Medical device companies are ideally suited for this, in part because they are required by regulatory bodies to provide long-term support through medical device reporting.

Integration With Insulin Dosing History

One unique benefit of connected insulin pump or pen-enabled ABCs over stand-alone apps or glucose meter–based ABCs is the ability to easily calculate IOB, a key measure for preventing insulin dose stacking and resultant hypoglycemia.^11,12 An accurate assessment of IOB requires knowledge of the exact timing and dose of bolus insulin injections, both of which are automatically collected by insulin pumps and connected insulin pens without the need for manual data entry.

Furthermore, an ABC-enabled connected insulin pump or pen can provide information about whether PWD are following suggested dosing recommendations. For example, a connected pen’s ABC app can compare the dose of bolus insulin administered and report whether this equals, exceeds, or falls short of the dose it suggested based on the PWD-entered data such as number of carbohydrates consumed and blood glucose. A pattern of underdosing or overdosing can suggest whether a PWD might be manually compensating for calculator parameters that they perceive as too aggressive or too conservative.

Data Synchronization and Reporting

An ABC for a connected insulin pen can automatically import a synchronized glucose value from a nearby CGM or glucose meter for the purpose of a bolus calculation. By eliminating the need to manually enter data, ABC-enabled connected insulin pens significantly reduce the potential for incorrect insulin doses from glucose data entry errors.

Although connected glucose meters also have the ability to wirelessly transfer a blood glucose reading to a smartphone ABC app, users primarily interact with blood glucose meters (BGMs) for monitoring rather than treatment. On the contrary, injecting a bolus dose of insulin with a connected insulin pen is directly related to treatment and requires the PWD to decide how many units to take. Thus, an ABC paired with a connected insulin pen provides more relevant utility to the user than an ABC paired with a glucose meter. Similarly, in the event of a dosing error, identifying the mistake is simplified when the ABC record is integrated seamlessly with the insulin delivery record. Put more simply, in the same way that bolus calculators are better suited for insulin pumps rather than CGMs, they are also better suited for connected insulin pens rather than connected glucose meters.

In addition to automatically compiling multiple streams of diabetes data (such as glucose value and insulin dose record), ABC-enabled connected insulin pens encourage additional recordkeeping that might have otherwise gone unrecorded. For example, a user who consistently utilizes an ABC with their connected insulin pen will automatically create a detailed log of meal timing information and carbohydrate counting. If not using an ABC, a connected insulin pen’s dosing log would not be able to easily differentiate between pure correction insulin dosing and mealtime insulin dosing. Therefore, ABC-enabled connected insulin pens may allow for more robust reports for PWD and health care professionals to analyze.

Future Directions

In combination with ABCs, connected insulin pens may be useful in assessing self-care behaviors or assisting the PWD with accurately and safely dosing their insulin.

Naturally, one opportunity for improving ABCs pertains to the logic behind how ABCs determine the recommended bolus dose. In their current state, connected insulin pen–enabled ABCs incorporate a standard calculation that factors in current blood glucose and expected carbohydrate consumption. With the rising popularity of CGM in MDI users, the suggested correction dose could incorporate glucose trend information rather than a single static blood glucose value. Multiple methods for how to adjust insulin dosing in response to trend information have been proposed. Some authors suggest utilizing trend information to adjust the final dose recommendation by a percentage ²⁹ or absolute value; ³⁰ others suggest adjusting the blood glucose reading^31,32 used in the calculation; and others suggest adjusting dose based on the insulin sensitivity (correction) factor.^33,34

Going beyond trend information, a connected insulin pen–enabled ABC could utilize an advanced algorithm to continually optimize its dosing parameters, with the end goal of creating an MDI version of automated insulin delivery. Breton et al demonstrated success in utilizing an “insulin informed advisory system with automated titration and dosing of insulin” to reduce glycemic variability in patients living with type 1 diabetes and utilizing MDI or insulin pump therapy. ⁸ Their system also incorporated an “exercise advisor” that gave PWD on MDI a recommendation when they were about to exercise: proceed with exercise, consume a small amount of carbohydrates, or consume a larger amount of carbohydrates. With decisions requiring PWD input and data integration across multiple devices, such a system would be a natural fit for deployment in a connected insulin pen and corresponding smartphone app.

As telehealth and remote patient monitoring (RPM) have exploded amidst the COVID-19 pandemic, connected insulin pens with ABCs remove all physical constraints by allowing valuable diabetes data to be transmitted without the need to walk into a health care professional’s office. Any connected pen’s smartphone app can share data wirelessly to the cloud, eliminating the need for any intimidating physical cables. The recently released Bigfoot Unity system already allows for health care professionals to push therapy parameter updates to PWD and these types of remote care interactions can scale the way we deliver health care to larger populations, both in number and geographic reach.

Conclusion

Adding wireless connectivity to insulin pens unlocks the limitless potential of smartphone apps and sharing to the cloud. Although smartphone ABC apps predate connected insulin pens, the two technologies are complementary. Much like insulin pumps, connected insulin pens are increasingly expected to integrate bolus dose calculation software with continuous glucose monitoring, unlocking the potential for future advancements such as automated insulin delivery algorithms for PWD who take multiple daily injections (MDI).