Approaches to rapid acting insulin intensification in patients with type 2 diabetes mellitus not achieving glycemic targets

Abstract

Type 2 diabetes mellitus (T2DM) is a growing problem in the USA, affecting 30.3 million Americans, or 9.4% of the US population. Given that T2DM is a progressive disease, intensification of rapid acting insulin (RAI) to address hyperglycaemia is often required. The American Diabetes Association and the European Association for the Study of Diabetes recommend individualizing the treatment approach to glucose control, considering factors such as age, health behaviours, comorbidities and life expectancy. There are several validated treatment algorithms in the literature, which can be helpful for providing guidance on initiation of RAI while simultaneously considering patient preferences and clinical needs during treatment intensification. This paper provides expert recommendations on prandial insulin regimens and how to use treatment algorithms to promote better glucose control through best practice guidelines. To help patients reach HbA1c targets through treatment intensification, the FullSTEP, SimpleSTEP, ExtraSTEP and AUTONOMY algorithms are discussed in this paper.

KEY MESSAGES

• Clinical inertia should be prevented with timely intensification of therapy when HbA1c levels are greater than 7% (or rising above a patient’s individual target) according to national guidelines.

• Increased personalization in the intensification of T2D treatment is necessary to improve HbA1c targets while addressing risk of hypoglycaemia, concern about weight gain, and overall health goals.

• Healthcare providers are encouraged to address glycaemic control with a variety of strategies, including prandial insulin, while developing evidence-based treatment plans on the basis of algorithms discussed in the literature.

Keywords:

• Algorithms
• bolus insulin; meal time insulin
• personalized care
• rapid acting insulin
• treatment intensification
• type 2 diabetes mellitus

Introduction

Type 2 diabetes mellitus (T2DM) is a growing problem in the USA, affecting 29 million Americans, or 9.3% of the US population [1]. National guidelines recommend target glycated haemoglobin (HbA1c) levels at <7.0% (without hypoglycaemia), with individualization based on patient circumstances [2], achieved through lifestyle modification and anti-hyperglycaemic medications, provided that this can be done safely. Oral diabetes medications are considered first-line therapy in treatment of T2DM; however, progressive decline of β-cell function is common [3] leading to hyperglycaemia and loss of glycaemic control, often necessitating intensification of therapy with multiple agents, including exogenous insulin treatment.

With the many challenges in addressing poorly controlled diabetes and intensifying treatment, healthcare providers play a crucial role in guiding personalized care in T2DM. Approximately half of patients with T2DM do not achieve blood glucose targets, which increases the risk for complications of diabetes, decreases quality of life in patients [4], and is costly to our healthcare system. As complexity of diabetes medication management can be overwhelming to patients and is further compounded by the need for lifestyle modification with adherence to nutrition and exercise recommendations, medication non-adherence often contributes to suboptimal glucose levels.

Clinical inertia, the delay in intensification of treatment, is a common problem in diabetes care and may occur because of fears of weight gain and hypoglycaemia among patients and leads to failure to act among healthcare providers [5]. Alarmingly, the median time from starting basal insulin to intensification of treatment is 3.7 years among patients with T2DM who are not meeting HbA1c targets [5]. Additionally, feelings of failure related to poorly controlled diabetes can further alienate patients and lead to poor investment in care. Insulin intensification algorithms are useful to both the clinician and patient to encourage the use of goal setting and to proactively address hyperglycaemia. The variety of published insulin algorithms enables individualization of treatment regimens, while also considering patient’s needs and preferences.

The American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) identify basal insulin, including first-generation insulins such as insulin glargine, as a necessary component of treatment in progressive β-cell failure. It is often initiated because of inadequate glucose control despite multiple noninsulin therapies [2,6]. Basal insulin may be adequate to address hyperglycaemia initially, but ultimately, basal insulin is not sufficient, and intensification of treatment must be addressed as glycaemic control deteriorates [7]. This is particularly relevant for management of postprandial glucose increases, which are not addressed with use of basal insulin [8]. As demonstrated in a treat-to-target trial with goal fasting plasma glucose <100 mg/dL, the addition of basal insulin to those patients who were suboptimally controlled on oral agents alone resulted in HbA1c <7% in only 60% of participants and highlights the need for additional prandial insulin management [9].

Treatment algorithms now recommend that glucagon-like peptide receptor agonists (GLP-1 RAs) may be used in conjunction with basal insulin when HbA1c goals are not met [2]. GLP-1 RAs improve both fasting and post-prandial glucose regulation function by enhancing glucose-dependent insulin secretion, reducing inappropriate glucagon secretion, increasing satiety and delaying gastric emptying [10]. Dosing regimens are administered by injection and range from twice daily to once weekly administration. Recent studies of GLP-1 RAs suggest that concomitant usage with basal insulin can lead to improvements in postprandial blood glucose concentrations with the added benefit of fewer hypoglycaemic episodes and mild weight loss [11].

When treatment intensification is warranted, the ADA and EASD recommend the use of either GLP-1RAs or prandial insulin based on clinical needs and patient preferences [2]. Rapid-acting insulin (RAI), also referred to as prandial, bolus or mealtime insulin, can be administered at mealtimes as an add-on to basal insulin, and allows for flexibility in meal timing compared with use of pre mixture insulin preparation. Very few studies have compared GLP-RAs and RAI intensification treatment options head-to-head. With two studies currently available in the literature [12,13], we know that basal plus RAI and basal plus GLP-1RAs both improve glycaemic control in patients with T2DM. A recent study comparing a fixed ratio combination of basal insulin and GLP-1RA versus basal-bolus showed that basal insulin and GLP-1RA was statistically superior with respect to lower hypoglycaemia rate and change in body weight [14]. Patient characteristics should be considered in the clinical decision-making process, given that patients desiring weight loss or those with modest hyperglycaemia and shorter duration of diabetes may be well suited for addition of GLP-RAs. However, a recent study showed that patients with a higher baseline HbA1c respond to dulaglutide, a GLP-1RA, irrespective of gender, duration of diabetes or baseline HbA1c [15]. Moreover, patients with adverse reactions to GLP-RAs, long duration of disease, and who are further from HbA1c targets may respond better to RAI [16]. A recent systematic review of the available add-on treatments to basal insulin supported the benefit of add-on treatments but suggested that other factors need to be considered on a patient-by-patient basis to optimize treatment outcomes [17].

RAI requires diligent self-monitoring of one’s glucose levels to achieve targets while minimizing the risk for hypoglycaemia. According to a long-term study, patients with T2DM on RAI were more likely to achieve an HBA1c <6.5% compared with patients treated with basal alone or biphasic insulin mixtures [18]. A number of algorithms that guide treatment intensification and titration of RAI offer evidence-based approaches to empower patients to perform self-titration to ultimately better control hyperglycaemia. This paper provides expert recommendations on insulin regimens, including basal plus and full basal-bolus. Further, discussion on how to use treatment algorithms to promote better glucose control among patients who are transitioning to prandial insulin will follow.

Intensification of basal insulin with rapid-acting insulin

The basal-plus strategy includes one injection of RAI at the meal with the highest postprandial spike in addition to the basal insulin. This approach may be suitable for patients who are hesitant to move to multiple daily injections. A second strategy, basal-bolus, may be more physiologically relevant as RAI is added at each meal to address postprandial increases.

The basal-plus strategy addresses the meal with the greatest postprandial glucose excursion, which contributes to suboptimal glucose control. Using RAI to address glucose levels at the largest meal may improve overall glucose control and reduce the need to cover additional meals. Another advantage to this approach is that there is less weight gain and fewer hypoglycaemic episodes [19]. The FullSTEP study, a Phase 4, randomized 32-week trial sought to compare a stepwise addition of a RAI basal-plus strategy to a full basal-bolus approach [20]. Patients in the stepwise group received one RAI bolus dose before the largest meal of the day. Additional doses of RAI were added to sequential meals at weeks 11 and 22 if HbA1c levels were not at target. Patients in the full basal-bolus arm received RAI before every meal. At the end of the study, HbA1c levels decreased in both groups, but the difference between these groups was non-significant. The benefits of basal plus were reflected in patient satisfaction, as it was higher in the stepwise group. Additionally, patients in the stepwise group had fewer hypoglycaemic events compared with the basal-bolus group [20].

The stepwise basal-plus approach was further analyzed using the SimpleSTEP and ExtraSTEP algorithms in a randomized, controlled trial [21]. Patients enrolled in the SimpleSTEP arm were started on insulin aspart with the largest meal of the day, while those in the ExtraSTEP group were started on insulin aspart at the meal with the highest postprandial excursion. All 269 patients enrolled had HbA1c levels greater than 7%, despite a 12-week run-in period of optimization of basal insulin titration. Additional doses of mealtime insulin were added at 12 and 24 weeks if HbA1c remained >7%. After 48 weeks, both the groups demonstrated a decrease in HbA1c by 1.2%; 75% of these patients were taking two or more injections of mealtime insulin. The rate of hypoglycaemic episodes was similar in both the groups but did increase as additional doses of RAI were added to the treatment regimen. Given that outcomes were similar between both the groups, the SimpleSTEP algorithm may be preferred because it requires monitoring only of pre-meal glucose levels compared with the ExtraSTEP regimen, which requires both pre- and post-prandial glucose measurements.

The basal-bolus strategy implements RAI with every meal in an attempt to mimic endogenous insulin secretion in response to oral intake. Stepwise intensification of RAI up to a full basal-bolus strategy as needed was applied in the AUTONOMY trial [22], which consisted of two independent studies (study A: N = 528; study B: N = 578) using a single protocol to validate reproducibility and assess safety of two patient-based self-titration algorithms. Randomization occurred 1:1 at baseline, and patients began RAI with either daily (Q1D) or every 3 days (Q3D) titration using a patient-directed algorithm. Prandial insulin was administered before the first meal of the day, with additional doses at subsequent meals as needed on the basis of pre-meal glucose readings from the previous day. At the end of the trial, both groups had statistically significant reductions in HbA1c levels that were comparable, and the incidence of hypoglycaemia was similar between the groups. The stepwise addition of bolus insulin resulted in only 39% of participants requiring three mealtime injections daily; 61% of patients required two mealtime injections or fewer, which allowed for a far simpler routine versus a full basal-bolus regimen [22].

Those patients who fail to reach HbA1c targets using a sequential regimen may require full basal-bolus treatment, which includes RAI administration before each meal along with basal insulin daily. Nocturnal hypoglycaemia may be a potential complication for these patients, as indicated in recent studies [23]. Further, weight gain is often greater in patients receiving bolus insulin at each meal. Despite these complications, patients who require a full basal-bolus treatment are able to meet HbA1c targets with mealtime injections of RAI [24].

If patients are uneasy about adding three RAI injections at once, an approach to mitigate against hypoglycaemia and weight gain is to offer a stepwise addition of bolus insulin where patients gradually increase injections (1–2–3) over time. Stepwise intensification of premixed insulin has also been tested and is non-inferior to full basal-bolus treatment.

Comparison of treatment algorithms

Use of algorithms

A brief overview of how each algorithm was used in a research setting is described in Table 1. Two of the algorithms initiated RAI with the largest meal of the day (FullSTEP, SimpleSTEP), while ExtraSTEP targeted the meal with the greatest postprandial glucose excursion. The AUTONOMY trial began RAI with the first meal of the day.

Table 1. Use of patient self-titration algorithms.

Algorithm	Insulin type	Timing of RAI administration	Titration schedule	Possible adverse events
Autonomy	Insulin lispro	Administered before the subject’s first meal of the day (pre-breakfast) If no breakfast, then administered before lunch (pre-lunch) Lispro dose started at 10% of the total daily basal dose	If necessary, added sequential bolus lispro injections at subsequent meals (pre-lunch followed by pre-dinner) for a maximum of three mealtime injections per day The Q1D algorithm, on the basis of pre-meal glucose readings from the previous day; Q3D algorithm was self-titrated every 3 days on the basis of the median blood glucose readings from the 3 days before	Hypoglycemia Incidence of serious adverse events was comparable between Q1D and Q3D (range: 4–8%)
SimpleSTEP	Insulin aspart	Starting dose of aspart was 4 units per largest self-reported meal If HbA1c ≥7.0 after 12 weeks, 2nd dose of prandial insulin aspart was added At week 24, if HbA1c ≥7.0, 3rd dose of prandial insulin aspart was added	Titration on the basis of pre-meal and bedtime plasma glucose concentrations from 4 daily plasma glucose measurements	Increased body weight (2 kg ExtraSTEP vs. 2.7 kg in SimpleSTEP) Hypoglycemia risk similar between regimens
ExtraSTEP	Insulin aspart	Starting dose of aspart was 4 units per meal with largest plasma glucose increment Same intensification schedule as SimpleSTEP	Titration on the basis of post-meal plasma glucose concentrations from 6 daily plasma glucose measurements	SAEs were similar between groups (n = 4, ExtraSTEP and n = 9 in SimpleSTEP
FullSTEP	Insulin aspart	Basal-bolus group: 2 U of aspart taken before breakfast, lunch, dinner Stepwise group: 4 U insulin aspart taken before the largest meal each day	Stepwise group: If HbA1c ≥7.0 after weeks 11 and/or 22, additional bolus is taken at next largest meal SMPG measurements guided intensification schedule, including pre-meal and bedtime recordings	Less hypoglycaemic episodes in stepwise group vs basal-bolus (RR 0.58; p < .0001)

HbA1c: haemoglobin A1c; RR: relative risk; Q1D: every day; Q3D: every 3 days; RAI: rapid acting insulin; SAE: serious adverse event; SMPG: self-monitored plasma glucose.

Titration of RAI dose was based on pre-meal glucose levels (SimpleSTEP, AUTONOMY and FullSTEP) or post-meal glucose levels (ExtraSTEP). The FullSTEP program also accounted for bedtime glucose levels. The AUTONOMY trial added sequential insulin doses on a Q1D versus Q3D regimen compared with the other algorithms, which adjusted RAI administration after 11–12 weeks if HbA1c levels were not <7.0. At week 22 in FullSTEP and week 24 in SimpleSTEP and ExtraSTEP, a third dose of RAI was added at mealtime for non-responders.

Outcomes across algorithms

As depicted in Table 2, the methodology and outcomes of studies are compared with the risk of adverse events and changes in HbA1c levels. In FullSTEP, the stepwise approach was non-inferior in reducing HbA1c compared with the full basal-bolus treatment. Fewer hypoglycaemic events were reported with patients in the stepwise group who also reported improved satisfaction. The use of stepwise titration on the basis of pre- or post-meal glucose readings (SimpleSTEP versus ExtraSTEP) was equally effective at reducing HbA1c levels in both groups; although, fasting plasma glucose decreased to a larger extent in patients assigned to ExtraSTEP. In AUTONOMY, 61% of patients were able to meet HbA1c targeted goals with two or fewer RAI injections, simplifying the treatment process for patients [22].

Table 2. Comparison of treatment algorithms for RAI intensification.

Purpose	Methodology	Outcomes
Autonomy – Multicenter, randomized, open label, parallel trial enrolled in 14-countries/1-territory; Edelman et al. [22], Diabetes care
Compared two self-titration algorithms for initiating and intensifying prandial insulin lispro in patients with T2DM inadequately controlled on basal insulin	The trial was designed in two studies (study A: N = 528, study B: N = 578) with a single protocol Patients were randomized 1:1 at baseline to begin insulin lispro (Humalog; Eli Lilly and Company) therapy with either the Q1D or Q3D self-titration algorithm	Target HbA1c ≤7.0, study A = 42.5%; study B = 42.4% Patients ≥65 years of age reaching target in study A between Q3D 58% and Q1D 58.5%; patients in study B more likely to reach target in Q1D (Q1D 67.9% vs Q3D 46.2%). The incidence of SAEs in study A were similar between Q1D (n = 18; 6.7%) and Q3D (n = 12; 4.6%) The incidence of SAEs in study B were similar between Q1D (n = 21; 7.3%) and Q3D (n = 25; 8.6%)
SimpleSTEP vs. ExtraSTEP – Randomized, controlled, parallel-group, open-label, 48-week trial, enrolled in 67 centers across 12 countries; Meneghini et al. [21], AACE
Compared two treatment strategies for stepwise addition of rapid-acting prandial insulin in patients with T2DM inadequately controlled by basal insulin plus OADs SimpleSTEP – sequential addition of insulin aspart to meal(s) perceived by the patient as being the largest of the day; titrations based on the pre-meal plasma glucose concentration ExtraSTEP – sequential addition of insulin aspart to meal(s) perceived by the patient as being the largest of the day; titrations based on the postmeal plasma glucose concentration	296 patients were randomly assigned to treatment with insulin aspart in the SimpleSTEP (n = 150) and ExtraSTEP (n = 146) groups After 12 weeks of insulin detemir optimization, participants with an HbA1c level of 7% or greater were randomly assigned 1:1 to either the SimpleSTEP or the ExtraSTEP strategy	Final HbA1c = 7.5 for SimpleSTEP and 7.7 for ExtraSTEP Mean FPG levels decreased from baseline to study end, SimpleSTEP (–11 ± 68 mg/dL) and ExtraSTEP (–16 ± 58 mg/dL) Changes in prandial glucose levels, weight loss, and BMI were similar between groups with no significant differences No significant differences in SAEs
FullSTEP – Phase 4, 32-week, randomized, open-label, two-arm, parallel-group, multinational, treat-to-target, non-inferiority trial done at 150 sites across seven countries; Rodbard et al. [20], Lancet Diabetes Endocrinology
Compared stepwise addition of bolus insulin (up to three prandial insulin boluses) with a full basal-bolus regimen in patients with type 2 diabetes inadequately controlled by basal insulin plus OADs	Patients were randomly assigned 1:1 to one of two groups: stepwise group (N = 173) or basal-bolus group (N = 148) In the basal-bolus group, patients received 2 U insulin aspart every day before breakfast, lunch, and dinner from study initiation (week 0) Patients in the stepwise group received 4 U insulin aspart before the largest meal each day starting at week 0, and if HbA1c remained ≥7% at weeks 11 and 22, additional bolus doses were added before the next largest meals	At 32 weeks, HbA1c change was −0.98% (95% CI: 1.09 to −0.87) for the stepwise treatment group and −1.12% (−1.23 to −1.00) for the basal-bolus treatment group Mean FPG was similar between groups at the end of the trial (basal-bolus 7.01 mmol/L and stepwise 7.12 mmol/L) Patients in the stepwise group had fewer overall hypoglycaemic episodes than did those in the basal-bolus treatment group (RR 0.58 (95% CI: 0.45–0.75, p < .0001)) Patient-reported outcomes indicate greater satisfaction among stepwise group vs basal-bolus group No significant differences in SAEs

CI: confidence interval; FPG: fasting plasma glucose; HbA1c: hemoglobin A1c; OAD: orally administered antidiabetic drugs; RAI: rapid acting insulin; Q1D: every day; Q3D: every 3 days; SAE: serious adverse event; SMPG: self-monitored plasma glucose.

Patient-reported outcomes

Given that T2DM involves significant self-management, understanding how patients perceive the treatment regimen and the intricacies of implementing insulin intensification therapy is paramount when striving for good clinical outcomes. When clinicians ask patients to provide feedback on the usability of treatments and satisfaction levels, optimal treatment plans can be developed that are sustainable in the long-term. Patient-reported outcomes (PROs) are measurements that come directly from patients to examine quality of life, satisfaction, mental/physical health status, pain levels and symptoms [25].

Of the algorithms presented, the FullSTEP trial measured PROs to assess the degree to which patients were content with their treatment approach and evaluated the burden of insulin intensification. Findings from the DiabMedSat questionnaire indicate that patients in the stepwise group were more content and reported less burden compared with the full basal-bolus group [20]. Further, the rate of hypoglycaemia was significantly lower in the stepwise group. This favourable result may suggest that patients felt more comfortable easing into rapid insulin injections via a stepwise approach.

The use of T2DM-specific instruments, as used in FullSTEP, provides a more in-depth look at patient experiences using validated instruments tested among patients with diabetes. This also provides a way to compare PROs across studies and may offer insight to the clinician when designing a treatment plan for patients. Future studies should consider incorporating PRO measures into the trial design to better gauge how patients perceive the treatment regimen.

Best practice recommendations for treatment intensification

Patient-centred approaches to treatment

Optimal diabetes care should be patient-centred and individualized, and self-management is essential if people with diabetes are to achieve HbA1c goals and reduce their risk for acute and long-term complications. The standards of care as outlined by leading organizations, such as the ADA, EASD and the American Association of Clinical Endocrinologists, provide guidance on treatment goals to improve health outcomes [2,26,27]. While clinicians often adjust insulin levels for patients with T2DM, there is rationale and evidence for patients to adjust their own insulin (self-titrate) and self-monitor blood glucose levels to optimize treatment. On the basis of the data presented in clinical studies, using insulin titration algorithms that are patient-driven can lessen the burden on clinicians [28]. When patients have the ability to self-titrate and display ownership of their treatment plan, this can increase feelings of empowerment and improve adherence and satisfaction rates. Ultimately, self-monitoring increases treatment optimization and leads to greater health outcomes over time [29].

The ADA and the EASD recommend personalization as an approach to glucose control, considering factors such as age, health behaviours, comorbidities and life expectancy [2]. For instance, less aggressive treatment goals may be indicated in older patients with comorbidities, while younger patients with long life expectancy may benefit from more stringent targets. When glycaemic targets are not achieved or maintained, healthcare providers need to review therapeutic options for treatment intensification with their patients. All treatment plans require acceptance on the part of the patient; thus, it is essential for healthcare providers to be familiar with various patient-directed insulin regimens to better customize treatment. Patient preferences in regards to treatment plans in T2DM should be identified through meaningful conversations with patients. Specific HbA1c goals should be targeted on the basis of the individual patient using the most suitable titration algorithm and treatment goals.

With an open communication style between patient and clinician, a satisfactory treatment plan can be achieved. Understanding the pathophysiology of T2DM can help target treatment choices and improve patient compliance. Patient education regarding the progressive nature of β-cell failure and need for polypharmacy can improve individuals’ investment in their care, eliminate feelings of failure, and improve health literacy, as well as optimize glucose control.

Minimizing side effects is also important to optimize patient engagement with a particular treatment regimen. One common barrier to intensification is fear of hypoglycaemia. Much of this fear can be addressed with adequate patient education regarding awareness of hypoglycaemia [30]. There is a risk for hypoglycaemia with all treatments involving insulin [4], although patient education concerning the triggers for hypoglycaemia, such as missed meals or exercise, may reduce the incidence. Clinicians who review patients’ history of hypoglycaemic events may help individuals increase their understanding of triggers and have better insight into the therapy that is best suited for the patient. Moreover, use of continuous glucose monitoring can alert patients to episodes of impending or actual hypoglycaemia and can be used as a way to replace or decrease the number of finger sticks, allowing for much easier viewing of blood glucose values. Interstitial glucose measurements are found to be accurate in comparison with capillary blood glucose measurements [31]. According to a recent 24-week study, patients with T2DM who used continuous glucose monitoring achieved a lower HbA1c target compared with usual care [32].

As highlighted in this comparison of algorithms, the stepwise approach to insulin intensification has less risk for hypoglycaemia than full basal-bolus treatment and may be a good option for patients who are prone to hypoglycaemic events. With greater patient satisfaction associated with stepwise, easing patients into insulin intensification has clinical benefits, such as reduced HbA1c and fasting plasma glucose levels and potentially better patient perceptions of the approach. Other suggestions for determining optimal treatment regimens include understanding patients’ needs:

• Patient lifestyle: If patients are less likely to self-measure glucose readings several times each day, a stepwise treatment regimen that is titrated on the basis of readings from 3 days may be more suitable than requiring daily adjustments.

• Extent of disease/patient characteristics: Patients with severe hyperglycaemia may require more intensive treatment, including full basal-bolus insulin intensification. In AUTONOMY study B, patients older than 65 years were more likely to reach HbA1c targets by self-titrating on a daily basis. This may indicate the need for greater self-management at older ages. Further, the stepwise approach is heterogeneous, meaning that some patients may require RAI once daily while in others 3–4 injections of RAI could be necessary.

• Patient preferences: Titrating insulin doses on the basis of pre or post-meal glucose levels led to equivalent changes in SimpleSTEP compared with ExtraSTEP. Patients who prefer to check glucose levels either before or after eating may have similar outcomes and could choose which approach fits better in their schedule.

Conclusions

Several approaches to treatment intensification are available for patients with T2DM who continue to struggle with hyperglycaemia in spite of oral medication and lifestyle modification. With the use of RAI in conjunction with basal insulin, there is more opportunity for patients to meet HbA1c targets while minimizing the risk of hypoglycaemia by using self-management techniques taught through algorithms. Easing patients into RAI intensification with a stepwise approach may increase patients’ satisfaction, reduce HbA1c to acceptable levels, reduce hypoglycaemic episodes and increase the likelihood of long-term adherence.

Acknowledgments

The authors thank Katie Crosslin, PhD, of Syneos Health for medical writing support.

Disclosure statement

Alexandra Migdal reports no conflicts of interest; Martin Abrahamson served on advisory boards for Novo Nordisk, WebMD Health Services and holds stock in Health IQ; Anne Peters served on advisory boards, consulted and spoke for Abbott Diabetes Care, Becton Dickinson, Boehringer Ingelheim, Eli Lilly and Company, Janssen, Lexicon, Medscape, Merck, Novo Nordisk, Omada Health, OptumRx, Roche, Sanofi in addition to receiving research support from Dexcom; Nan Vint reports employment with Eli Lilly and Company.

Additional information

Funding

Eli Lilly and Company funded this manuscript.