The Current and Future Role of Insulin Therapy in the Management of Type 2 Diabetes: A Narrative Review

Abstract

Early initiation of intensive insulin therapy has been demonstrated to be effective in controlling glycemia and possibly preserving beta-cell function. Innovations in insulin formulations and delivery systems continue. However, we have seen an acceleration in the development of new classes of diabetes medications for individuals with type 2 diabetes and obesity, such as, for example, glucagon-like peptide-1 receptor agonists (GLP-1 RAs). These formulations have been shown to confer significant benefits in achieving good glycemic control with reduced hypoglycemia risk, weight loss, and cardiorenal protection. Therefore, it is reasonable to question whether there is still a role for insulin therapy in the management of type 2 diabetes. However, there are clear limitations inherent to GLP-1 RA therapy, including high rates of suboptimal adherence and treatment discontinuation due to high cost and side effects, which diminish long-term efficacy, and supply issues. In addition, newer formulations have shown improvements in convenience and tolerability, and have been shown to be even more effective when used in conjunction with basal insulin. In this narrative review, we discuss current evidence that supports GLP-1 RA use in combination with insulin therapy and the potential pitfalls of reliance on GLP-1 RAs as a substitute for insulin therapy.

Key Summary Points

A large proportion of the type 2 diabetes (T2D) population have poor glycemic control, which puts individuals at high risk for chronic and debilitating microvascular and macrovascular complications

Early initiation of basal-bolus therapy quickly resolves glucotoxicity and lipotoxicity and has been shown to protect β-cell function; however, transition to basal-bolus therapy is often delayed due to therapeutic inertia

Increased use of glucagon-like peptide-1 receptor agonist (GLP-1 RA) further delays basal-bolus transition; however, because the effectiveness of GLP-1 RA therapy is dependent on available insulin production, most individuals will eventually require insulin therapy

Numerous studies support the use of GLP-1 RA formulations in conjunction with basal insulin; fixed-ratio combinations of long-acting insulin and short-acting GLP-1 RA preparations are now available

Introduction

The increasing prevalence of diabetes remains a significant global health concern. As reported by the International Diabetes Federation (IDF), the number of people with diabetes is expected to grow from a current estimate of 537 million to 643 million by 2030, worldwide, with an estimated annual cost of over $1 trillion (USD) [1]. A substantial portion of this cost is associated with suboptimal glycemic outcomes and resulting complications [2].

Despite innovations in diabetes technologies and new medications, the proportion of the individuals with diabetes who are achieving their target glycated hemoglobin (HbA1c) has failed to improve [3, 4]. In their 2017 analysis, Carls et al. reported that the proportion of individuals who achieved their recommended glycemic goals decreased from 52.2% during the 2003–2010 observation period to 50.9% during the 2007–2014 period [3]. In a similar study that compared National Health and Nutrition Examination Survey (NHANES) data between the periods of 2007–2010 and 2015–2018, investigators observed a decline in the percentage of individuals who achieved HbA1c levels of < 8.0%, from 79.4% to 75.4%, respectively [4].

Over the past several years, we have seen an acceleration in the development of new classes of diabetes medications for individuals with type 2 diabetes (T2D) and obesity, such as glucagon-like peptide-1 receptor agonists (GLP-1 RA) [5, 6]. Therefore, it is reasonable to question whether there is still a role for insulin therapy in the management of T2D. Consequently, in this narrative review we discuss current evidence that supports use of GLP-1 RA use in combination with insulin therapy and discuss the potential pitfalls of reliance on GLP-1 RA as a substitute for insulin therapy.

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Strengths and Limitations of Insulin Therapy

Type 2 diabetes is a complex metabolic disorder characterized by progressive deterioration of pancreatic beta-cell function, unrestrained hepatic glucose production, increasing insulin resistance, dyslipidemia, and cardiovascular disease (CVD) [7–10]. As insulin resistance worsens over time, the body compensates by secreting more insulin, thereby placing increasing stress on the beta-cells, eventually leading to beta-cell failure in the long term [7, 8]. An analysis of the UK Kingdom Prospective Diabetes Study (UKPDS) cohort showed that 40–50% of beta-cell function had already been lost at the time of T2D diagnosis and progressively declined by approximately 5% annually [11]. As such, in the absence of specific interventions to preserve beta-cell function, individuals with T2D will eventually require treatment with exogenous insulin, typically starting with basal insulin followed by intensification of therapy with multiple daily insulin injections (MDI) comprising basal plus prandial insulin [12]. Although the initiation of insulin therapy may be considered a “last resort” option [13] and usually occurs late in disease progression due to therapeutic inertia [14], earlier insulin initiation may have advantages, including achievement of glucose targets and possible preservation of beta-cell function [15].

For individuals treated with anti-hyperglycemic medications (e.g., insulin, secretagogues), hypoglycemia is a major concern and a major obstacle to achieving target treatment goals [16]. Another obstacle for insulin-treated patients is weight gain, especially in individuals who are already obese. Weight gain in diabetes is due to the metabolic effects of insulin [17], increased caloric intake, and the lack of a structured meal plan [18]. These factors can affect both treatment adherence and long-term outcomes [19, 20].

Nevertheless, innovations in insulin formulations and delivery systems continue. Over the past three decades, we have seen significant advances in the efficacy and safety of the various insulin formulations, with the development of rapid-acting insulin analogs, long-acting analogs, and inhaled insulin, all of which more closely mimic normal physiologic insulin secretion with less hypoglycemia [21]. Importantly, researchers and pharmaceutical companies are in various stages of developing glucose-responsive insulin (GRI) formulations; often referred to as “smart insulins,” these formulations are designed to provide insulin activity in response to current glucose levels [22].

We have also seen the development of advanced insulin delivery technologies, such as insulin pumps, automated insulin delivery (AID) systems, and connected insulin pens. In addition to improving glycemic outcomes, the flexibility that these technologies provide enhances treatment satisfaction, a key contributor to medication adherence [23], and reduces some of the clinical and psychological burden of insulin therapy [24].

Strengths and Limitations of GLP-1 RA Therapy

Exenatide, the first commercial GLP-1 RA formulation, was introduced almost 20 years ago as a twice-daily injectable treatment for the management of T2D [25]. Liraglutide and lixisenatide, given as once-daily injections, followed soon thereafter. These formulations are now widely available as once-daily and once-weekly injectables [5] and once-daily oral medications [6]. Most recently, we have seen the introduction of tirzepatide, which in a single molecular entity combines a GLP-1 and glucose-dependent insulinotropic polypeptide receptor (GIP RA) agonism to lower HbA1c and reduce body weight [26–29]. Compared with insulin, these medications have been shown to improve glycemic control with lower hypoglycemia risk [30, 31] and reduce body weight [31, 32].

The most notable weight loss has been observed in adults with T2D treated with tirzepatide [26–29]. In a phase 3, double-blind, randomized trial involving 2539 adults with obesity (body mass index ≥ 30 kg/m²), 50% of participants treated with tirzepatide at dosages of 10 mg and 15 mg per week experienced body weight reductions of ≥ 20% over a 72-week treatment period [26]. Recent studies have also shown an association between GLP-1 RA therapy and significant cardiorenal protection [31, 33, 34].

Importantly, in a treat-to-target study of 814 suboptimally controlled adults treated with insulin lispro, Rosenstock et al. reported that 54% of participants who transitioned to a once-weekly GLP-1 RA (n = 412) were able to discontinue insulin therapy [35]. In the remaining insulin + GLP-1 RA cohort, investigators observed improved glycemic control with reduced injections, lower insulin dosages, less hypoglycemia, and weight loss. Another significant benefit of GLP-1RA therapy is the cardiorenal protective quality of these formulation. In a recent systematic review and network meta-analysis of current diabetes medications, investigators reported that GLP-1 RA formulations were effective in reducing all-cause death, non-fatal stroke, cardiovascular death, non-fatal myocardial infarction, hospitalization for heart failure, and end-stage renal disease [36]. Based on an emerging body of evidence, the American Diabetes Association (ADA) recommends use of GLP-1 RA medications in all patients with demonstrated atherosclerotic CVD (ASCVD) or renal disease [37]. The GLP-1 RA should be initiated regardless of insulin therapy or achievement of HbA1c or time in range (%TIR) goals.

Lack of Long-Term Efficacy

The addition of a GLP-1 RA formulation to current oral medication regimens is often recommended when patients are not achieving their glycemic goals [38]. However, because GLP-1 RAs are dependent upon beta-cell function and insulin availability, basal insulin and, eventually, prandial insulin are often required due to the progressive nature of T2D [7, 8]. In a cohort of 620 adults with T2D and HbA1c levels > 7.5%, Jones et al. observed a significantly reduced glycemic response to GLP-1 RA therapy in individuals with severe insulin deficiency, leading to the conclusion that C-peptide levels and islet autoantibodies—both indicators of low beta-cell function—are potential biomarkers for determining the appropriateness of GLP-1 RA therapy in insulin-treated individuals [39].

Genetic variability of the GLP-1 receptor gene has also been shown to influence the response to treatment with GLP-1 RA medications [40]. It has been suggested that pharmacogenetic testing may facilitate more personalized and effective and safer treatment of type 2 diabetes and obesity [40].

Suboptimal Adherence and Persistence

Individuals may require insulin therapy even earlier if they cannot afford the cost or tolerate the side effects and/or the lack of efficacy of GLP-1 RA medications [41]. Recent real-world studies have reported relatively high rates of poor adherence and discontinuation of GLP-1 RA therapy over time [32, 42, 43]. For example, among 589 UK adults with T2D who were started on GLP-1 RA therapy and followed for 2 years, Weiss et al. observed that 40.8% were nonadherent and 64.7% had discontinued therapy at 24 months [32]. In a similar U.S. study of 4791 adults, Weiss et al. reported a discontinuation rate of 70.1% at 24 months [42]. In a propensity score matched analysis of 4074 adults with T2D treated with once-weekly dulaglutide (n = 2037) and liraglutide (n = 2.037), investigators reported that discontinuation rates at 6 months were relatively high in both the liraglutide (35.6%) and dulaglutide (28.0%) treatment arms [43]. In a more recent analysis of 15,111 adults with T2D who initiated GLP-1 RA therapy, investigators reported that 52.2% of patients had discontinued therapy during the 12-month observation period [44]. In a large, randomized, controlled, double-blinded trial, Husain et al. observed that more patients permanently discontinued oral semaglutide than placebo (184 of 1591 patients [11.6%] vs. 104 of 1592 [6.5%]) [45].

The reasons for discontinuation of GLP-1 RA therapy are multifactorial. In a recent study that investigated weight loss outcomes associated with semaglutide treatment in 408 individuals with overweight or obesity, Ghusn et al. reported that nausea and vomiting were the most commonly encountered adverse events (36.6%), followed by diarrhea (8.6%), and fatigue (6.3%) [46]. Moreover, five (2.9%) participants discontinued due to these adverse effects and 15 (8.6%) either reduced their dosage or remained on the same dose. In the 2-year STEP-5 trial, ten (6.6%) of the 152 individuals randomized to once-weekly semaglutide discontinued due to adverse events [47].

In a real-world cross-sectional survey of 449 primary care physicians and 352 diabetologists/endocrinologists, the reasons most frequently reported for discontinuation of GLP-1 RA therapy were lack of blood glucose control (45.6%), nausea/vomiting (43.8%), and other gastrointestinal (GI) side effects (36.8) [41]. Among the 10,987 persons with diabetes included in the survey, the reasons most frequently reported (apart from cost) were nausea (64.4%), vomiting (45.4%), and inadequate glucose levels (34.5%). Interestingly, inadequate (or no) weight loss was reported by 25.3%. Whether discontinuation rates can be reduced by dose titration, change in background therapy, or other management efforts that experienced providers use in the clinic needs additional study since many of the side effects are dose dependent.

Adverse Events and Consequences of Discontinuation

Discontinuation of therapy can be life-threatening in insulin-treated patients with T2D when insulin dosages are significantly reduced or discontinued [48]. In its 2019 guidance, the European Medicines Agency (EMA) warned that the occurrence of diabetic ketoacidosis reported in a consistent number of cases could be attributed to the abrupt dose reduction or discontinuation of insulin while initiating the GLP-1 RA therapy [48]. However, it is possible that deterioration of glucose control in many of these patients is due a misdiagnosis of T2D. Studies have shown that approximately 10% of adults initially diagnosed with clinical T2D have latent autoimmune diabetes in adults (LADA) [49]. Identifying insulin deficiency may be important before adding non-insulin therapies to insulin requiring patients, especially if insulin dose reduction is contemplated. As with the injectable GLP-1 RA, Husain et al. reported that discontinuation of oral GLP-1 RA was primarily driven by gastrointestinal adverse events, including nausea, vomiting, and diarrhea [44].

Recent studies have revealed increased risks of GI adverse events in individuals with T2D, including biliary disease, pancreatitis, gastroparesis, and bowel obstruction [50]. In a retrospective assessment of intestinal obstruction risk associated with GLP-1 RA use, Faillie et al. used the UK Clinical Practice Research Datalink and linked databases to evaluate 25,617 GLP-1 RA users and 40,616 adults treated with dipeptidyl peptidase-4 inhibitors (DPP-4i) compared with those on sodium-glucose cotransporter-2 inhibitor (SGLT-2i) therapy [51]. DPP-4i formulations are oral medications that inhibit the DPP-4 enzyme, thereby increasing GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) levels [47]. Investigators in one study reported that GLP-1 RA were associated with an increased risk of intestinal obstruction compared with SGLT-2i (1.9 vs. 1.1 per 1000 person-years, respectively: hazard ratio [HR] 1.69, 95% confidence interval [CI] 1.04–2.74), with the highest risk observed after 1.6 years of therapy [52]. DPP-4i medications were also associated with increased risk compared with SGLT-2i therapy (2.7 vs. 1.0 per 1000 person-years, respectively), with the highest risk observed after 1.8 years of use. These concerns regarding impaired gut motility has prompted anesthesiologists to recommend stopping GLP-1 RA and DPP-4i medications for a period of time prior to surgery or procedures to reduce the risk of aspiration [52].

On 7 July 2023, the Pharmacovigilance Risk Assessment Committee (PRAC), EMA’s safety committee, announced its investigation into reports of “suicidal thoughts and self injury” associated with individuals treated with semaglutide and liraglutide medications [53]. The alert was in response to data from 150 case reports of possible self-harm and/or thoughts of suicide collected by the Icelandic Medicines Agency. It is unclear whether suicidal thoughts are, in fact, linked to therapy, psychopathology associated with diabetes (e.g., depression, distress), and/or other factors [54]. Nevertheless, clinicians should be vigilant in openly discussing this reported risk and encouraging patients to talk about any issues or situations that may be impacting their emotional well-being.

Long-Term Adverse Consequences of Discontinuation

In addition to losing the cardiorenal protection benefits, individuals who discontinue GLP-1 RA medications typically gain back much of the weight they had lost during therapy [55]. In a retrospective cohort study of adults with T2D, investigators assessed changes in cardiovascular risk and other outcomes in 395 individuals with no history of CVD (primary prevention group) and 155 individuals with a known history of CVD (secondary prevention) [55]. In the primary prevention arm of the trial (n = 395), 40.25% of patients discontinued therapy after mean of 3.2 years. At year 4, weight loss was significantly greater among patients who continued therapy than among those who discontinued therapy (− 4.14 vs. − 1.19 kg; respectively; p < 0.001), and even greater differences were observed in the secondary prevention group (− 4.46 vs. − 0.75 kg, respectively; p = 0.006). The investigators reported that discontinuation of therapy was independently associated with a significant increase in the risk of developing a major adverse cardiovascular event (MACE) [55].

More significant differences in weight change were observed in a randomized trial that compared treatment with once-weekly semaglutide with a switch to placebo for weight maintenance in 902 adults with overweight or obesity after a 20-week run-in with subcutaneous semaglutide [56]. Among the 803 participants who completed the run-in period, mean weight loss over the 48-week follow-up period was significantly greater among those who continued therapy (− 7.9%) compared with a 6.9% increase among those who were switched to placebo (p < 0.01).

There is also concern regarding the loss of fat-free mass(FFM), an indicator of lean body mass, and bone density associated with semiglutide [57] and tirzepatide [57]. This is particularly worrisome for older patients who are susceptible to poor musculoskeletal health, resulting in poor physical performance, increased risk of falling, and bone breakage [58, 59]. Importantly, although treatment with tirzepatide was recently reported to actuate greater weight loss compared with semaglutide (− 11.2 vs. − 6.9 kg, respectively; p < 0.001), FFM reductions were also significantly greater with tirzepatide versus semaglutide therapy (− 1.5% vs. − 0.8%, respectively; p = 0.018) [59].

Availability of Safe and Effective Medications

The inability to obtain diabetes medications can have a direct impact on treatment adherence and long-term clinical outcomes [60]. Although the cost of insulin remains a key obstacle for patients, healthcare providers, and payers, insulin formulations are readily available in most high-income countries [61]. However, recently, as many patients currently treated with a GLP-1 RA have discovered, the unanticipated shortage of these medications that began late 2022 due to an unexpected increase in demand [62] has made it difficult and, in some cases, impossible to refill their prescriptions [62]. These shortages predominately occurred because of an unexpected increase in demand for GLP-1 RA without adequate adjustment in production [62]. Although this shortage is expected to resolve in mid-2024 [63], ongoing challenges persist, with potential harm for patients, and clinicians who have had to seek alternative approaches. For example, in the UK, clinicians are advised to immediately initiate remedial actions [62] (Table 1).

Table 1.

UK Advisory: recommended actions until the supply chain shortage is fully resolved

1. Only prescribe GLP-1 RA for their licensed indications

2. Do not initiate new patients on GLP-1 RA for the duration of the shortage

3. Proactively identify patients established on affected GLP-1 RA and consider prioritizing for review based on the criteria set out in the clinical guidance and discuss stopping treatment with patients who have not achieved treatment targets

Do not switch between brands of GLP-1 RA, including between injectable and oral forms

Do not double up a lower dose preparation where a higher dose preparation of GLP-1 RA is not available

Do not prescribe excessive quantities; limit prescribing to minimize risk to the supply chain whilst acknowledging the needs of the patient

4. Use the principles of shared decision-making where an alternative agent needs to be considered, as per NICE guidelines 3 and in conjunction with the clinical guidance 2.4

5. Support patients to access structured education and weight management programs where available

6. If switching a patient on to insulin, ensure an insulin is chosen as per information on the SPS page on prescribing available insulins as not all suppliers are able to manage an uplift in demand

Actions recommended by Diabetes UK [63] (https://www.diabetes.org.uk/about-us/news-and-views/our-response-serious-supply-issues-drugs-people-living-type-2-diabetes)

GLP-1 RA Glucagon-like peptide-1 receptor agonist, NICE National Institute for Health and Care Excellence, SPS Specialist Pharmacy Service

A key concern is that patients may resort to alternative sources for their medication. As reported by Whitley et al., many social media sites and on-line clinics are promoting compounded versions of GLP-1 RA medications [62]. Although most compounded medications are regulated and safe, there is a danger that these specific medications do not include the correct active ingredient. For example, because manufacturers hold the patents for their GLP-1 RA molecule and do not sell this ingredient for compounding, the compounded medications may not be as safe and effective, which could adversely impact the millions of patients currently using GLP-1 RA therapy [64]. Thus, patients who choose to purchase compounded formulations put themselves at severe risk for adverse consequences, primarily due to a lack of efficacy and safety [65].

Most recently, the U.S. Food and Drug Administration (FDA) issued a warning concerning the appearance of counterfeit semaglutide drug supply chain in the USA [66]. The investigations have revealed that needles from these products are also counterfeit, which raises concerns about a lack of needle sterility and the resultant increased risk of infection. Therefore, clinicians who are considering working with compounders should be mindful that these GLP-1 RA “knock-offs” may not be using ingredients that are approved by the relevant regulatory agencies, and they should caution patients of the risks if planning to obtain ore use these potentially dangerous formulations.

GLP-1 RA in Combination with Insulin Therapy

Numerous studies have shown that combined GLP-1 RA/basal insulin therapy provides effective glycemic management and cardiorenal protection, with reduced hypoglycemia risk [31, 33, 34, 67–85]. Combined therapy with GLP-1 RA and basal insulin leverages the complementary effects of each medication [86–88]. GLP-1 RA act upon postprandial glucose by stimulating insulin secretion, increasing satiety, slowing gastric emptying, and reducing the glucagon-release responses [86], whereas basal insulin addresses elevated fasting glucose by primarily suppressing hepatic glucose production.

In an early randomized, double blind, placebo controlled trial, 124 participants treated with MDI were randomized 1:1 to adjunct therapy with subcutaneous liraglutide or placebo [84]. At the end of the 24-week treatment period, investigators observed significant improvements in glucose levels in the liraglutide treatment group compared with the placebo group (HbA1c difference − 1.5% vs. − 0.4%, respectively; p < 0.001), without increase in hypoglycemia risk, and with significant reductions in body weight. Adjunctive treatment with liraglutide resulted in lower total daily insulin doses (− 18.1 U vs. − 2.3 U, respectively; p < 0.001).

In recent years, we have seen the introduction of fixed-ratio combinations (FRCs) of long-acting insulin and short-acting GLP-1 RA preparations in which both medications are administered via a single delivery pen at a pre-determined ratio. With these formulations, the GLP-1 RA dosage is adjusted automatically as patients “dial in” their prescribed basal insulin dosages [89]. Currently, two different FRC products have received FDA and EMA approval: iDegLira (insulin degludec/liraglutide) and iGlarLixi (insulin glargine/lixisenatide). Table 2 presents a brief summary of the findings from randomized trials of these new FRCs.

Table 2.

Randomized fixed-ratio combination trials

Study	Duration (weeks)	Baseline therapy	Treatment	Comparator	Relative HbA1c change vs. comparator (all p < 0.0001) (%)
Watada et al. [79]	26	OAD	iGlarLixi	Lixisenatide	−1.07
Terauchi et al. [80]	26	OAD	iGlarLixi	iGlar	− 0.63
Kaneto et al. [81]	26	Basal insulin + Met	iGlarLixi	iGlar	− 0.74
Yuan et al. [82]	30	Basal insulin ± OAD	iGlarLixi	iGlar	− 0.7

IDegLira insulin glargine/liraglutide, IGlarLixi insulin glargine/lixisenatide, iGlar insulin glargine, Lira liraglutide, Met metformin, OAD oral anti-diabetic agents

Overall, studies have shown reductions in HbA1c in patients treated with FRC therapy compared with GLP-1 RA or non-insulin therapies [67–83], with less weight gain and reduced hypoglycemia compared with those treated with insulin alone [68, 70, 71, 73, 74, 77, 81, 82]. It is notable that although treatment with insulin therapy caused fewer GI adverse effects compared with FRC therapy, some studies reported fewer GI effects in patients treated with FRC formulations compared with those treated with GLP-1 RA therapy [72, 75, 83].

Summary

New therapies and advances in diabetes technologies have the potential to lessen the clinical and financial impacts of the growing global prevalence of diabetes, which remains a significant health concern that threatens to overwhelm many healthcare systems. As demonstrated in numerous studies [5, 26–34, 90], treatment with GLP-1 RA medications has enabled many individuals to improve their diabetes management and, in many cases, delay the need for insulin. However, it is important that clinicians understand the risks, limitations, and benefits of this drug class.

In this article we have reviewed the benefits and potential adverse consequences associated with GLP-1 RA therapy relevant to discontinuation of therapy, which is often due to intolerable GI side effects. However, it is not our intention to discourage the use of these effective medications. Rather, our goal is to provide information about how use of GLP-1 RAs in combination with prandial [35] and basal insulin [31, 33, 34, 67–85] can help patients safely achieve their desired glycemic goals while minimizing the side effects associated with GLP-1 RA medications.

Early-stage efforts are currently underway in developing oral, small molecules to improve the tolerability and convenience of these medications [91, 92]. However, it may take years before these compounds become available to patients. Until then, clinicians should be aware of the significant discontinuation rates associated with GLP-1 RA medications, investigate and monitor any side effects their patients are experiencing, adjust dosages as needed, and provide guidance for minimizing these effects. Although the benefits of GLP-RA therapy are substantial, insulin will remain a viable therapy for the management of T2D, particularly when used in conjunction with GLP-1 RA medications.

Author Contributions

Janet B. McGill, Irl B. Hirsch, Christopher G. Parkin, Grazia Aleppo, Carol J Levy, and James R. Gavin, III contributed to the focus and content of the manuscript. Janet B. McGill, Irl B. Hirsch, and Christopher G. Parkin wrote the initial draft of the manuscript. All authors reviewed and revised the final draft and approved its submission.

Funding

Embecta provided funding for the development of this manuscript and the Rapid Service Fee. The sponsor had no input in the content of this manuscript.

Declarations

Conflict of Interest

Janet B McGill has received research support from the NIH, Helmsley foundation, JDRF, Novo Nordisk, and Beta Bionics. JBM has received consulting fees from Bayer, Boehringer Ingelheim Lilly, Mannkind, Novo Nordisk, and Thermo Fisher outside of this work. Irl B Hirsch reports grant support from Dexcom, Tandem, and Mannkind; and consulting fees from Abbott Diabetes Care, Roche, Hagar, and Vertex. Christopher G Parkin has received consulting fees from Abbott Diabetes Care, CeQur, Dexcom, Embecta, GWave, LifeScan, Insulet, Tandem, Mannkind, Roche Diabetes Care, and Provention bio. Grazia Aleppo has received research support to Northwestern University from Astra-Zeneca, Dexcom, Eli-Lilly, Emmes, Fractyl Health, Insulet, MannKind, Novo Nordisk, Tandem Diabetes Care, and WellDoc; and consulting fees from Eli -Lilly, Dexcom, and Insulet outside of this work. Carol J Levy has received research support by the NIDDK and Helmsley Foundation and industry support paid to the Icahn School of Medicine at Mount Sinai from Abbott Diabetes, Dexcom, Insulet, Novo Nordisk, Senseonics; and Tandem; and consulting fees from Eli-Lilly and Dexcom outside of this work. James R. Gavin, III, has served on advisory boards and/or speaker bureaus for Abbott Diabetes Care, Novo Nordisk, Medtronic, and Boehringer Ingelheim.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.