key: cord-0741775-hetxkzq9
authors: D’Souza, Sherwin C.; Kruger, Davida F.
title: Considerations for Insulin-Treated Type 2 Diabetes Patients During Hospitalization: A Narrative Review of What We Need to Know in the Age of Second-Generation Basal Insulin Analogs
date: 2020-09-30
journal: Diabetes Ther
DOI: 10.1007/s13300-020-00920-z
sha: 2bb52279c56a302790e1d336e525ddfd34b74280
doc_id: 741775
cord_uid: hetxkzq9

With the availability of second-generation basal insulin analogs, insulin degludec (100 and 200 units/ml [degludec]) and insulin glargine 300 units/ml (glargine U300), clinicians now have long-acting, efficacious treatment options with stable pharmacokinetic profiles and associated low risks of hypoglycemia that may be desirable for many patients with type 2 diabetes. In this narrative review, we summarize the current evidence on glycemic control in hospitalized patients and review the pharmacokinetic properties of degludec and glargine U300 in relation to the challenges these may pose during the hospitalization of patients with type 2 diabetes who are receiving outpatient regimens involving these newer insulins. Their increased use in clinical practice requires that hospital healthcare professionals (HCPs) have appropriate protocols to transfer patients from these second-generation insulins to formulary insulin on admission, and ensure the safe discharge of patients and transition back to degludec or glargine U300. However, there is no guidance available on this. Based on the authors’ clinical experience, we identify key issues to consider when arranging hospital care of such patients. We also summarize the limited available evidence on the potential utility of these second-generation basal insulin analogs in the non-critical inpatient setting and identify avenues for future research. To address current knowledge gaps, it is important that HCPs are educated about the differences between standard formulary insulins and second-generation insulins, and the importance of clear communication during patient transitions.

have long-acting, efficacious treatment options with stable pharmacokinetic profiles and associated low risks of hypoglycemia that may be desirable for many patients with type 2 diabetes. In this narrative review, we summarize the current evidence on glycemic control in hospitalized patients and review the pharmacokinetic properties of degludec and glargine U300 in relation to the challenges these may pose during the hospitalization of patients with type 2 diabetes who are receiving outpatient regimens involving these newer insulins. Their increased use in clinical practice requires that hospital healthcare professionals (HCPs) have appropriate protocols to transfer patients from these second-generation insulins to formulary insulin on admission, and ensure the safe discharge of patients and transition back to degludec or glargine U300. However, there is no guidance available on this. Based on the authors' clinical experience, we identify key issues to consider when arranging hospital care of such patients. We also summarize the limited available evidence on the potential utility of these second-generation basal insulin analogs in the non-critical inpatient setting and identify avenues for future research. To address current knowledge gaps, it is important that HCPs are educated about the differences between standard formulary insulins and second-generation insulins, and the importance of clear communication during patient transitions.

Keywords: Clinical guidance; Glycemic control; Hospital setting; Hyperglycemia; Hypoglycemia; Insulin degludec; Insulin glargine U300; Transition of care

The past decade has seen many advances in diabetic therapies and devices, allowing healthcare professionals (HCPs) to better tailor treatment strategies to patient needs [1, 2] . As the use of these recently available therapies in clinical practice increases, and as the prevalence of type 2 diabetes (T2D) continues to rise [3] , it is likely that more patients will be admitted to the hospital on these newer therapies. At present, however, the guidance on diabetes care for hospitalized patients does not take this into account [4] .

Among the newer treatment choices available are the second-generation basal insulin analogs, namely insulin degludec 100 units/ml and 200 units/ml formulations (degludec U100 and U200, respectively [bioequivalent formulations]) [5] and insulin glargine 300 units/ml (glargine U300) [6] . These insulins have lower variation in glucose-lowering effect (across 24 h and from day to day) [7, 8] and a reduced risk of hypoglycemia at a given level of HbA 1c compared with previously available products [9] [10] [11] . An extended duration of action with low peak:trough ratios at steady state also enables some flexibility in dose timing, and these properties all facilitate glycemic management in the context of everyday living [12] . A few studies investigating the use of degludec and glargine U300 in hospitalized patients have recently published findings, but the evidence is limited and the nuances of insulin management for inpatient scenarios where degludec and glargine U300 are involved have not been fully explored. Therefore, it is timely to take stock of what is known about managing T2D in hospitalized patients, and it is essential to educate HCPs about the differences between the standard formulary insulins and second-generation insulins.

In this narrative review, we aim to summarize current evidence on glycemic control in hospitalized patients with T2D and review the pharmacokinetic (PK)/pharmacodynamic (PD) properties of degludec U100 or U200 (hereafter referred to as degludec) and glargine U300 in relation to the challenges they may pose during hospitalization of patients with T2D on outpatient regimens involving these insulins.

Hospitalization presents unique challenges to glycemic control, including variation in nutritional status, mobility, and presence of acute illness. A number of physiological changes (e.g., stress-induced counter-regulatory hormone secretion) or therapeutic choices (e.g., glucocorticoid use) can result from acute illness and exacerbate hyperglycemia, which, in turn, can worsen acute illness [13] . The factors associated with hyperglycemia and hypoglycemia in insulin-treated hospitalized patients with diabetes are summarized in Table 1 ; the impact of these must be considered when managing care. Diabetes is rarely the primary focus of care in hospitalized patients, and it can be difficult to achieve glycemic control, but the increased cost, length of stay, and adverse outcomesincluding death-that are associated with both uncontrolled hyper-and hypoglycemia demonstrate how important it is [14, 15] . There is great debate, however, on the optimal blood glucose (BG) target for hospitalized patients. Table 1 Factors that influence BG control in insulin-treated hospitalized patients with diabetes Factors that increase the risk of hyperglycemia [59, 60] Factors that increase the risk of hypoglycemia [59] [60] [61] [62] [15] . Evidence since has shown that clinical outcomes may be modified by preadmission glycemic control in hospitalized patients [16, 17] . In one retrospective observational study, relaxed BG targets were associated with lower mortality in critically ill patients with poorly controlled diabetes (HbA 1c [ 7% [53 mmol/mol]), but not in patients with well-controlled diabetes (HbA 1c B 7% [53 mmol/mol]) [16] . This led Marik and Egi to propose differential therapeutic BG targets in intensive care unit patients with diabetes based on preadmission glycemic control: 140-200 mg/dl (7.8-11.1 mmol/l) in patients with preadmission HbA 1c \ 7% (53 mmol/mol) and 160-220 mg/dl (8.9-12.2 mmol/l) in those with preadmission HbA 1c C 7% (53 mmol/mol) [18] .

The optimal glycemic target during the perioperative period is still controversial [19] . In a recent meta-analysis, perioperative 'tight' (B 150 mg/dl [8.3 mmol/l]) versus 'liberal' (B 220 mg/dl [12.2 mmol/l]) control was associated with reduced rates of some complications (surgical-site infections, sepsis, atrial fibrillation, and acute kidney injury [21-43% lower]), but there was no survival benefit, and an increased risk of hypoglycemia (114% higher) and severe hypoglycemia (382% higher) [19] .

The 2020 ADA standards of care do not recommend glycemic targets that are any tighter than 80-180 mg/dl (4.4-10.0 mmol/l) during the perioperative period, since this is associated with a higher incidence of hypoglycemia [14] .

Hypoglycemia is relatively common in hospitalized patients, with prevalence ranging from 3 to 28% (depending on the definition and setting) in patients with T2D [20] [21] [22] . In hospitalized patients with diabetes, hypoglycemia is associated with increased costs, mainly through longer hospital stays, alongside higher rates of morbidity and mortality [23, 24] . In critically ill patients, hypoglycemia is independently associated with increased risk of mortality [25] and, in non-critically ill patients (T2D: 99.4%) admitted to hospital for infections, mortality risk was increased by hypoglycemia (2.66 times more likely than in patients without hypoglycemia) [26] . In combination with previous findings [27, 28] , this provides a strong evidence base for the goal of avoiding hypoglycemia [25] .

In conclusion, it appears that, while the optimal glucose target may vary between patients (with more research on this required), the best outcomes are achieved when hypoglycemia is avoided and BG variability minimized. It might be appropriate (or at least pragmatic) to relax glucose targets slightly during hospitalization, but nevertheless aim for the best level of control that can be achieved without incurring episodes of hypoglycemia.

Insulin is the most appropriate agent for controlling glycemia in hospitalized patients because it has no absolute contraindications, it is the most efficacious pharmacologic agent for lowering blood glucose, and it can be rapidly titrated. Oral antidiabetic drugs are generally discontinued upon admittance to hospital, since fewer data are available on their safety in hospitalized patients and it is not easy to adjust their dose based on the clinical status of the patient. In the critical care setting, continuous intravenous insulin infusion is the preferred method for achieving glycemic targets, as it allows quick correction for any sudden changes in insulin requirements. For non-critical care, choosing the most appropriate insulin regimen is not as clear and the choice depends on the individual circumstances, including whether patients have good nutritional intake, but a basal-bolus regimen is often the preferred regimen of choice for non-critically ill hospitalized patients [14, 29] .

This section focuses on PK/PD properties and associated clinical outcomes of degludec and glargine U300 in clinical practice and the impact of their availability on insulin management of hospitalized patients with T2D.

Degludec is a second-generation basal insulin that forms a depot of multi-hexamer chains after subcutaneous injection [30] . Gradual diffusion of readily absorbed degludec monomers from this depot provides a slow delivery of degludec into the circulation [30] . Table 2 provides an overview of its PK/PD properties. Degludec has an ultra-long duration of action (beyond 42 h) and an elimination half-life of * 25 h [31] ; clinicians may be concerned that this results in an excessive accumulation of insulin in the circulation (insulin stacking) with once-daily dosing. However, basal insulin only accumulates until steady state is reached, at which time the daily injected dose is balanced by elimination [32] . Degludec has a stable and consistent glucose-lowering profile over the daily dosing interval with little peak effect [8, 31] . These properties of degludec are preserved across pediatric and elderly patients, and those with renal or hepatic impairment [33] [34] [35] [36] .

Randomized controlled trials (RCTs) have demonstrated comparable glycemic control and a lower risk of hypoglycemia with degludec compared with glargine U100 in patients with diabetes [10, 11, 37] . The long-term safety of degludec has been established in DEVOTE, a dedicated cardiovascular outcomes trial [37] . Degludec is also available in an up-concentrated formulation, insulin degludec 200 units/ml (degludec U200), which is bioequivalent to degludec U100 [38] and may help to address the needs of patients with a high injection volume burden.

Glargine U300 contains the same active molecule as the first-generation basal insulin analog glargine U100 but is an up-concentrated formulation delivering the same number of insulin units in one-third of the injection volume [6] . After subcutaneous injection, the acidic glargine solution is neutralized and the glargine component precipitates, forming an amorphous depot, slowing its absorption from subcutaneous tissue [6] . Upon redissolution, glargine is predominantly locally converted into a metabolite that is responsible for its glucose-lowering effect [39] . There are differences in the PK/PD profiles between the two glargine formulations (U100 and U300) [7] , and these are thought to result from differences in injection volume and, therefore, depot size, leading to slower and more prolonged redissolution from a more compact glargine U300 depot [40] . Glargine U300 has a long duration of action (C 36 h), an elimination half-life of 18-19 h (Table 2) [6, 7] , and a more stable glucose-lowering profile than glargine U100 [7] .

In the EDITION trials program, patients with diabetes achieved equivalent glycemic control with glargine U300, but at a higher insulin dose (10-18%) compared with glargine U100 [6, 9] . There were comparable or lower risks of experiencing at least one confirmed (BG B 70 mg/dl [3.9 mmol/l]) or severe episode of hypoglycemia at any time (24-h period) or during the night with glargine U300 versus glargine U100 [9] . However, lower rates of hypoglycemia with glargine U300 in the EDITION program appear to be largely driven by data from the titration period (week 0-week 8) and might be attributed to differences in potency between the U100 and Table 2 PK/PD properties and relevant practical aspects of basal insulin products Second-generation basal insulin analogs First-generation basal insulin analogs Intermediateacting basal insulin Degludec [5, 63] Glargine U300 [6, 64] Detemir [65] [66] [67] [68] [41] , and that of glargine U300 is demonstrated in the CONCLUDE head-to-head trial [42] .

Studies have compared the PK profiles of the second-generation basal insulins and found that degludec achieves its (more or less) peakless profile from dose to dose more consistently than either glargine U100 or U300 formulations [8] . However, head-to-head trials investigating clinical outcomes have been inconsistent in their findings [43] [44] [45] . [42] .

To summarize, it remains to be established if one of the second-generation basal insulin analogs currently available has an advantage over the other for reducing risk of hypoglycemia at a given level of glycemic control [46] , but they provide a much-needed treatment option for patients who require insulin therapy but are fearful of, or vulnerable to, hypoglycemia.

A lower risk of hypoglycemia and low variability in glucose-lowering effect are desirable properties to have in an insulin used to treat patients in the hospital setting, as well as in clinical practice; hence, several studies are investigating the utility of second-generation basal insulin analogs in hospitalized patients. The unique PK/PD profile of these newer insulins may be of benefit in certain hospital situations, but problematic in others. For example, day-to-day variability in glucoselowering effect can make it challenging to dose insulin correctly and safely, so the relatively low day-to-day variation demonstrated by degludec and glargine U300 may help address this issue. In addition, these insulins are appropriate for once-daily dosing and offer some dosing flexibility; degludec can be injected at any time of day, and flexibly from day to day as long as dosing is within an 8-40-h interval following the previous dose [5] . Glargine U300 can be injected ± 3 h of the same time each day without compromising glycemic control [6, 47] . Such flexibility may be more practical and safe for hospitalized patients and those who rely on district or community nursing teams to administer insulin injections. The steady-state profiles of degludec and glargine U300 have a markedly lower peak:trough ratio than other insulin analogs with shorter half-lives. Consequently, fluctuations in glucose-lowering effect are dampened and insulin dosing errors, which are particularly prevalent in hospitals [48] , have fewer acute effects [32] .

However, their long half-lives (that afford these benefits) mean that they take longer to achieve steady state than first-generation basal insulins, and so titration should take place less frequently (label recommends every 3-4 days) than with other insulins to avoid overshooting the BG target [5, 6] . This could make them unsuitable for use in hospitalized patients who may have fluctuating insulin requirements and unstable health status.

The majority of data available on degludec in the hospital setting are from small studies, but a large randomized trial comparing degludec with glargine U100, as part of a basal-bolus regimen, for the management of hospitalized and discharged patients with T2D is ongoing [49] . Findings from a small (n = 74), open-label, randomized, controlled trial conducted in Japanese hospitals have recently been published, albeit the patients were hospitalized for the specific purpose of initiating insulin; hence, the findings are not applicable to patients hospitalized as a result of acute illness/scheduled surgery. Nevertheless, this study provides insights into titrating degludec to target over a short period of time [50] . In this study, patients with poorly controlled (HbA 1c C 8% [64 mmol/mol]) T2D were randomized to receive either degludec or glargine U100 as part of a basal-bolus regimen. Basal insulin was initiated at 4 units before bedtime, with dose adjustment every 2 days, and bolus insulin was started at 4 units before each meal. After 12 days, the percentage of patients achieving glycemic control was similar between groups (* 30%), as was the proportion experiencing hypoglycemia [* 41%, BG 54-70 mg/dl (3.0-3.9 mmol/l), * 10% BG \ 54 mg/dl (3.0 mmol/l)]. The glycemic targets and protocol used here are likely unsuitable for hospitalized patients, but it is reassuring that there was no increased risk of hypoglycemia with degludec versus glargine U100 [50] . Furthermore, a study in 12 patients who had a 24-h fasting period around their scheduled colonoscopy found patients could avoid hypoglycemia by skipping a single dose of degludec on the morning of the procedure [51] .

There are few small observational studies on degludec use in acutely ill patients. One retrospective study assessed the impact of degludec on 13 patients with and 13 patients without T2D who were hospitalized and required parenteral/enteral nutrition [52] . The starting dose of degludec was calculated according to the carbohydrate content of the parenteral/enteral nutrition, usually applying a 1:10 ratio of insulin units:carbohydrate (g). For patients coming from basal-bolus insulins, the dose of shortacting insulin had to be 50% of the total daily insulin dose at day 1, 25% at day 2, and 12.5% at day 3, while degludec reached steady state. In other patients, short-acting insulin was used when BG exceeded 250 mg/dl (13.9 mmol/l). In the T2D patients, mean glucose intake was 181 g per day, mean degludec dose was 24--26 units per day, 46.1% of patients received short-acting insulin, and mean (SD) BG levels improved from 210 (66.5) mg/dl [11.7 (3.7) mmol/l to 192 (48.6) mg/dl [10.7 (2.7) mmol/l] during the 7-day follow-up. No symptomatic or severe hypoglycemic episodes occurred during the hospital stay, and there was evidence of a reduction in within-day glycemic variability (as measured by the coefficient of variation of glycemia every 6 h) [52] . Similar results were observed in an observational study of 52 noncritical patients with diabetes who received degludec as part of a basal-bolus regimen while hospitalized [53] . It is not possible to draw conclusions on the effect and safety of degludec-based regimens in hospitalized patients based on the current data available; it remains to be seen whether the outcomes described in these small observational studies will also be observed in large, randomized trials.

The largest study with published findings so far is the glargine U300 hospital trial [54] , in which 176 patients with poorly controlled T2D were randomized to receive a basal-bolus regimen with either glargine U300 or glargine U100 and insulin glulisine before meals after admission to hospital. Insulin-experienced patients received 80% of their total daily outpatient insulin dose, and starting dose for insulin-naïve patients was ) inpatient stay was 6 (4; 8) days with glargine U300 and 4 (3; 7) days with glargine U100, and, overall, the level of glycemic control achieved was not impacted by duration of hospital stay. Capillary point-ofcare testing before meals and bedtimes revealed that the percentages of patients with BG \ 70 mg/dl (3.9 mmol/l) were similar between the glargine U100 group (8.7%) and the glargine U300 group (9.5%), but clinically significant hypoglycemia (BG \ 54 mg/dl [3.0 mmol/l]) occurred in 6% of glargine U100treated patients versus 0% of glargine U300treated patients (p = 0.02), and a single episode of severe hypoglycemia (BG \ 40 mg/dl [2.2 mmol/l]) occurred with glargine U100.

There were no significant differences in glycemic control in a subset of 82 patients using continuous glucose monitoring during their stay.

Not all hospital formularies include secondgeneration basal insulins, so patients may need to be transferred to the available formulary basal insulin, and, in some cases, it might be more practical or desirable to transfer patients temporarily to continuous intravenous (IV) insulin infusion. The current lack of data and restricted formularies will mean that the vast majority of patients being treated with degludec or glargine U300 are likely to be switched to an insulin with a shorter half-life. Despite this, there are no guidelines on safely switching between second-and first-generation basal insulin analogs upon admittance and discharge from hospital [4] . While the prescribing information gives recommendations on how to switch to these newer insulins (unit-for-unit conversions except when switching from twicedaily basal insulin to glargine U300, where a 20% dose reduction is recommended) [5, 6] , it is unknown whether these are suitable for patients who may have just undergone major changes in glucose handling before being discharged from hospital, and there is even less information on switching from these insulins. Table 3 presents a comparison of guidance (drawn from the authors' clinical experience) on the hospital care of patients with T2D receiving outpatient basal insulin regimens involving a first-or second-generation basal insulin analog.

In a recent paper, Hirsch and Draznin explored several clinical scenarios in which challenges may arise when switching from degludec to a basal insulin with a shorter halflife [4] . The authors surveyed 30 other HCPs on what they would do in each situation, and also offered their own recommendation, based on the PK/PD profile of the insulins involved. The most popular answer selected by HCPs often involved making unit-to-unit conversions between degludec and formulary insulins, but this may not be appropriate, especially in hospitalized patients who are vulnerable to hypoglycemia, because of the carry-over effect of previously injected degludec. For patients admitted to the hospital on degludec, the authors recommended halving their basal insulin dose on the first day they are switched to a first-generation formulary basal insulin and then upping the dose to 75-100% of the preadmittance insulin dose the next day (depending on BG levels) [4] . This is based on the knowledge that 50% of the last degludec dose is still contributing to the serum insulin levels 25 h post-injection, as indicated by the terminal half-life. This is a conservative approach to avoid hypoglycemia when switching from a second-to first-generation basal insulin in hospitalized patients. It is important to consider when exactly the patient's last dose was given, especially given the flexibility in degludec dosing. For example, if the last dose of insulin (degludec) was [ 30 h ago, halving the next dose of insulin (e.g., glargine U100, onset of action B 6 h) may result in a temporary rise in glycemia. It is impossible to provide a precise and universal calculation for conversion, as every situation is different, and the factors listed in Table 1 will also determine patients' insulin requirements. Nevertheless, we would recommend considering a reduction in total daily insulin dose of between 20 and 50% when switching non-critical patients from degludec to a first-generation basal insulin upon admittance to hospital and a similar magnitude in dose reduction when switching back to degludec upon discharge to reduce the risk of hypoglycemia.

While Hirsch and Draznin discussed the challenges pertaining to degludec, to the best of our knowledge, these same challenges have not been explored with explicit reference to glargine U300. For the most part, the same principles will apply; indeed, the glargine U300 hospital trial reduced insulin dose by 20% when switching from U100 to U300 formulations. However, given the relatively shorter half-life and lower unit dose potency of glargine U300 compared with degludec, somewhat smaller dose reductions may be appropriate when switching between glargine U300 and formulary insulin.

Another important point to consider when adjusting insulin during hospitalization is whether the patient's pre-admission insulin dose was appropriate. In cases where patient adherence is poor, the insulin dose can sometimes be inappropriately increased. Therefore, it may be best to also consider the insulin dose expected based on the patient's body weight and nutritional needs. This scenario is possibly less likely, however, in patients on degludec/ glargine U300 regimens, as the impact of missing a basal insulin dose becomes smaller as the half-life increases.

While there may not be enough evidence to draw conclusions on the utility of starting second-generation basal insulin analogs in hospitalized patients, the findings so far may help HCPs decide whether patients who are already being treated with a newer basal insulin should remain on that insulin during their hospital If the patient remains on the second-generation basal insulin analog in hospital, the basal insulin dose should be titrated no more frequently than every 3-4 days, with adjustments made to nutritional and/or supplemental insulin dosing as required and the patient should be closely followed up

Discharge from hospital Written and verbal instructions on self-monitoring of BG, an explanation of home BG goals, and the importance of consistent nutritional habits

Caution that BG levels may be higher than normal for a few days after discharge Transfer from formulary insulin products a to the previous basal insulin analog: convert the basal insulin dose on a unit-per-unit basis with glargine U300

Reintroduction and dosing of any non-insulin glucose lowering agents (if discontinued during hospitalization)

Therapeutic intensification or adjustment, if required

Emphasis that BG levels may be higher than normal for a few days after discharge, with verbal and written instructions advising that the basal insulin dose should be titrated no more frequently than every 3-4 days to avoid overshooting the BG target, putting the patient at risk of hypoglycemia Consider at least a 20% dose reduction in the hospital formulary basal insulin a dose to the degludec dose to be conservative Provide verbal and written instructions to the patient that it may take up to 4 days to see the full effect of degludec or up to 5 days to see the full effect of glargine U300

BG blood glucose, glargine U300 insulin glargine 300 units/ml, POC point of care a First-generation basal insulin analogs (e.g., insulin glargine 100 units/ml or insulin detemir) stay or be switched to an insulin with a shorter half-life. For example, the findings from the glargine U300 hospital trial do not indicate that a patient with T2D poorly controlled with glargine U300 would have better outcomes by being switched to glargine U100 upon admittance. This may mean that HCPs take the decision to keep patients on glargine U300 throughout, thereby avoiding the challenges and potential risks associated with switching between a first-and second-generation basal insulin. However, further study is required to support hospital HCPs in this decision and to ensure that future guidelines contain sufficient information on the challenges these new therapies pose to insulin management in an inpatient setting.

Irrespective of the inpatient diabetes treatment regimen, the transition of care from the inpatient to the outpatient setting represents a clinical challenge [55] . Discharge planning should commence at hospital admission and include steps to ensure appropriate communication across caregivers, reconciling medication across the continuum of care, arranging for timely follow-up, and encouraging active involvement from patients in their diabetes care [55] . Additional steps are advisable for patients switching back from the hospital formulary insulin to their pre-admission regimen involving a second-generation basal insulin analog (Table 3) . For instance, patients should receive verbal and written instructions advising that the second-generation basal insulin dose should be titrated no more frequently than every 3-4 days to avoid overshooting the BG target, putting the patient at risk of hypoglycemia. A dose reduction should be considered in patients switching back to their home regimen involving degludec, while patients should be advised that it may take up to 4 days to see the full effect of degludec or up to 5 days to see the full effect of glargine U300 following discharge (Table 3) .

Due to the recent emergence of COVID-19, there has not been an opportunity to study the relationship between T2D and susceptibility to COVID-19 infection in large cohorts; thus, a conclusive relationship is yet to be determined. However, retrospective studies of hospitalized patients with COVID-19 have demonstrated that, compared with non-diabetic patients, patients with T2D require more intensive treatments in the management of COVID-19 symptoms, and have a significantly higher inhospital death rate [56] . Furthermore, wellcontrolled BG levels during COVID-19 infection are associated with better survival [56] . One retrospective study, although limited by patient numbers, indicated that patients with T2D who are critically ill with COVID-19 seem have a greater need for insulin at the peak of their COVID-19 infection [57] . The management of diabetes in patients with COVID-19 poses a clinical challenge that requires a balance between glucose-lowering treatments and treatments to manage the viral infection, in addition to careful consideration regarding the multiple factors that contribute to poor prognosis in patients with both COVID-19 and T2D [58] . The authors feel that it is too early to discuss the use of second-generation basal insulin analogs in COVID-19 patients.

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

Optimal use of insulin in hospitalized patients with diabetes remains to be fully elucidated and continues to be a subject of ongoing study. The increased use of second-generation basal insulin analogs in clinical practice presents hospital HCPs with a challenge, since there is no guidance available on how to safely switch hospitalized patients from second-to first-generation basal insulin analogs. As more data become available on the possible utility of these newer insulins as part of a basal-bolus regimen in the hospital setting, hospital HCPs will be better able to decide whether non-critically ill patients can remain on their ultra-long-acting basal insulin. In any case, a carefully considered treatment plan for each individual patient is required, and this may require thought to be given to the initiation, continuation, adjustment, discontinuation, and recommencement of these insulins.

Authorship. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Authorship Contributions. SD is the guarantor of the work and, as such, takes responsibility for the integrity of the manuscript content. SD and DK provided input at the conception of this narrative review, their opinions and recommendations based on their clinical experience throughout the drafting process. Both authors critically revised the article during the drafting process and approved of the final version to be published.

Disclosures. Sherwin C. D'Souza has participated as a speaker for AstraZeneca, BL-Lilly, Dexcom, and Novo Nordisk A/S and received consultancy fees from Novo Nordisk A/S. Davida F. Kruger has participated on advisory boards for Novo Nordisk, Abbott, Eli Lilly and Company, Sanofi Aventis, Janssen, Dexcom, Intarcia, and Merck; participated in speakers' bureaus for Janssen, Valeritas, AstraZeneca, BL-Lilly, Novo Nordisk, Dexcom, Lilly, Abbott, and Insulet; holds stocks or shares in Dexcom; and the Henry Ford Health System has received grants and/or research support from Novo Nordisk, the Helmsley Charitable Trust, Dexcom, Lexicon, and Abbott.

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

Data Availability. Data sharing not applicable to this article, as no datasets were generated or analyzed during the current study.

Open Access. This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/bync/4.0/.

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Economic and clinical impact of inpatient diabetic hypoglycemia

Diabetes Ther

Diabetic status and the relation of the three domains of glycemic control to mortality in critically ill patients: an international multicenter cohort study

Hypoglycemia and glycemic variability are associated with mortality in non-intensive care unit hospitalized infectious disease patients with diabetes mellitus

Mild hypoglycemia is independently associated with increased mortality in the critically ill

Hypoglycemia and outcome in critically ill patients

Insulin therapy in hospitalized patients

Design of the novel protraction mechanism of insulin degludec, an ultra-long-acting basal insulin

Ultra-long-acting insulin degludec has a flat and stable glucose-lowering effect in type 2 diabetes

Insulin stacking versus therapeutic accumulation: understanding the differences

Insulin degludec: Pharmacokinetic properties in subjects with hepatic impairment

Insulin degludec: pharmacokinetics in patients with renal impairment

Insulin degludec's ultra-long Diabetes

Ultra-long pharmacokinetic properties of insulin degludec are comparable in elderly subjects and younger adults with type 1 diabetes mellitus

Efficacy and safety of degludec versus glargine in type 2 diabetes

A comparison of the steady-state pharmacokinetic and pharmacodynamic profiles of 100 and 200 U/mL formulations of ultra-long-acting insulin degludec

Investigational new insulin glargine 300 U/mL has the same metabolism as insulin glargine 100 U/mL

Differentiating basal insulin preparations: Understanding how they work explains why they are different

Basal insulin and cardiovascular and other outcomes in dysglycemia

Risk of hypoglycaemia with insulin degludec versus insulin glargine U300 in insulin-treated patients with type 2 diabetes: the randomised, head-to-head CONCLUDE trial

Efficacy and safety of insulin glargine 300 U/mL vs insulin degludec in patients with type 2 diabetes: a randomized, open-label, cross-over study using continuous glucose monitoring profiles

More similarities than differences testing insulin glargine 300

Units/mL versus insulin degludec 100 Units/mL in insulin-naive type 2 diabetes: The randomized head-to-head BRIGHT trial

A comparative effectiveness study of degludec and insulin glargine 300 U/mL in insulin-naive patients with type 2 diabetes

How conclusive is the CONCLUDE trial?

Efficacy and safety of flexible versus fixed dosing intervals of insulin glargine 300 U/mL in people with type 2 diabetes

Insulin use: Preventable errors

A trial comparing insulin degludec and glargine U100 for management of hospitalized and discharged patients with type 2 diabetes

Efficacy and safety of insulin degludec U100 and insulin glargine U100 in combination with meal-time bolus insulin in hospitalized patients with type 2 diabetes: an open-label, randomized controlled study

Evaluation of safety of insulin degludec on undergoing total colonoscopy using continuous glucose monitoring

Impact of insulin degludec in hospitalized patients with and without type 2 diabetes requiring parenteral/enteral nutrition: an observational study

Efficacy and safety of insulin degludec for hyperglycemia management in noncritical hospitalized patients with diabetes: an observational study

A randomized controlled trial comparing glargine U300 and glargine U100 for the inpatient management of medicine and surgery patients with type 2 diabetes: Glargine u300 hospital trial. Diabetes Care

Hospital discharge algorithm based on admission HbA1c for the management of patients with type 2 diabetes

Association of blood glucose control and outcomes in patients with COVID-19 and pre-existing type 2 diabetes

COVID-19 and Diabetes: insulin requirements parallel illness severity in critically unwell patients

COVID-19 in people with diabetes: understanding the reasons for worse outcomes

Management of critically ill patients with diabetes

Management of hyperglycemia in hospitalized patients in non-critical care setting: an endocrine society clinical practice guideline

Management of diabetes and hyperglycemia in hospitalized patients

Understanding hypoglycemia in hospitalized patients

Steady state is reached within 2-3 days of once-daily administration of degludec, a basal insulin with an ultralong duration of action

Single-dose new insulin glargine 300 U/mL provides prolonged, stable glycaemic control in Japanese and European people with type 1 diabetes

Switching basal insulins in type 2 diabetes: Practical recommendations for health care providers

Towards peakless, reproducible and long-acting insulins. An assessment of the basal analogues based on isoglycaemic clamp studies

LevemirÒ dosing and administration

LevemirÒ prescribing information 2020

LantusÒ prescribing information

Pharmacokinetics and pharmacodynamics of NPH insulin in type 1 diabetes: The importance of appropriate resuspension before subcutaneous injection

HumulinÒN prescribing information

Insulin management of type 2 diabetes mellitus

Funding. This review and the journal's Rapid Service Fee were funded by Novo Nordisk Inc.Medical Writing, Editorial, and Other Assistance. Medical writing support was provided by Anna Campbell and technical editing support by Helen Marshall of Watermeadow Medical, an Ashfield company, part of UDG Healthcare plc, funded by Novo Nordisk Inc. The authors thank Michael Santiago (Novo Nordisk Inc.) for providing a medical accuracy review of the outline and final draft. This was funded by Novo Nordisk Inc.