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 . Gradual diffusion of readily absorbed degludec monomers from this depot provides a slow delivery of degludec into the circulation . 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 ; 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 . 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 . Degludec is also available in an up-concentrated formulation, insulin degludec 200 units/ml (degludec U200), which is bioequivalent to degludec U100  and may help to address the needs of patients with a high injection volume burden.
Insulin Glargine U300
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 . After subcutaneous injection, the acidic glargine solution is neutralized and the glargine component precipitates, forming an amorphous depot, slowing its absorption from subcutaneous tissue . Upon redissolution, glargine is predominantly locally converted into a metabolite that is responsible for its glucose-lowering effect . There are differences in the PK/PD profiles between the two glargine formulations (U100 and U300) , 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 . Glargine U300 has a long duration of action (≥ 36 h), an elimination half-life of 18–19 h (Table 2) [6, 7], and a more stable glucose-lowering profile than glargine U100 .
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 ≤ 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 . 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 U300 formulations. The long-term safety of glargine U100 has been demonstrated in the ORIGIN cardiovascular outcomes trial , and that of glargine U300 is demonstrated in the CONCLUDE head-to-head trial .
Head-to-Head Studies of Degludec and Glargine U300
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 . However, head-to-head trials investigating clinical outcomes have been inconsistent in their findings [43,44,45]. The latest data are from the CONCLUDE clinical trial. This randomized, open-label, treat-to-target trial compared the risk of hypoglycemia with degludec U200 versus glargine U300 over a 36-week maintenance period (total treatment period: 88-weeks) in 1609 insulin-treated patients with T2D . Although the rate of overall symptomatic hypoglycemia (primary endpoint) was lower with degludec U200 compared with glargine U300 (216.8 versus 243.9 events per 100 patient-years of experience [PYE]), the difference did not reach statistical significance (RR 0.88 [0.73; 1.06]95% CI). As a result of the trial not meeting its primary endpoint, the confirmatory testing procedure for superiority was stopped and the prespecified confirmatory secondary hypoglycemia endpoints (nocturnal symptomatic hypoglycemia and severe hypoglycemia) were analyzed using prespecified statistical models but were now considered exploratory, since they could not be controlled for family-wise type I error. Nevertheless, these endpoints showed lower rates with degludec U200 versus glargine U300 for nocturnal symptomatic hypoglycemia (62.3 versus 93.8 events per 100 PYE, RR 0.63 [0.48; 0.84]95% CI) and severe hypoglycemia (1.0 versus 4.9 events per 100 PYE, RR: 0.20 [0.07; 0.57]95% CI) .
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 , but they provide a much-needed treatment option for patients who require insulin therapy but are fearful of, or vulnerable to, hypoglycemia.
Studies of Second-Generation Basal Insulin Analogs in Hospital Settings
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 glucose-lowering 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 . 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 , have fewer acute effects .
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.
Studies of Degludec in a Hospital Setting
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 . 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 . In this study, patients with poorly controlled (HbA1c ≥ 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 . 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 .
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 . 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 short-acting 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) . Similar results were observed in an observational study of 52 non-critical patients with diabetes who received degludec as part of a basal–bolus regimen while hospitalized . 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.
Studies of Glargine U300 in a Hospital Setting
The largest study with published findings so far is the glargine U300 hospital trial , 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 determined according to weight and glycemic control: 0.4 and 0.5 units/kg/day for patients with BG levels of 140–200 and 201–400 mg/dl [7.8–11.1 and 11.2–22.2 mmol/l], respectively. The total daily dose was split evenly between basal and prandial insulin, the latter divided in three equal doses before meals. The final titration protocol was to adjust basal and rapid-acting doses on a daily basis with increases of 10% [BG 140–180 mg/dl (7.8–10.0 mmol/l), 20% (BG 180–240 mg/dl (10.0–13.3 mmol/l)], and 30% [BG > 240 mg/dl (13.3 mmol/l)] if patients were in poor glycemic control, but, during the first 6 months of study (before the first prespecified interim analysis), adjustments were only made if BG was > 180 mg/dl (10.0 mmol/l). Mean (SD) BG at admission was 228 (82) mg/dl [12.7 (4.6) mmol/l], and this improved in both treatment arms, with mean daily BG levels of 186 (40) mg/dl [10.3 (2.2) mmol/l] for the glargine U100 group and 184 (46) mg/dl [10.2 (2.6) mmol/l] with glargine U300. The median (interquartile range [IQR]) 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-of-care 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 U100-treated patients versus 0% of glargine U300-treated 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.
Challenges of Interrupting Treatment with Second-generation Basal Insulin Analogs during Hospitalization
Not all hospital formularies include second-generation 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 . While the prescribing information gives recommendations on how to switch to these newer insulins (unit-for-unit conversions except when switching from twice-daily 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 half-life . 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 pre-admittance insulin dose the next day (depending on BG levels) . 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 ≤ 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.
Admitting a Patient on Newer Therapies to Hospital
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 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.
Discharging a Patient from Hospital Formulary Insulin Back to Their Pre-Admission Regimen
Irrespective of the inpatient diabetes treatment regimen, the transition of care from the inpatient to the outpatient setting represents a clinical challenge . 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 . 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).
COVID-19 Infection in Patients with T2D
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 in-hospital death rate . Furthermore, well-controlled BG levels during COVID-19 infection are associated with better survival . 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 . 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 . The authors feel that it is too early to discuss the use of second-generation basal insulin analogs in COVID-19 patients.