Open access Original research Efficacy and safety of insulin glargine 300 U/mL (Gla-300) during hospitalization and therapy intensification at discharge in patients with insufficiently controlled type 2 diabetes: results of the phase IV COBALTA trial Antonio Perez ‍ ‍,1 Francisco Javier Carrasco-­Sánchez ‍ ‍,2 Carlos González,3 José Miguel Seguí-Ripoll ‍ ‍,4 Carlos Trescolí,5 Javier Ena ‍ ‍,6 Mireia Borrell ‍ ‍,7 Ricardo Gomez Huelgas8 To cite: Perez A, ABSTRACT Carrasco-­Sánchez FJ, Introduction This study assessed the efficacy and Significance of this study González C, et al. Efficacy safety of insulin glargine 300 U/mL (Gla-300) during and safety of insulin glargine hospitalization and therapy intensification at discharge in What is already known about this subject? 300 U/mL (Gla-300) during ►► Hospitalization is an opportunity to evaluate the met- insufficiently controlled people with type 2 diabetes. hospitalization and therapy abolic situation of insufficiently controlled patients intensification at discharge Research design and methods COBALTA (for its acronym in Spanish, COntrol Basal durante la hospitalizacion y al with type 2 diabetes and to intensify their antidia- in patients with insufficiently ALTA) was a multicenter, open-­label, single-­arm, phase betic treatment at discharge. controlled type 2 diabetes: IV trial including 112 evaluable inpatients with type 2 ►► Glargine 300 U/mL (Gla-300) is a basal insulin ana- results of the phase IV COBALTA trial. BMJ Open Diab Res Care diabetes insufficiently controlled (glycosylated hemoglobin log that results in more even pharmacokinetic and 2020;8:e001518. doi:10.1136/ (HbA1c) 8%–10%) with basal insulin and/or non-­insulin pharmacodynamic profiles compared with insulin bmjdrc-2020-001518 antidiabetic drugs. Patients were treated with a basal– glargine 100 U/mL, which translates into similar gly- bolus–correction insulin regimen with Gla-300 during cosylated hemoglobin (HbA1c) reductions and less the hospitalization and with Gla-300 and/or non-­insulin hypoglycemic events with once-­daily subcutaneous ►► Additional material is injections. antidiabetics for 6 months after discharge. The primary published online only. To view, endpoint was the HbA1c change from baseline to month 6 please visit the journal online What are the new findings? (http://​dx.​doi.​org/​10.​1136/​ postdischarge. ►► The use of Gla-300 during hospitalization and thera- bmjdrc-​2020-​001518). Results HbA1c levels decreased from 8.8%±0.6% py intensification at discharge in hospitalized people at baseline to 7.2%±1.1% at month 6 postdischarge with type 2 diabetes insufficiently controlled with (p<0.001, mean change 1.6%±1.1%). All 7-­point blood For ‘Presented at statement’ basal insulin and/or non-­insulin antidiabetic drugs glucose levels decreased from baseline to 24 hours see end of article. significantly improved their glycemic status, reach- predischarge (p≤0.001, mean changes from 25.1±66.6 to ing HbA1c levels close to 7%, with an adequate 63.0±85.4 mg/dL). Fasting plasma glucose also decreased Received 28 April 2020 safety profile and a high degree of treatment satis- Revised 26 June 2020 from baseline to 24 hours predischarge (p<0.001), month 3 (p<0.001) and month 6 (p<0.001) postdischarge (mean faction 6 months after the hospital discharge. Accepted 18 July 2020 changes 51.5±90.9, 68.2±96.0 and 77.6±86.4 mg/dL, How might these results change the focus of respectively). Satisfaction was high and hyperglycemia/ research or clinical practice? hypoglycemia perception was low according to the ►► Gla-300 can be a treatment choice for hospital and Diabetes Treatment Satisfaction Questionnaire at postdischarge diabetes management when type 2 month 6 postdischarge. The incidence of confirmed © Author(s) (or their diabetes is insufficiently controlled with other basal (glucose<70 mg/dL)/severe hypoglycemia was 25.0% employer(s)) 2020. Re-­use insulin and/or non-­insulin antidiabetic medication. during hospitalization and 59.1% 6 months after discharge. permitted under CC BY-­NC. No commercial re-­use. See rights No safety concerns were reported. and permissions. Published Conclusions Inpatient and intensification therapy at by BMJ. discharge with Gla-300 improved significantly glycemic INTRODUCTION control of patients with type 2 diabetes insufficiently For numbered affiliations see Insulin is the antihyperglycemic treatment of end of article. controlled with other basal insulin and/or non-­insulin antidiabetic medication, with high treatment satisfaction. choice for inpatients due to its rapid action Correspondence to Gla-300 could therefore be a treatment choice for hospital and effectiveness to control blood glucose Dr Antonio Perez; and postdischarge diabetes management. in most clinical situations.1 2 Physiological ​aperez@​santpau.​cat insulin programs can best accomplish the BMJ Open Diab Res Care 2020;8:e001518. doi:10.1136/bmjdrc-2020-001518 1 Clinical care/Education/Nutrition flexibility needed to achieve glycemic control in the MATERIALS AND METHODS challenging situation of hospitalized patients.1 They Study design and participants mimic the one-­half of daily insulin secretion that serves COBALTA (for its acronym in Spanish, COntrol Basal a basal function and one half secreted in response to durante la hospitalizacion y al ALTA) (EudraCT number intake, with regimens including basal and nutritional 2015-004715-20) was an open-­label single-­arm phase IV insulins.1 3 4 Basal–bolus insulin therapy is proven safe trial conducted at 15 Spanish hospitals (online supple- and effective for type 2 hyperglycemia in the inpatient mentary appendix) according to the Declaration of setting,5–7 and clinical practice guidelines consider regi- Helsinki, good clinical practices and national regulations. mens with basal, prandial and correction components Patients meeting selection criteria were consecutively the preferred treatment for non-­critically ill hospitalized recruited between June 2016 and December 2017. Main patients.2–4 8 inclusion criteria comprised type 2 diabetes insuffi- The growing evidence of the inpatient glycemic ciently controlled (HbA1c 8%–10%) after ≥3 months of control benefits on morbimortality and associated unchanged antidiabetic therapy with basal insulin and/ costs7 9 support hospitalization as an opportunity to eval- or non-­insulin antidiabetic drugs and hospitalization for uate the metabolic situation of insufficiently controlled an expected length of 5–14 days. Main exclusion criteria patients and intensify their antidiabetic treatment at included patient hospitalization due to hyperglycemic discharge. While prehospitalization treatment can be decompensation of diabetes, being critically ill, treat- maintained when preadmission control is acceptable, ment with premixed or rapid-­acting insulin for ≥1 week insufficiently controlled patients will need their outpa- before hospital admission, glomerular filtration rate tient therapy intensification.3 6 10–12 According to the <30 mL/minute, need of treatment intensification with American Diabetes Association (ADA) and the European rapid-­acting insulin at hospital discharge. All inclusion Association for the Study of Diabetes (EASD), another and exclusion criteria are presented in online supple- antidiabetic drug should be administered in patients mentary table 1. insufficiently controlled with lifestyle management and The study included a first visit at hospital admis- metformin.13 14 Advancing to triple therapy is reasonable sion (baseline), a hospitalization period of 5–14 days when glycemic targets are not reached after 3-­ month throughout which patients were daily monitored, and dual therapy, and basal insulin may be an alternative to a second study visit at discharge. Follow-­up visits were add-­on therapy.13 14 scheduled at months 1, 3 and 6 postdischarge (online Glargine 300 U/mL (Gla-300) is a second-­generation supplementary figure 1). A postdischarge telephone basal insulin analog with a slow-­ release mechanism follow-­up was scheduled for patients who were hospital- after subcutaneous injection that results in more even ized for <7 days. and prolonged pharmacokinetic and pharmacody- namic profiles compared with insulin glargine 100 U/ mL (Gla-100).15 The more gradual release of Gla-300 Study treatment from the subcutaneous depot enables blood glucose to Patients started Gla-300 and prandial/correction insulin be controlled beyond 24 hours, allowing more flexibility at hospital admission, and previous non-­insulin therapy in its once-­daily injection time.16 Moreover, the phase was discontinued. The individual insulin dose was at the III EDITION program evidenced similar glycosylated investigator’s discretion, but 50% had to be basal insulin hemoglobin (HbA1c) reductions that were better and 50% rapid-­acting insulin. Gla-300 was subcutaneously sustained over 12 months, along with less hypoglycemic administered once daily at bedtime (±3 hours). Prandial events and weight gain with Gla-300 compared with insulin was administered before the main meals and at Gla-100.17–21 The recently published DELIVER cohort bedtime only when patients ate carbohydrates. Supple- studies also supported the comparable HbA1c reduction mental correction doses were administered to correct with less hypoglycemic events after switching to Gla-300 preprandial hyperglycemia. Gla-300 doses were adjusted versus other basal insulins even in older patients in the to target fasting plasma glucose (FPG) 90–140 mg/dL real-­world setting.22 23 As hypoglycemia, weight gain and and prandial/correction insulin to achieve preprandial injection burden are frequent concerns that may nega- and postprandial blood glucose 90–140 and <180 mg/dL, tively affect the efficacy of diabetes treatments,24–27 the respectively (online supplementary table 2). lower hypoglycemia risk and weight gain after Gla-300 Treatment at discharge was based on the preadmission once-­daily subcutaneous injection may facilitate treat- therapy and HbA1c levels (online supplementary figure ment intensification. In addition, the absence of data 2). The Gla-300 dose was 80% of the total insulin required on Gla-300 administration in the hospital setting and within the 24 hours prior to discharge. Subsequent doses therapy intensification at discharge warrants further were adjusted every 3–7 days, considering the median assessment. capillary blood glucose level of the previous 3 days and We therefore assessed Gla-300 efficacy and safety during the ADA/EASD consensus targets14 80–130 mg/dL hospitalization and therapy intensification at discharge (online supplementary table 2). Non-­insulin antidiabetic in people with type 2 diabetes insufficiently controlled treatment was prescribed according to the patient’s status with basal insulin and/or non-­insulin antidiabetic drugs. and the investigator’s criteria. 2 BMJ Open Diab Res Care 2020;8:e001518. doi:10.1136/bmjdrc-2020-001518 Clinical care/Education/Nutrition Study endpoints a significance level of 0.05 was used. Statistical analyses The primary study endpoint was the mean HbA1c change were performed with the Statistical Package for the Social from baseline to month 6 postdischarge. Sciences V.22.0 (SPSS Inc, Chicago, USA). Secondary efficacy endpoints included changes in mean 7-­point blood glucose profile measurements during RESULTS hospitalization and FPG levels during hospitalization and Study population months 3 and 6 postdischarge. Safety endpoints included A total of 115 patients were screened from 11 internal the incidence of confirmed or severe hypoglycemia medicine and 4 endocrinology and nutrition depart- during hospitalization and at 6-­ month follow-­ up, the ments, 3 of whom were screening failures due to absence number of rehospitalizations or visits to emergency room of poor control or previous treatment with premixed/ 6 months after discharge and the adverse event profile rapid-­acting insulin (online supplementary figure 3). The throughout the study. Confirmed hypoglycemia was any remaining 112 patients received Gla-300 and comprised symptomatic/asymptomatic event with blood glucose of the safety population (table 1 and online supplementary <70 mg/dL; severe hypoglycemia was any hypoglycemia figure 4). Eighteen patients did not perform the 3-­month requiring assistance from another person. study visit and were excluded from the ITT population, Other study endpoints included changes in body which finally included 94 patients. weight and body mass index from hospital discharge to month 6, and treatment satisfaction according to Study treatment Diabetes Treatment Satisfaction Questionnaire (DTSQ) At baseline, the mean Gla-300 daily dose was 18.8±11.8 at month 6. The DTSQ is an 8-­item questionnaire with U (online supplementary table 3). The Gla-300 dose six items assessing treatment satisfaction and two items increased by 23.4%±46.7% until the 24 hours prior to assessing the perceived frequency of hyper- and hypogly- hospital discharge, reaching a mean of 21.4±10.9 U. cemia.28 29 Satisfaction items were scored from 6 (very The mean Gla-300 dose during the whole hospital stay satisfied) to 0 (very dissatisfied), accounting for an overall (mean stay, 10.5±5.9 days) was 20.7±12.3 U. In addition, score from 36 (very satisfied) to 0 (very dissatisfied), and 110 (98.2%) patients received ≥1 dose of prandial insulin the frequency of hyper/hypoglycemia from 6 (most of (mean dose, 23.6±13.7 U) and 92 (82.1%) received the time) to 0 (none of the time). ≥1 dose of correction insulin (mean dose, 5.1±3.4 U). At hospital discharge, the mean Gla-300 daily dose was Statistical methods 38.0±19.3 U (online supplementary table 3). This dose A sample size of 106 patients was estimated considering decreased by 1.3%±50.6% from discharge to month 1 the mean HbA1c reduction of 1.42%±0.05% in the and increased by 2.6%±37.0% from months 1 to 3 and EDITION 3 trial after 6 month Gla-300 treatment,30 a by 10.1%±50.9% from months 3 to 6, reaching 36.3±18.3 bilateral alpha risk of 0.05, a precision of 0.01% and a U at study end. Ninety-­ eight (93.3%) patients were patient loss of ≤10%. prescribed non-­insulin antidiabetic drugs at hospital, and Efficacy endpoints and treatment satisfaction were 89 (89.9%) continued with them at month 1, 83 (89.2%) assessed in patients with ≥1 Gla-300 dose, baseline effi- at month 3 and 84 (90.3%) at month 6 postdischarge. cacy measure and follow-­ up visit (intention-­ to-­ treat No significant differences in insulin doses were (ITT)). Weight, body mass index and safety endpoints observed according to insulin-­naïve versus previous basal were analyzed in patients with ≥1 Gla-300 dose (safety insulin use or age <75 vs ≥75 years (online supplementary population). table 4). Changes in mean HbA1c, 7-­point blood glucose, FPG, weight and body mass index were assessed using Wilcoxon Glycemic control or t-­ tests. Treatment satisfaction was analyzed using The primary endpoint analysis revealed that mean HbA1c frequency distributions and mean scores. Frequency levels significantly decreased from 8.8%±0.6% at base- distributions were also used to assess the severe or line to 7.2%±1.1% at month 6 (p<0.001), representing confirmed hypoglycemia incidence—along with annu- a mean change of 1.6%±1.1% (figure 1A and online alized rates—patients with ≥1 rehospitalizations/visits to supplementary table 5). The decline was evident from emergency room and adverse events. Adverse events were month 3 (p<0.001), with a mean variation of 1.6%±1.2% coded using the Medical Dictionary for Regulatory Activ- (figure 1A and online supplementary table 5). Although ities V.20.0. insulin-­ naïve versus previous basal insulin use showed Subanalyses post hoc comparing insulin-­naïve versus a higher HbA1c decrease from baseline to month 3 previous basal insulin use and age <75 vs ≥75 years were (1.9±1.2 vs 1.3±1.1%, p=0.025), no significant differences performed using χ2, Fisher, Mann-­Whitney, Wilcoxon or were observed at month 6 nor in the <75 and ≥75 years of t-­tests. Odds ratios (ORs) or relative risks (RRs), 95% subanalyses (online supplementary figure 5). confidence intervals (CIs) and p values of hypoglycemia Glucose levels in all 7-­point measurements signifi- incidences and rates were also calculated. cantly decreased from baseline to 24 hours pre-­discharge Means are presented with standard deviation (SD); (p≤0.001), with mean changes from 25.1±66.6 mg/dL missing data were not considered in the analyses, and prebreakfast to 63.0±85.4 mg/dL postlunch (figure 2 BMJ Open Diab Res Care 2020;8:e001518. doi:10.1136/bmjdrc-2020-001518 3 Clinical care/Education/Nutrition Table 1 Baseline patient characteristics (N=112) Characteristics Value Age (years)    Mean±SD 72.3±10.8  <75 years, n (%) 65 (58.0)  ≥75 years, n (%) 47 (42.0) Male, n (%) 68 (60.7) Caucasian, n (%) 110 (98.2) Weight (kg), mean±SD 80.1±16.6 Body mass index (kg/m2), mean±SD 30.1±5.9 Renal function, mean±SD    Creatinine (mg/dL) 1.1±0.4  GFR (mL/min) 75.4±32.4 Diabetes duration (years), mean±SD 10.9±7.9 Previous insulin treatment, n (%)    Previous basal insulin 57 (50.9)  Insulin-­naïve 55 (49.1) Non-­insulin treatment schedule, n (%)    Monotherapy 45 (45.5) Figure 1 HbA1c levels (A) and FPG levels (B) during the  Dual therapy 42 (42.4) study. *P≤0.001 vs baseline. FPG, fasting plasma glucose;  Triple therapy or more 11 (11.1) HbA1c, glycosylated hemoglobin.  GLP-1 receptor analogue monotherapy 1 (1.0) HbA1c (%), mean±SD 8.9±0.7 Decreasing blood glucose levels of the 7-­point profile FPG (mg/dL), mean±SD 205.4±83.9 and FPG were evidenced regardless of previous basal 7-­point capillary blood glucose profile (mg/dL), mean±SD  insulin treatment and age (online supplementary figure 5). However, a greater change was observed before break-  Prebreakfast 182.0±65.6* fast in insulin-­naïve versus previous basal insulin use  Postbreakfast 237.0±80.1† (48.5±73.5 vs 4.2±52.3 mg/dL, p=0.003) and age <75 vs  Prelunch 222.7±72.2‡ ≥75 years (39.6±68.2 vs 5.5±59.9 mg/dL, p=0.019), and  Postlunch 236.6±78.0§ also before meal in insulin-­naïve versus previous basal  Predinner 232.5±79.3‡ insulin use (59.3±67.5 vs 29.2±71.1 mg/dL, p=0.038). No significant differences between groups were observed in  Postdinner 227.0±82.4¶ FPG levels (online supplementary figure 5).  Bedtime 208.1±80.5** *Missing data, n=7. Weight and body mass index †Missing data, n=26. No significant changes from hospital discharge to month ‡Missing data, n=3. 6 postdischarge were evidenced in patients’ weight §Missing data, n=20. ¶Missing data, n=21. **Missing data, n=14. FPG, fasting plasma glucose; GFR, glomerular filtration rate according to the MDRD-4 equation; GLP-1, glucagon-­like peptide-1; HbA1c, glycosylated hemoglobin. and online supplementary table 5). Similarly, FPG levels significantly decreased during hospitalization (p<0.001), with a mean variation of 51.5±90.9 mg/dL from base- line to 24 hours predischarge (figure 1B and online supplementary table 5). Significant decreases were also observed at months 3 (p<0.001) and 6 (p<0.001) post-­ discharge, with mean changes of 68.2±96.0 mg/dL and 77.6±86.4 mg/dL, respectively (figure 1B and online Figure 2 Seven-­point blood glucose profile at baseline and supplementary table 5). 24 hours predischarge. *P≤0.001 vs baseline. 4 BMJ Open Diab Res Care 2020;8:e001518. doi:10.1136/bmjdrc-2020-001518 Clinical care/Education/Nutrition Table 2 Hypoglycemia during hospitalization and after hospital discharge During hospitalization (N=112) Month 6 postdischarge (N=93) Type of hypoglycemia n (%) Mean±SD* Rate† n (%) Mean±SD* Rate† Overall confirmed‡ or severe hypoglycemia 28 (25.0) 2.2±1.4 20.3 55 (59.1) 8.0±10.1 9.2 Asymptomatic confirmed‡ hypoglycemia 21 (18.8) 1.7±0.7 11.6 49 (52.7) 6.9±7.4 7.2 Symptomatic confirmed‡ hypoglycemia 12 (10.7) 1.3±0.6 5.0 21 (22.6) 3.0±3.1 1.3 Severe hypoglycemia 4 (3.6) 1.8±1.0 2.3 4 (4.3) 2.3±1.3 0.2 Nocturnal hypoglycemia 2 (1.8) 1.5±0.7 0.1 1 (1.1) 24.0±NA 0.5 Severe nocturnal hypoglycemia 1 (0.9) 1.0±NA 0.3 1 (1.1) 4.0±NA 0.1 *The mean number of hypoglycemic events was calculated over the number of patients with each type of hypoglycemia. †Hypoglycemic episodes per person-­year was calculated as Ʃ number of hypoglycemias/Ʃ time (years). ‡Confirmed: glucose<70 mg/dL. NA, not applicable. (78.2±14.3 vs 78.2±14.7 kg, p=0.467) and body mass index Severe hypoglycemia (29.3±4.6 vs 29.1±4.4 kg/m2, p=0.710). Four (3.6%) patients reported severe hypoglycemia Subanalyses according to insulin-­naïve versus previous during hospitalization and four (4.3%) after discharge basal insulin use and age <75 vs ≥75 years showed neither (table 2). Moreover, one (0.9%) patient reported significant variations nor differences between groups severe nocturnal hypoglycemia during hospitalization (data not shown). and another (1.1%) 6 months postdischarge (table 2). The rates of severe hypoglycemia and severe nocturnal hypoglycemia 6 months postdischarge were 0.2 and 0.1 Hyperglycemia and hypoglycemia episodes/person-­year, respectively (table 2). Hyperglycemia Three (2.7%) of the 112 included patients experienced Hyperglycemia and hypoglycemia subanalyses symptoms of hyperglycemia during their hospitalization. When hypoglycemia was analyzed according to insulin-­naïve In addition, 5 (5.4%) of the 93 patients with data avail- versus previous basal insulin use, no significant differences able at month 6 reported having experienced hypergly- were found in hypoglycemia incidence during hospitaliza- cemia symptoms after discharge. tion or after discharge. With regard to hypoglycemia rates during hospitalization, there was a higher risk of asymp- Anytime hypoglycemia tomatic hypoglycemia in insulin-­ naïve patients (RR=2.32, Twenty-­eight (25.0%) patients exhibited ≥1 confirmed 95% CI 1.08 to 5.42, p=0.029) and symptomatic hypogly- or severe hypoglycemia during hospitalization and 55 cemia in those with previous basal insulin (RR=0.23, 95% CI (59.1%) within the 6-­ month postdischarge follow-­ up, 0.04 to 0.86, p=0.025). After hospital discharge, patients mostly asymptomatic (table 2). The rate of confirmed with previous basal insulin also showed a higher risk of or severe hypoglycemia 6 months postdischarge was 9.2 confirmed or severe hypoglycemia (RR=0.48, 95% CI 0.39 to episodes/person-­year (table 2). Only one was reported as 0.59, p<0.001) and asymptomatic hypoglycemia (RR=0.48, a serious adverse event. 95% CI 0.37 to 0.60, p<0.001) rates. Subanalyses according Only one confirmed or severe hypoglycemia (according to age showed that patients aged ≥75 years had a higher risk to ADA guidelines) was reported as a serious adverse event of confirmed or severe hypoglycemia incidence (OR=0.29, (ie, an adverse event that met at least one of the following 95% CI 0.11 to 0.78, p=0.008) during hospitalization, without conditions: resulted in death, was life-­threating, required significant differences after discharge. With regard to hypo- inpatient hospitalization or caused prolongation of glycemia rates, there was a higher risk of confirmed or severe existing hospitalization, resulted in persistent or signifi- hypoglycemia (RR 0.26, 95% CI 0.14 to 0.47, p<0.001) and cant disability/incapacity, caused a congenital anomaly/ asymptomatic hypoglycemia (RR=0.33, 95% CI 0.15 to birth defect, and/or prolonged an existing hospitaliza- 0.69, p=0.002) during hospitalization in patients aged ≥75 tion, was considered an important medical event or was a years. A higher risk of asymptomatic hypoglycemia rate was suspected transmission of an infectious agent). also evidenced in patients aged ≥75 years after discharge (RR=0.72, 95% CI 0.58 to 0.89, p=0.003). Nocturnal hypoglycemia Rehospitalizations and visits to emergency rooms Two (1.8%) patients reported nocturnal hypogly- Forty-­five (40.2%) patients reported 64 visits to emergency cemia during hospitalization and another (1.1%) after rooms and 46 rehospitalizations. The main reasons for emer- discharge (table 2). The rate of nocturnal hypoglycemia gency room visits (frequency ≥5%) were acute complications during the 6 months postdischarge was 0.5 episodes/ (n=15, 23.4%) and acute bronchitis (n=7, 10.9%); only one person-­year (table 2). (1.6%) was related to hypoglycemia. The main reasons for BMJ Open Diab Res Care 2020;8:e001518. doi:10.1136/bmjdrc-2020-001518 5 Clinical care/Education/Nutrition Table 3 DTSQ scores (N=91) n (%) Item 0 1 2 3 4 5 6 Mean±SD Satisfaction with current 0 (0.0) 1 (1.1) 0 (0.0) 5 (5.5) 11 (12.1) 18 (19.8) 56 (61.5) 5.3±1.0 treatment Perceived frequency of 27 (29.7) 22 (24.2) 16 (17.6) 8 (8.8) 10 (11.0) 5 (5.5) 3 (3.3) 1.8±1.7 hyperglycemia Perceived frequency of 32 (35.2) 28 (30.8) 12 (13.2) 8 (8.8) 6 (6.6) 5 (5.5) 0 (0.0) 1.4±1.5 hypoglycemia Treatment convenience 0 (0.0) 0 (0.0) 2 (2.2) 4 (4.4) 17 (18.7) 25 (27.5) 43 (47.3) 5.1±1.0 Treatment flexibility 1 (1.1) 2 (2.2) 3 (3.3) 10 (11.0) 19 (20.9) 28 (30.8) 28 (30.8) 4.6±1.3 Satisfaction with diabetes 0 (0.0) 0 (0.0) 1 (1.1) 15 (16.5) 11 (12.1) 26 (28.6) 38 (41.8) 4.9±1.1 understanding Recommendation of this 0 (0.0) 0 (0.0) 0 (0.0) 5 (5.5) 4 (4.4) 24 (26.4) 58 (63.7) 5.5±0.8 treatment Satisfaction with continuing 0 (0.0) 0 (0.0) 0 (0.0) 5 (5.5) 6 (6.6) 21 (23.1) 59 (64.8) 5.5±0.8 this treatment Total score 31.0±4.5 DTSQ score 0–36, higher scores reflecting higher satisfaction. DTSQ, Diabetes Treatment Satisfaction Questionnaire. rehospitalization (frequency ≥5%) were cardiovascular The DTSQ covers eight items with regard to the diabetes disease (n=16, 34.8%) and infection (n=10, 21.7%); no treatment over the past weeks and measures overall satis- rehospitalization was associated with treatment. faction, convenience, flexibility, understanding of diabetes, Subanalyses according to insulin-­naïve versus previous willingness to recommend current treatment to others and basal insulin use and age <75 vs ≥75 years showed no willingness to continue the current treatment. Each item is significant differences (data not shown). rated on a 7-­point Likert scale with a score ranging from 0 (ie, very dissatisfied) to 6 (ie, very satisfied). DTSQ items 2 and Adverse events 3 assess glycemic control rather than satisfaction (perceived Eighty-­four (75.0%) patients reported 286 adverse events, hyperglycemia and perceived hypoglycemia). These items with urinary tract infections and hypoglycemia being the are rated differently: 0 reflects ‘never’ and 6 reflects ‘most of most frequent (online supplementary table 6). Adverse the time’. All scores, except those from DTSQ items 2 and 3, events were serious in 37 (33.0%) patients, led to treatment are added up to produce a DTSQ total score (range 0–36). discontinuation in 10 (8.9%) and were fatal in 8 (7.1%). Higher scores on the DTSQ total score indicate higher treat- Subanalyses according to insulin-­ naïve versus previous ment satisfaction, and lower scores indicate lower treatment basal insulin use and age <75 vs ≥75 years showed no signifi- satisfaction. cant differences in the number of adverse events per patient, action taken, resolution and relationship with Gla-300 (data not shown). DISCUSSION Patient-reported outcomes This study assessed the efficacy and safety of insulin Ninety-­one patients completed the DTSQ at month 6 post- Gla-300 during hospitalization and therapy intensification discharge (table 3). Patient responses showed a low percep- at discharge in people with type 2 diabetes insufficiently tion of hyperglycemia/hypoglycemia and high satisfaction controlled with basal insulin and/or non-­insulin antidiabetic regarding the different items of the questionnaire (total drugs. It was mostly conducted in general internal medicine score, 31.0±4.5). wards, which have a relevant role in diabetes management Similar results were observed when data were analyzed and often includes more clinically compromised patients,31 according to insulin-­naïve versus previous basal insulin use and demonstrated that using basal–bolus regimens with and age <75 vs ≥75 years (online supplementary table 7). Gla-300 as basal insulin is effective during the hospital stay. Significant differences were only evidenced when comparing The study results also indicate that restarting oral agents mean scores of satisfaction with continuing treatment and in combination with 80% of hospital daily insulin dose diabetes understanding, showing higher satisfaction with as Gla-300 at discharge is an effective strategy for therapy continuing treatment in patients with previous basal insulin intensification when admission HbA1c ranges between 8% (5.7±0.6 vs 5.2±1.0, p=0.011) and with diabetes under- and 10% (1.6% HbA1c reduction at months 3 and 6 post- standing in those aged <75 years (5.1±1.1 vs 4.7±1.1, p=0.044) discharge). These findings support using Gla-300 for type 2 (data not shown). diabetes management of inpatients and offer an algorithm 6 BMJ Open Diab Res Care 2020;8:e001518. doi:10.1136/bmjdrc-2020-001518 Clinical care/Education/Nutrition to guide discharge therapy in those insufficiently controlled therapy with basal insulin and/or non-­insulin antidia- with basal insulin and/or non-­insulin antidiabetic drugs. betic drugs and used a more ambitious approach to calcu- Insulin therapy is the most appropriate method for late initial Gla-300 dose than previous studies focused on controlling glycemia in the hospital, but its higher risk hospital discharge, in which the initial dose was generally of hypoglycemia is a barrier to achieving glycemic goals. estimated as 50%–80% of the baseline dose during hospi- Basal–bolus insulin regimen with reduction or withdrawal talization.6 11 12 In patients with oral agents with/without of boluses in people who are not eating regularly is the insulin prior to admission who were discharged with oral preferred method for achieving and maintaining glucose agents plus basal insulin Gla-100, Umpierrez et al11 calcu- control in non-­ critically ill inpatients.6 8 32–36 Because of lated glargine doses at discharge as 50% of total hospital their flatter pharmacodynamic profile (a much lower peak daily insulin dose during hospitalization when admis- of action and prolonged duration), once-­daily administra- sion HbA1c was 7%–9% and 80% when it was >9%. They tion and lower perceived hypoglycemia risk (particularly observed an HbA1c reduction from 9.2% to 7.5% 12 nocturnal hypoglycemia),37 neutral protamine Hagedorn weeks after discharge and ≥1 episode of hypoglycemia in insulin has been largely supplanted by basal insulin Gla-100. 30% of patients. Our strategy improved HbA1c by 1.6% Gla-300 is a second-­ generation basal insulin analog with with an acceptable rate of hypoglycemia, an adequate prolonged pharmacokinetic and pharmacodynamic profiles safety profile and high treatment satisfaction during the compared with Gla-100,15 allowing more flexible once-­daily 6-­month study period. The rate of overall hypoglycemia injections,16 and similar glycemic control with less hypogly- (9.2 episodes/person-­year) observed in our study is lower cemic events and weight gain than Gla-100.17–23 However, than the incidence rates (18.8 events/person-­years) of information on Gla-300 administration in the hospital setting symptomatic hypoglycemia reported in patients treated is limited to a small study.38 In our study, the Gla-300 basal– with insulin in the Hypos-1 Study48 and within the range bolus regimen resulted in a reduction in blood glucose from (0.286–16.4 episodes/patient-­year) of people with type admission to discharge with an incidence of hypoglycemia 2 diabetes receiving basal–oral regimens in random- of 25%, which are in the range (1% and 42%) observed in ized controlled trials.49 The event rate of hypoglycemia other studies conducted in non-­critical patients, depending was also similar to the BRIGHT trial with Gla-300 and on the objectives of glycemic control, treatment received insulin degludec-100 (9.3 and 10.8 events/patient-­year, and hypoglycemia definition.6 32 33 36 39–41 There were few respectively) in insulin-­naïve patients with uncontrolled events of severe hypoglycemia (4 of 112 patients), and only long-­standing type 2 diabetes on multiple oral antihy- 2 (1.8%) patients presented nocturnal hypoglycemia during perglycemic drugs and similar diabetes duration and hospitalization. This low frequency of nocturnal hypogly- HbA1c.50 In addition, the lower risk of hypoglycemia cemia was also observed in a small study with Gla-300 versus evidenced in our study in insulin-­naïve patients versus Gla-100.38 Previous studies in the outpatient setting with previous basal insulin users agree with the hypoglycemia large sample sizes have also shown that the risk of hypogly- rates evidenced in the EDITION 3 and EDITION 2 trials cemia, particularly nocturnal, is lower with Gla-300 than in insulin-­naïve patients (6.4 episodes/patient-­year) and Gla-100.17–19 42 43 Therefore, the Gla-300 basal-­bolus regimen previous basal insulin users (11.6 episodes/patient-­year) improves glycemic status, with low frequency of hypergly- receiving Gla-300, respectively.17 30 Finally, the 6-­month cemia and nocturnal hypoglycemia in adult inpatients with persistence of discharge insulin dose, absence of rehos- type 2 diabetes. These benefits were achieved regardless of pitalizations associated with treatment, low perception of previous basal insulin treatment and age, with a manageable hyperglycemia/hypoglycemia and high-­ treatment satis- safety profile even in more fragile patients as those aged >75 faction reinforce the effectiveness of this approach to years. calculate initial Gla-300 dose. Hospital admission can be an useful time to intensify We acknowledge that the study has certain limita- antidiabetic treatment at discharge and improve long-­ tions that should be considered when interpreting its term glycemic control in people with diabetes, but this is a findings, including the lack of a control group and its clearly deficient area and clinical inertia is a major factor open-­label nature. However, this study provides valuable that contributes to inadequate management at the time information on the inpatient and postdischarge type 2 of hospital discharge.44–46 Evaluating the best strategies to diabetes management that warrant further assessment in establish treatment at discharge may help to ensure a safe controlled trials and observational studies. Our post hoc and effective transfer to the community. According to the analyses also includes relevant data in people aged >75 ADA/EASD consensus, basal insulin may be considered years and in both insulin-­naïve and insulin-­experienced an alternative to add-­on therapy in patients insufficiently people. controlled with dual non-­insulin therapy13 14 and adding In conclusion, the use of Gla-300 during hospitaliza- basal insulin is the most frequent change in treatment tion and therapy intensification at discharge in hospital- from admission to discharge in patients with uncon- ized adults with type 2 diabetes insufficiently controlled trolled diabetes.6 11 12 47 with basal insulin and/or non-­insulin antidiabetic drugs In the present study, we focused on a subgroup of significantly improved their glycemic status, reaching people with type 2 diabetes with poor control (HbA1c HbA1c levels close to 7% with an adequate safety profile 8%–10%) after ≥3 months of unchanged antidiabetic and a high treatment satisfaction. Gla-300 could therefore BMJ Open Diab Res Care 2020;8:e001518. doi:10.1136/bmjdrc-2020-001518 7 Clinical care/Education/Nutrition be considered a treatment choice for inpatient and post- Málaga, Málaga, Spain); Ana María Gómez (Hospital Quironsalud Málaga, Málaga, discharge diabetes management. Further studies are Spain); Rosario Fernández (Hospital Quironsalud Málaga, Málaga, Spain); Isabel Cornejo (Hospital Quironsalud Málaga, Málaga, Spain); Analía Emilce Ramos needed to confirm the effects of this algorithm of treat- (Hospital de la Santa Creu i Sant Pau, Barcelona, Spain); Pedro Gil (Hospital de la ment for clinical practice. Santa Creu i Sant Pau, Barcelona, Spain). Contributors AP contributed to the study design, conduct/data collection, analysis Author affiliations and writing of the manuscript. FJC-­S, JE and RGH contributed to the study design, 1 Department of Endocrinology and Nutrition, Hospital de la Santa Creu i Sant Pau, conduct/data collection and writing of the manuscript. MB contributed to the study CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Universitat design, analysis and writing the manuscript. The remaining authors contributed to Autònoma de Barcelona, Barcelona, Spain the conduct of the study/data collection and writing of the manuscript. All authors 2 Department of Internal Medicine, Hospital Universitario Juan Ramón Jiménez, gave final approval of the version to be published, participated sufficiently in Huelva, Spain the work to take public responsibility for appropriate portions of the content and 3 Department of Internal Medicine, Hospital Universitario 12 de Octubre, Madrid, agreed to be accountable for all aspect of the work in ensuring that questions Spain related to the accuracy or integrity of any part of the work are appropriately 4 Department of Internal Medicine, Hospital Universitario San Joan d’Alacant, Sant investigated and resolved. Joan d'Alacant, Spain Funding Financial support for the present study was provided by Sanofi, which 5 Department of Internal Medicine, Hospital Universitario de La Ribera, Alzira, Spain was involved in the study design; in the collection, analysis and interpretation of 6 Department of Internal Medicine, Hospital Marina Baixa, Villajoyosa, Spain the data; in the writing of the report; and in the decision to submit the paper for 7 Medical Department, Sanofi, Barcelona, Spain publication. Medical writing support was provided by Esther Álvarez-­García and 8 Department of Internal Medicine, Hospital Regional Universitario de Málaga, Antonio Torres-­Ruiz at Dynamic Science S.L. during the preparation of this paper, Málaga, Instituto de Investigación Biomédica de Málaga, Universidad de Málaga; funded by Sanofi. CIBER Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Competing interests This work was funded by Sanofi. MB is employed by and Carlos III, Madrid, Spain has ownership interest in Sanofi. AP has received personal consulting fees and/or speaker honoraria or travel expenses from Sanofi Aventis, Almirall, Novo Nordisk, Presented at Eli Lilly, MSD, Boehringer Ingelheim, Esteve, Novartis, Amgen, Menarini, and Astra This study was presented at the 38th Spanish Society of Internal Medicine (SEMI) Zeneca. The remaining authors have no conflict of interest to disclose. Congress (22–24 November 2017; Madrid, Spain); the XXIX Spanish Society of Diabetes (SED) Congress (18–20 April 2018; Oviedo, Spain); the XXXIX SEMI Patient consent for publication Not required. Congress (21–23 November 2018; Burgos, Spain); the XXX SED Congress (24–26 Ethics approval This study was approved by the ethics committee of the Hospital April 2019; Seville, Spain); and the XXXX SEMI Congress (27–29 November 2019; de la Santa Creu i Sant Pau (Barcelona, Spain; 15/320 (R)), and all patients gave their Barcelona, Spain). written informed consent. Provenance and peer review Not commissioned; externally peer reviewed. Collaborators The following investigators of the COBALTA study group also Data availability statement All data relevant to the study are included in the collaborated in the study: Raquel Díaz (Hospital Universitario 12 Octubre, Madrid, Spain); Antonio Lalueza (Hospital Universitario 12 Octubre, Madrid, Spain); María article or uploaded as supplementary information. Qualified researchers may Soto (Hospital Universitario Juan Ramón Jiménez, Huelva, Spain); Mariano request access to patient-­level data and related study documents, including the Aguayo (Hospital Universitario Juan Ramón Jiménez, Huelva, Spain); Juana clinical study report, study protocol with any amendments, blank case report García (Hospital Universitario Juan Ramón Jiménez, Huelva, Spain); Silvia Herrojo form, statistical analysis plan, and dataset specifications. Patient-­level data will be (Hospital Universitario Juan Ramón Jiménez, Huelva, Spain); María Ángeles anonymized, and study documents will be redacted to protect the privacy of trial García (Hospital Universitario Juan Ramón Jiménez, Huelva, Spain); Alicia Hidalgo participants. Further details on Sanofi’s data sharing criteria, eligible studies, and (Hospital Universitario Juan Ramón Jiménez, Huelva, Spain); Esther Ortiz (Hospital process for requesting access can be found online (https://www.​clin​ical​stud​ydat​ Universitario Juan Ramón Jiménez, Huelva, Spain); Anabel Ostos (Hospital arequest.​com). Universitario Juan Ramón Jiménez, Huelva, Spain); Inmaculada Páez (Hospital Open access This is an open access article distributed in accordance with the Universitario Juan Ramón Jiménez, Huelva, Spain); Patricia Platero (Hospital Creative Commons Attribution Non Commercial (CC BY-­NC 4.0) license, which Universitario de La Ribera, Alzira, Spain); Andrea Pérez (Hospital Universitario permits others to distribute, remix, adapt, build upon this work non-­commercially, de La Ribera, Alzira, Spain); José Luis Díaz (Hospital Abente y Lago, A Coruña, and license their derivative works on different terms, provided the original work is Spain); Sonia Ruanova (Hospital Abente y Lago, A Coruña, Spain); Patricia Vázquez properly cited, appropriate credit is given, any changes made indicated, and the (Hospital Abente y Lago, A Coruña, Spain); María Dolores López (Hospital Regional use is non-­commercial. See: http://​creativecommons.​org/​licenses/​by-​nc/​4.​0/. Universitario de Málaga, Málaga, Spain); Sergio Jesús Jansen (Hospital Regional Universitario de Málaga, Málaga, Spain); María Guil (Hospital Regional Universitario ORCID iDs de Málaga, Málaga, Spain); Miguel Marcos (Hospital Universitario de Salamanca, Antonio Perez http://​orcid.​org/​0000-​0001-​5528-​1143 Salamanca, Spain); Antonio Javier Chamorro (Hospital Universitario de Salamanca, Francisco Javier Carrasco-­Sánchez http://​orcid.​org/​0000-​0002-​9275-​7056 Salamanca, Spain); Silvio Ragozzino (Hospital Universitario de Salamanca, José Miguel Seguí-Ripoll http://​orcid.​org/​0000-​0002-​3574-​3619 Salamanca, Spain); Hugo Ternavasio (Hospital Universitario de Salamanca, Javier Ena http://​orcid.​org/​0000-​0002-​1181-​7396 Salamanca, Spain); Cristina Carbonell Muñoz (Hospital Universitario de Salamanca, Mireia Borrell http://​orcid.​org/​0000-​0002-​1309-​147X Salamanca, Spain); Domingo Acosta (Hospital Universitario Virgen del Rocío, Seville, Spain); Antonio Jesús Martínez (Hospital Universitario Virgen del Rocío, Seville, Spain); Fermín Javier Jiménez (Complejo Hospitalario de Navarra, Pamplona, REFERENCES 1 Wesorick D, O'Malley C, Rushakoff R, et al. Management of diabetes Spain); Vanesa Antoñana (Complejo Hospitalario de Navarra, Pamplona, Spain); and hyperglycemia in the hospital: a practical guide to subcutaneous Judith Poblet (Complejo Hospitalario de Navarra, Pamplona, Spain); Lander Badiola insulin use in the non-­critically ill, adult patient. J Hosp Med (Complejo Hospitalario de Navarra, Pamplona, Spain); David Pérez (Complejo 2008;3:17–28. Hospitalario de Navarra, Pamplona, Spain); Leire Huete (Complejo Hospitalario 2 Moghissi ES, Korytkowski MT, DiNardo M, et al. American de Navarra, Pamplona, Spain); Cristóbal Morales (Hospital Universitario Virgen association of clinical endocrinologists and American diabetes de la Macarena, Seville, Spain); Mariola Méndez (Hospital Universitario Virgen association consensus statement on inpatient glycemic control. de la Macarena, Seville, Spain); Ignacio Jiménez (Hospital Universitario Virgen Diabetes Care 2009;32:1119–31. de la Macarena, Seville, Spain); Miriam Romero (Hospital Universitario Virgen de 3 Umpierrez GE, Hellman R, Korytkowski MT, et al. Management of hyperglycemia in hospitalized patients in non-­critical care setting: la Macarena, Seville, Spain); María Riestra (Hospital de Cabueñes, Gijón, Spain); an endocrine Society clinical practice guideline. J Clin Endocrinol Joaquín Morís (Hospital de Cabueñes, Gijón, Spain); Mercedes Cadenas (Hospital Metab 2012;97:16–38. de Cabueñes, Gijón, Spain); Florentino Casal (Hospital de Cabueñes, Gijón, Spain); 4 Pérez Pérez A, Conthe Gutiérrez P, Aguilar Diosdado M, Brenda Veiguela (Hospital de Cabueñes, Gijón, Spain); Joaquín Antón (Hospital San et al. [Hospital management of hyperglycemia]. Med Clin Pedro de Alcántara, Cáceres, Spain); José Manuel García (Hospital Quironsalud 2009;132:465–75. 8 BMJ Open Diab Res Care 2020;8:e001518. doi:10.1136/bmjdrc-2020-001518 Clinical care/Education/Nutrition 5 María María MA, Ramos A, Martínez Roldán MJ, et al. 25 Khunti K, Millar-­Jones D. Clinical inertia to insulin initiation and Implementation of an inpatient hyperglycemia management intensification in the UK: a focused literature review. Prim Care program incorporating a nurse consultant. Endocrinol Diabetes Nutr Diabetes 2017;11:3–12. 2020;67:461–8. 26 Khunti K, Nikolajsen A, Thorsted BL, et al. Clinical inertia with regard 6 Pérez A, Reales P, Barahona MJ, et al. Efficacy and feasibility to intensifying therapy in people with type 2 diabetes treated with of basal-­bolus insulin regimens and a discharge-­strategy in basal insulin. Diabetes Obes Metab 2016;18:401–9. hospitalised patients with type 2 diabetes--the HOSMIDIA study. Int 27 Mata-­Cases M, Franch-­Nadal J, Real J, et al. Therapeutic inertia J Clin Pract 2014;68:1264–71. in patients treated with two or more antidiabetics in primary care: 7 Pérez A, Ramos A, Carreras G. Insulin therapy in hospitalized factors predicting intensification of treatment. Diabetes Obes Metab patients. American Journal of Therapeutics 2019. 2018;20:103–12. 8 American Diabetes Association. 15. Diabetes Care in the Hospital: 28 Bradley C, Lewis KS. Measures of psychological well-­being and Standards of Medical Care in Diabetes-2019. Diabetes Care treatment satisfaction developed from the responses of people with 2019;42:S173–81. tablet-­treated diabetes. Diabet Med 1990;7:445–51. 9 Spanakis EK, Umpierrez GE, Siddiqui T, et al. Association of 29 Felici A, Plowright R, Wilson A, et al. Diabetes treatment satisfaction glucose concentrations at hospital discharge with readmissions questionnaire (DTSQ) for Spain and Latin America: are multiple and mortality: a nationwide cohort study. J Clin Endocrinol Metab language versions really necessary? Patient Reported Outcomes 2019;104:3679–91. Newsletter 2011;45:19. 10 Perez Perez A, Gomez Huelgas R, Alvarez Guisasola F, et al. 30 Bolli GB, Riddle MC, Bergenstal RM, et al. New insulin glargine [Consensus document on the management after hospital discharge 300 U/ml compared with glargine 100 U/ml in insulin-­naïve people of patient with hyperglycaemia]. Med Clin 2012;138:666 e1–6. with type 2 diabetes on oral glucose-­lowering drugs: a randomized 11 Umpierrez GE, Reyes D, Smiley D, et al. Hospital discharge controlled trial (edition 3). Diabetes Obes Metab 2015;17:386–94. algorithm based on admission HbA1c for the management of 31 Zapatero-­Gaviria A, Gómez-­Huelgas R, Canora-­Lebrato J, et al. patients with type 2 diabetes. Diabetes Care 2014;37:2934–9. Analysis of hospitalizations by cardiovascular disease in the 12 Pérez A, Ramos A, Reales P, et al. Indicator performance after the population with diabetes in Spain. Rev Clin Esp 2019;219:124–9. implementation of the Spanish consensus document for the control 32 Umpierrez GE, Smiley D, Jacobs S, et al. Randomized study of of hyperglycemia in the hospital and at discharge. Rev Clin Esp basal-­bolus insulin therapy in the inpatient management of patients 2019;219:18–25. with type 2 diabetes undergoing general surgery (rabbit 2 surgery). 13 Davies MJ, D'Alessio DA, Fradkin J, et al. Management of Diabetes Care 2011;34:256–61. hyperglycaemia in type 2 diabetes, 2018. A consensus report 33 Umpierrez GE, Smiley D, Zisman A, et al. Randomized study of by the American diabetes association (ADA) and the European basal-­bolus insulin therapy in the inpatient management of patients association for the study of diabetes (EASD). Diabetologia with type 2 diabetes (rabbit 2 trial). Diabetes Care 2007;30:2181–6. 2018;61:2461–98. 34 Bellido V, Suarez L, Rodriguez MG, et al. Comparison of Basal-­Bolus 14 Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of and premixed insulin regimens in hospitalized patients with type 2 hyperglycemia in type 2 diabetes, 2015: a patient-­centered diabetes. Diabetes Care 2015;38:2211–6. approach: update to a position statement of the American diabetes 35 Umpierrez GE, Hor T, Smiley D, et al. Comparison of inpatient association and the European association for the study of diabetes. insulin regimens with detemir plus aspart versus neutral protamine Diabetes Care 2015;38:140–9. Hagedorn plus regular in medical patients with type 2 diabetes. J 15 Becker RHA, Dahmen R, Bergmann K, et al. New insulin glargine Clin Endocrinol Metab 2009;94:564–9. 300 units · mL-1 provides a more even activity profile and prolonged 36 Umpierrez GE, Smiley D, Hermayer K, et al. Randomized study glycemic control at steady state compared with insulin glargine 100 comparing a Basal-­bolus with a basal plus correction insulin regimen units · mL-1. Diabetes Care 2015;38:637–43. for the hospital management of medical and surgical patients with 16 Riddle MC, Bolli GB, Home PD, et al. Efficacy and Safety of Flexible type 2 diabetes: basal plus trial. Diabetes Care 2013;36:2169–74. Versus Fixed Dosing Intervals of Insulin Glargine 300 U/mL in People 37 Pieber TR, Eugène-­Jolchine I, Derobert E. Efficacy and safety of with Type 2 Diabetes. Diabetes Technol Ther 2016;18:252–7. HOE 901 versus NPH insulin in patients with type 1 diabetes. The 17 Yki-­Järvinen H, Bergenstal RM, Bolli GB, et al. Glycaemic control European Study group of HOE 901 in type 1 diabetes. Diabetes Care and hypoglycaemia with new insulin glargine 300 U/ml versus 2000;23:157–62. insulin glargine 100 U/ml in people with type 2 diabetes using basal 38 Okajima F, Nakamura Y, Yamaguchi Y, et al. Basal-­bolus insulin insulin and oral antihyperglycaemic drugs: the edition 2 randomized therapy with Gla-300 during hospitalization reduces nocturnal 12-­month trial including 6-­month extension. Diabetes Obes Metab hypoglycemia in patients with type 2 diabetes mellitus: a randomized 2015;17:1142–9. controlled study. Diabetes Ther 2018;9:1049–59. 18 Riddle MC, Yki-­Järvinen H, Bolli GB, et al. One-­Year sustained 39 Christensen MB, Gotfredsen A, Nørgaard K. Efficacy of basal-­bolus glycaemic control and less hypoglycaemia with new insulin insulin regimens in the inpatient management of non-­critically glargine 300 U/ml compared with 100 U/ml in people with type 2 ill patients with type 2 diabetes: a systematic review and meta-­ diabetes using basal plus meal-­time insulin: the edition 1 12-­month analysis. Diabetes Metab Res Rev 2017;33. doi:10.1002/dmrr.2885 randomized trial, including 6-­month extension. Diabetes Obes Metab 40 Cook CB, Kongable GL, Potter DJ, et al. Inpatient glucose control: a 2015;17:835–42. glycemic survey of 126 U.S. hospitals. J Hosp Med 2009;4:E7–14. 19 Bolli GB, Riddle MC, Bergenstal RM, et al. Glycaemic control 41 Suzuki J, Yamakawa T, Oba M, et al. Efficacy and safety of insulin and hypoglycaemia with insulin glargine 300U/mL versus insulin degludec u100 and insulin glargine u100 in combination with meal-­ glargine 100U/mL in insulin-­naïve people with type 2 diabetes: time bolus insulin in hospitalized patients with type 2 diabetes: an 12-­month results from the EDITION 3 trial. Diabetes Metab open-­label, randomized controlled study. Endocr J 2019;66:971–82. 2017;43:351–8. 42 Riddle MC, Bolli GB, Ziemen M, et al. New insulin glargine 300 units/ 20 Ritzel R, Roussel R, Giaccari A, et al. Better glycaemic control and mL versus Glargine 100 units/mL in people with type 2 diabetes less hypoglycaemia with insulin glargine 300 U/mL vs glargine using basal and mealtime insulin: glucose control and hypoglycemia 100 U/mL: 1-­year patient-­level meta-­analysis of the edition clinical in a 6-­month randomized controlled trial (edition 1). Diabetes Care studies in people with type 2 diabetes. Diabetes Obes Metab 2014;37:2755–62. 2018;20:541–8. 43 Yki-­Järvinen H, Bergenstal R, Ziemen M, et al. New insulin glargine 21 Terauchi Y, Koyama M, Cheng X, et al. Glycaemic control and 300 units/mL versus Glargine 100 units/mL in people with type 2 hypoglycaemia with insulin glargine 300 U/mL compared with diabetes using oral agents and basal insulin: glucose control and glargine 100 U/mL in Japanese adults with type 2 diabetes using hypoglycemia in a 6-­month randomized controlled trial (edition 2). basal insulin plus oral anti-­hyperglycaemic drugs (edition JP 2 Diabetes Care 2014;37:3235–43. randomised 12-­month trial including 6-­month extension). Diabetes 44 Lipska KJ, Wang Y, Kosiborod M, et al. Discontinuation of Metab 2017;43:446–52. antihyperglycemic therapy and clinical outcomes after acute 22 Zhou FL, Ye F, Berhanu P, et al. Real-­World evidence concerning myocardial infarction in older patients with diabetes. Circ Cardiovasc clinical and economic outcomes of switching to insulin glargine 300 Qual Outcomes 2010;3:236–42. units/mL vs other basal insulins in patients with type 2 diabetes 45 Griffith ML, Boord JB, Eden SK, et al. Clinical inertia of discharge using basal insulin. Diabetes Obes Metab 2018;20:1293–7. planning among patients with poorly controlled diabetes mellitus. J 23 Bailey TS, Wu J, Zhou FL, et al. Switching to insulin glargine 300 Clin Endocrinol Metab 2012;97:2019–26. units/mL in real-­world older patients with type 2 diabetes (deliver 3). 46 Lovig KO, Horwitz L, Lipska K, et al. Discontinuation of Diabetes Obes Metab 2019;21:2384–93. antihyperglycemic therapy after acute myocardial infarction: 24 Kunt T, Snoek FJ. Barriers to insulin initiation and intensification and medical necessity or medical error? Jt Comm J Qual Patient Saf how to overcome them. Int J Clin Pract 2009;63:6–10. 2012;38:403–7. BMJ Open Diab Res Care 2020;8:e001518. doi:10.1136/bmjdrc-2020-001518 9 Clinical care/Education/Nutrition 47 Wexler DJ, Beauharnais CC, Regan S, et al. Impact of inpatient 49 Elliott L, Fidler C, Ditchfield A, et al. Hypoglycemia event rates: a diabetes management, education, and improved discharge transition comparison between real-­world data and randomized controlled trial on glycemic control 12 months after discharge. Diabetes Res Clin populations in insulin-­treated diabetes. Diabetes Ther 2016;7:45–60. 50 Rosenstock J, Cheng A, Ritzel R, et al. More similarities than Pract 2012;98:249–56. differences testing insulin glargine 300 Units/mL versus insulin 48 Giorda CB, Ozzello A, Gentile S, et al. Incidence and correlates of degludec 100 Units/mL in Insulin-­Naive type 2 diabetes: hypoglycemia in type 2 diabetes. The Hypos-1 Study. J Diabetes the randomized head-­to-­head bright trial. Diabetes Care Metab 2014;5:3. 2018;41:2147–54. 10 BMJ Open Diab Res Care 2020;8:e001518. doi:10.1136/bmjdrc-2020-001518