Received: 15 July 2019 Revised: 16 December 2019 Accepted: 18 December 2019 DOI: 10.1111/dom.13946 REVIEW ARTICLE The importance of the initial period of basal insulin titration in people with diabetes Kamlesh Khunti MD1 | Francesco Giorgino MD2 | Lori Berard3 | Didac Mauricio MD4,5 | Stewart B. Harris MD6 1 Diabetes Research Centre, University of Leicester, Leicester General Hospital, Abstract Leicester, UK Achieving target glycaemic control is essential in people with diabetes to minimize 2 University of Bari Aldo Moro, Department of the risk of long-term complications, and many people with type 2 diabetes will ulti- Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, mately require basal insulin (BI) therapy to achieve their individualized glycaemic tar- Andrology and Metabolic Diseases, Bari, Italy gets. Usually, the first 12 weeks following initiation of BI therapy represents the 3 Winnipeg Regional Health Authority, Health Sciences Centre, Winnipeg, Manitoba, Canada period when the greatest dose increases and glycaemic reductions occur. Effective 4 Institut Investigació Biomèdica Sant Pau, glycaemic control combined with minimizing the risk of hypoglycaemia is important Barcelona, Spain to enable the achievement of glycaemic control in the longer term. However, sub- 5 Department of Endocrinology and Nutrition, CIBER of Diabetes and Associated Metabolic stantial therapeutic inertia exists in clinical practice, both in initiation and up-titration Diseases, Hospital de la Santa Creu i Sant Pau, of BI, owing to patient-, physician- and healthcare system-related barriers, including Barcelona, Spain 6 fear of hypoglycaemia and the perception of a burdensome regimen. The more pro- The Schulich School of Medicine and Dentistry, Western University, London, longed duration of action, reduced glycaemic variability and lower risk of Ontario, Canada hypoglycaemia seen with second-generation versus first-generation BI analogues Correspondence may help alleviate patients’ and physicians’ concerns and facilitate titration. In turn, Kamlesh Khunti, Diabetes Research Centre, optimal BI titration and subsequent metabolic benefits may help improve therapy University of Leicester, Leicester General Hospital, Gwendolen Road, Leicester, LE5 adherence and self-management. This review details the clinical implications of 4PW, UK. prompt titration of BI to achieve early glycaemic control, and the importance of mini- Email: kk22@le.ac.uk mizing hypoglycaemia risk within the initial titration period. Facilitation of patients’ Funding information self-management of BI is also addressed. Sanofi Peer Review KEYWORDS The peer review history for this article is basal insulin, glycaemic control, hypoglycaemia, insulin analogues, insulin therapy available at https://publons.com/publon/10. 1111/dom.13946. 1 | I N T RO DU CT I O N 10-year post-trial follow-up of the UK Prospective Diabetes Study showed that early intensive glycaemic treatment (and initial greater Tight glycaemic control is essential in people with diabetes to pro- reductions in HbA1c) during the first year resulted in significant mote better clinical outcomes, particularly to reduce the incidence improvements in long-term clinical outcomes, including microvascular and progression of microvascular complications such as retinopathy disease, myocardial infarction and mortality.6 Additionally, a retrospec- 1-5 and nephropathy. The benefits of tight glycaemic control are par- tive analysis on data from the UK Clinical Practice Research Datalink on ticularly pronounced if control is achieved soon after the initiation patient records from people with type 2 diabetes (T2D) showed that a of antihyperglycaemic therapy, especially during the first year. A 1-year delay in antihyperglycaemic therapy intensification (either This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. © 2020 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd. 722 wileyonlinelibrary.com/journal/dom Diabetes Obes Metab. 2020;22:722–733. 14631326, 2020, 5, Downloaded from https://dom-pubs.pericles-prod.literatumonline.com/doi/10.1111/dom.13946 by Readcube (Labtiva Inc.), Wiley Online Library on [25/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License KHUNTI ET AL. 723 adding further oral antihyperglycaemic drugs [OADs] or insulin) was patient-, physician- and healthcare system-related barriers. These barriers associated with significantly increased risk of adverse cardiovascular include fear of hypoglycaemia (highlighted by the fact that 75.5% of physi- 7 outcomes (eg, myocardial infarction, heart failure and stroke). cians would treat more aggressively were it not for the risk of Despite this, real-world evidence has consistently shown that many hypoglycaemia with insulin16,17), weight gain, lack of healthcare provider people with T2D still have poor glycaemic control for prolonged periods time or resources, lack of perceived therapy efficacy, limited patient moti- of time.8 Clinical practice guidelines recommend therapy intensification vation, lack of experience in diabetes self-management, and the perception by the addition of basal insulin (BI) therapy in people with T2D inade- of burdensome or complex treatment regimens (Figure 1).15-18 The quately controlled with OADs and glucagon-like peptide-1 receptor ago- healthcare system-related issue of lack of resources and time for individual nists.9,10 Despite these recommendations, therapeutic inertia with insulin physicians may also make it difficult to determine optimal dose adjust- therapy is widespread. The Study of Once Daily Levemir (SOLVE) trial ments.15 Other system-level barriers, particularly in developing countries, showed that the majority of patients with T2D are poorly controlled at may include lack of access to appropriate therapies or reimbursement poli- the time of BI therapy initiation; regional differences were observed, but cies.19 Many of the barriers to optimal insulin titration also contribute to an the proportion of patients with HbA1c ≥9.0% when insulin therapy was increased probability of overall poor glycaemic control. initiated ranged from 23% to 64%.11 Even after BI initiation, attainment Historically, clinical practice guidelines have emphasized a step- of the general HbA1c target is often inadequate in clinical practice, with wise approach to antihyperglycaemic therapy. Recently, to reduce one large observational study of European and US people with T2D therapeutic inertia, the American Diabetes Association (ADA) and showing that 79.1% and 72.2% of people initiating insulin failed to joint ADA/European Association for the Study of Diabetes (EASD) achieve an HbA1c of ≤7.0% after 3 and 24 months, respectively.12 This consensus recommendations have suggested regular (every agrees with another European study in both insulin-naïve people initiat- 3–6 months) re-evaluation of antihyperglycaemic regimens, to ensure ing BI, or those previously treated who switched to a new BI, which that intensification of antihyperglycaemic regimens is considered in showed poor achievement of HbA1c <7.0% (53.6%) after 12 months.13 patients who are not achieving glycaemic targets.9,10 Other recom- Data from developing countries also show poor achievement of mendations to help alleviate therapeutic inertia and avoid suboptimal glycaemic targets, with 85.8% of people using insulin in combination with therapy include ongoing monitoring of metabolic variables and cardio- OADs showing inadequate glycaemic control.14 vascular risk factors (eg, HbA1c, self-monitoring of blood glucose, Therapeutic inertia of BI therapy includes initiation inertia (delayed ini- weight, blood pressure and lipids), self-management education tiation of BI), titration inertia (lack of BI dose adjustment) and intensification programmes, support for emotional well-being, and the use of regular inertia (delayed intensification of BI with additional antihyperglycaemic self-titration of BI with an evidence-based titration algorithm to drugs).15 Inertia in initiating and titrating BI probably reflects a number of achieve a fasting plasma glucose (FPG) target.9,10 Insulin titration can Depression/anxiety15 Fear of Limited weight gain15,18 motivation18 Severe psychological Lack of insulin resistance15 perceived efficacy18 Unaware of need Concerns about to titrate insulin18 impact on daily life15 Patient-related Burdensome treatment regimens15 Fear of hypoglycaemia15,18 HCP-related Poor System-related communication/ HCP reluctance to patient Lack of time/resources titrate aggressively15 engagement15 for education15 F I G U R E 1 Factors contributing to therapeutic inertia of insulin. HCP, healthcare professional 14631326, 2020, 5, Downloaded from https://dom-pubs.pericles-prod.literatumonline.com/doi/10.1111/dom.13946 by Readcube (Labtiva Inc.), Wiley Online Library on [25/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 724 KHUNTI ET AL. be facilitated using simplified and, ideally, patient-directed titration from the SOLVE study are also in agreement with these results, algorithms. The optimal titration algorithm should be simple to follow, showing that the greatest changes in insulin dose and the greatest effective, and should minimize the risk of hypoglycaemia, particularly HbA1c reductions occurred during the initial 12 weeks of BI therapy during the initial titration stage. with insulin detemir (IDet).22 This review details the clinical evidence for the benefits of titrating Although less frequent, insulin dose adjustments are still impor- BI to achieve early glycaemic control and minimizing hypoglycaemia tant after the titration period. During the maintenance period, which risk, with examples from both randomized controlled trials (RCTs) and may resemble day-to-day reality for most patients using BI therapy, real-world evidence studies of BI therapy. The importance of facilitating patients usually need to make slight adjustments to their insulin patients’ self-management of BI therapy to further improve adherence dose to maintain glycaemic targets while continuing to avoid and early glycaemic control attainment is also explored. hypoglycaemia. 2 | HOW IS THE TITRATION PERIOD 3 | THE CLINICAL I MPO R TANCE OF T HE DEFINED? TITRATION PERIOD RCTs of BI treatment are typically separated into two phases: (i) the As described previously, there is evidence suggesting that early initiation and titration phase, defined in many clinical trials as the first glycaemic control promotes improved glycaemic outcomes in the lon- 8–12 weeks of treatment; and (ii) the maintenance phase, where insu- ger term, and fewer vascular complications in people with diabetes,1-5 20 lin dose is more stable, with fewer adjustments required. Recent suggesting that prompt titration is important for people with T2D ini- guidelines recommend that once BI therapy is initiated (at 10 units tiating BI therapy. [U]/day or 0.1 to 0.2 U/kg/day), titration is performed every 3 days to One real-world study in insulin-naïve people with T2D newly ini- reach a suitable FPG target.10 tiating BI therapy showed that failure to achieve HbA1c ≤7% during In a pooled analysis of 15 treat-to-target studies of insulin the initial 3 months was associated with increased risk of failure to glargine 100 U/mL (Gla-100) initiation in insulin-naïve people with achieve glycaemic targets at 2 years (odds ratio, 3.70 [95% CI: diabetes, 89% of the overall increase in BI dose occurred in the first 3.41–4.00]).12 In addition, an observational study of electronic health 12 weeks (BI doses: at baseline, 0.16; at 12 weeks, 0.40; at record data showed that many previously insulin-naïve people with 21 24 weeks, 0.45 U/kg; Figure 2). In addition, most of the overall diabetes discontinue insulin shortly after initiation: 41% in the first improvements in HbA1c and FPG were achieved by week 12.21 Data month, 62% in the first 3 months and 82% in the first year.23 Similarly, 0.60 Insulin glargine + metformin Insulin glargine + sulphonylurea 0.55 Insulin glargine + metformin + sulphonylurea Pooled 0.50 0.45 0.40 Insulin dose (U/kg) 0.35 0.30 Baseline Week 12 Week 24 0.60 0.25 0.52 0.50 0.45 0.44 0.45 0.39 0.42 0.40 0.20 0.40 0.37 0.30 0.15 0.20 0.20 0.16 0.16 0.13 0.10 0.10 0.00 0.05 Metformin Sulphonylurea Metformin + Pooled sulphonylurea 0.00 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Week FIGURE 2 Insulin dose titration with insulin glargine. Figure reproduced from Owens DR, et al. Diab Res Clin Pract 2014;106:264–274 14631326, 2020, 5, Downloaded from https://dom-pubs.pericles-prod.literatumonline.com/doi/10.1111/dom.13946 by Readcube (Labtiva Inc.), Wiley Online Library on [25/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License KHUNTI ET AL. 725 another real-world study looking at data from the UK Clinical Practice conditions.28-30 As such, first-generation BI analogues helped to sim- Research Datalink database showed that, in people with T2D with plify treatment regimens, with once-daily dosing becoming possible inadequate HbA1c control (≥7.5%) while receiving BI treatment, dis- for a large proportion of patients.30 Additional benefits of first- 24 continuation of BI therapy was 32.1%. Only 30.9% of those individ- generation BI analogues include lower glycaemic variability and lower uals had their treatment intensified, and the median time to risk of hypoglycaemia compared with NPH insulin.30 intensification was 3.7 years.24 BI discontinuation is associated with Second-generation BI analogues, such as Gla-300 and IDeg, have increased acute care costs (hospitalization and emergency room visits) a more prolonged duration of action, flatter pharmacokinetic and and may be associated with poorer long-term outcomes.23 pharmacodynamic profiles, and a lower risk of hypoglycaemia com- While pursuing glycaemic targets in the early stages of treatment is pared with first-generation BIs.30,31 The prolonged duration of action important, it is also key to minimize the risk of hypoglycaemia to results in only once-daily dosing,30,31 which can help to alleviate the encourage treatment adherence, reduce hypoglycaemia in the long treatment burdens in people otherwise requiring more frequent dos- term, and reduce the risks of hypoglycaemia-associated morbidity and ing with older intermediate-acting insulins, such as NPH insulin, or mortality.12,16,25 In a retrospective study of over 55 000 insulin-naïve first-generation BIs, Gla-100 or IDet. individuals with T2D, ~ 5% experienced hypoglycaemia that required Fear of hypoglycaemia is also a key factor in titration inertia; the medical assistance during the first 6 months after starting BI therapy, lower risk of hypoglycaemia observed in clinical trials with second- and over 33% experienced a hypoglycaemic event in the first month generation BI analogues compared with first-generation BI analogues after initiation.16 Those who experienced hypoglycaemia within may help to alleviate such concerns during insulin initiation or titra- 6 months of initiating BI were more probable to discontinue therapy tion. Given that burden of treatment is a factor influencing within the first 12 months of treatment compared with those who did adherence,32 these second-generation BI analogues could help further 16 not (hazard ratio 1.16 [95% CI: 1.03–1.32]; P = 0.016). Although there improve patient adherence, although there are no studies that have were several limitations to the study, being a retrospective analysis of directly examined this relationship. US claims data, the authors highlighted that the presence of comparable results across several databases emphasized the trend for discontinua- tion being more probable among those who experienced 4.1 | Evidence from randomized controlled trials hypoglycaemia within 6 months of initiating BI therapy.16 Another observational real-world study in insulin-naïve people with T2D in The EDITION clinical trial programme compared Gla-300 with Gla- Europe and the USA showed that hypoglycaemia during the initial 100 in people with T2D using the same titration algorithm 3-month period after starting BI therapy was strongly associated with (Figure 3).33-35 While EDITION 1 (prior BI and mealtime insulin) and longer-term risk of these events between 3 months and 2 years (odds EDITION 2 (prior BI) included people with T2D who were already ratio: 5.71 [95% CI: 4.67–6.99]).12 Similar findings have also been receiving BI therapy and provided insights into the efficacy and safety reported in a post hoc analysis of the BRIGHT RCT, a 24-week, treat- of up-titration of BI in BI-switcher populations,33,34 EDITION 3 to-target study, which compared the two second-generation BI ana- included previously insulin-naïve individuals with T2D, and was repre- logues insulin glargine 300 U/mL (Gla-300) and insulin degludec (IDeg; sentative of BI initiation and titration.35 In EDITION 3, the mean 100 U/mL) in insulin-naïve people with T2D.26 Results showed that the change in HbA1c from baseline to month 6 and proportion of partici- incidence of anytime (24 hours) hypoglycaemic events within the main- pants reaching their target HbA1c or FPG at month 6 was similar tenance period (weeks 13–24) was lower for individuals who did not between the two treatment groups. Additionally, the percentage of experience hypoglycaemia within the initial 12-week titration period participants experiencing ≥1 nocturnal (00:00–05:59 hours) confirmed compared with those who did (38.2% vs. 75.4%).26 Additionally, an (≤3.9 mmol/L [≤70 mg/dL]) or severe hypoglycaemic event during the analysis of 16 RCTs of Gla-100 initiation showed that a higher risk of maintenance period (week 9 to month 6; main secondary efficacy hypoglycaemia during titration was associated with a continued higher endpoint) was similar in both groups (relative risk [RR] 0.89 [95% CI: risk of non-severe and severe hypoglycaemia for up to 6 months.27 0.66–1.20]). However, over the full 6-month treatment period, the incidence of nocturnal confirmed (≤3.9 mmol/L [≤70 mg/dL]) hypoglycaemia was significantly lower with Gla-300 versus Gla-100 4 | CAN NEWER BI ANALOGUES ASSIST (RR: 0.76 [95% CI: 0.59–0.99]). Furthermore, rates of anytime WI T H I N SU L I N TI T RA TI ON A N D TR E A TM E N T (24 hours) hypoglycaemia were significantly lower with Gla-300 ver- A D H E RE N C E ? sus Gla-100 over the full 6-month treatment period, particularly dur- ing the initial 8-week titration period.35 However, it should be noted First-generation BI analogues, such as Gla-100 and IDet, have a pro- that FPG at month 6 was higher and prebreakfast self-measured longed and more stable duration of action compared with previous plasma glucose (SMPG) decreased more gradually with Gla-300 versus intermediate-acting insulins, such as twice-daily neutral protamine Gla-100, which may indicate that while the insulin dose increase was Hagedorn (NPH) insulin, with Gla-100 (0.3 U/kg) showing glucose- greater with Gla-300 versus Gla-100 throughout the study, the lowering activity of up to 22 ± 4 hours and IDet (0.4 U/kg) possessing increase in circulating Gla-300 may still have been more gradual as a slightly shorter duration of 21.5 ± 3.3 hours under single-dose Gla-300 and Gla-100 are not bioequivalent.36 It may be relevant to 14631326, 2020, 5, Downloaded from https://dom-pubs.pericles-prod.literatumonline.com/doi/10.1111/dom.13946 by Readcube (Labtiva Inc.), Wiley Online Library on [25/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 726 KHUNTI ET AL. 11.8 200 10.8 Pre-breakfast SMPG (mmol/L) 9.8 Pre-breakfast SMPG (mg/dL) 8.8 150 7.8 6.8 5.8 100 4.8 3.8 50 2.8 * * s† ‡ † § ¶ e¶ ise‡ 2* –3 HT pt hys pt hys † pt ‡ HT pl R‡ 1 I G p hy – p – p – G m w C H I O N L I i N IO BR S – TU S – AS L – RO INS – S step WIT SE D IT TU N L A S ATL O NT S – S A R E AN AT.L AT NT CO vs S .L O S vs T C K E I N S A IN KE TA G BE EG TA B +8 U Target +6 U Not specified +6–8 U −2 U +4 U −3 U +3 U −4 U +2 U +1 U +0–2 U F I G U R E 3 Titration algorithms in randomized controlled trials of basal insulins. For the EDITION 1–3 studies, if a blood glucose (BG) of <3.3 mmol/L (<60 mg/dL) was recorded, the dose could be reduced by 3 units (U) or at the investigator's discretion. In BRIGHT, if a BG of <4.4 mmol/L (<80 mg/dL) was recorded, the dose could be reduced by either 2 U or at the investigator's discretion. In ATLAS, if a BG of ≤3.1 mmol/L (≤56 mg/dL) was recorded, the dose was reduced at the physician's discretion. In TAKE CONTROL, the dose was reduced by 3 U in both the physician-managed or self-managed titration groups if either a BG of <4.4 mmol/L (<80 mg/dL) or ≥2 symptomatic or 1 severe hypoglycaemic event(s) in the preceding week were recorded. In SENIOR, the dose was reduced by 3 U if either a BG of <5.0 mmol/L (<90 mg/ dL) or ≥2 symptomatic or 1 severe hypoglycaemic event(s) in the preceding week were recorded. Phys, physician-managed titration group; pt, patient-managed titration group; S vs. S, simple versus stepwise titration; SMPG, self-measured plasma glucose. *Doses were adjusted weekly; †doses were adjusted at every visit (AT.LANTUS: weekly during clinic visits or telephone contact visits; ATLAS: clinic visits at baseline, weeks 2, 6, 12, 16 and 24; telephone contact visits were made at weeks 1, 3, 4, 5, 8, 10 and 20; TAKE CONTROL: weekly for the first 8 weeks, biweekly until week 12, monthly until week 24); ‡doses were adjusted every 3 days; §doses were adjusted twice a week; ¶ doses were adjusted daily consider these results when interpreting the hypoglycaemia risk pro- hypoglycaemia observed with IDeg versus Gla-100 was not observed files of Gla-300 and Gla-100. Similar results to those described for during the titration period.37 It should be noted that the BEGIN RCTs EDITION 3 were observed in the EDITION 1 and 2 trials.33,34 adopted a very stringent FPG target of >4.0 to <5.0 mmol/L (>70 to A pooled meta-analysis that compared the efficacy and safety of <90 mg/dL),37 which is seldom used in adults with T2D in routine clin- IDeg versus Gla-100 across BEGIN RCTs, which included both insulin- ical practice, and this may have increased the risk of hypoglycaemia pretreated and insulin-naïve people with T2D, showed similar observed in these trials. glycaemic control with IDeg and Gla-100 and a lower risk of Results of the previously mentioned BRIGHT study showed simi- hypoglycaemia with IDeg versus Gla-100 during the overall study lar HbA1c reductions between Gla-300 and IDeg over 24 weeks and period (rate ratio: 0.83 [95% CI: 0.74–0.94]), particularly during the comparable incidence and rates of hypoglycaemia during the overall maintenance period (0.75 [0.66–0.87]).37 However, the lower risk of 24-week study period.38 There were, however, statistically 14631326, 2020, 5, Downloaded from https://dom-pubs.pericles-prod.literatumonline.com/doi/10.1111/dom.13946 by Readcube (Labtiva Inc.), Wiley Online Library on [25/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License KHUNTI ET AL. 727 significantly lower incidences and rates of anytime confirmed was limited in that it compared first-generation BI analogues, insulin (≤3.9 mmol/L [≤70 mg/dL] and <3.0 mmol/L [<54 mg/dL]) detemir or Gla-100, and utilized data from a time period preceding clini- hypoglycaemia and significantly lower rates of nocturnal confirmed cal use of Gla-300 (January 2006–December 2014).44 As such, the (≤3.9 mmol/L [≤70 mg/dL]) hypoglycaemia during the titration period impact of second-generation BIs Gla-300 and IDeg cannot be deter- (0–12 weeks) with Gla-300 versus IDeg.38 The lower hypoglycaemia mined from these data. The study also did not assess the proportion of risk appears not to reflect differences in glycaemic control, as HbA1c people in each treatment group who achieved their glycaemic target. reductions and target achievement (<7.0%) were similar between A second recent study assessed the clinical and economic impact treatment groups at week 12.39,40 However, as seen with EDITION of switching from insulin analogue treatment (unspecified basal or 3, mean change in FPG appeared to decrease more gradually with prandial insulin analogues and secretagogues) to human insulin (pre- Gla-300 than IDeg, and the impact this may have on hypoglycaemia mixed human 70/30 or NPH) in 14 635 older individuals (mean age: risk is unknown. 72.2 years) with diabetes, filling in a total of 221 866 prescriptions.45 As previously mentioned, a post hoc analysis of BRIGHT showed Results showed that the change in insulin use did not affect the rate that the incidence of participants who experienced hypoglycaemic of serious hypo- or hyperglycaemic events (defined by hospitalization events within the maintenance phase (weeks 13–24) was lower for or ED admissions) and was associated with a decrease in total cost of individuals who did not experience hypoglycaemia within the initial ~ $2 million per month at the end of the second year following imple- 12-week titration period compared with those who did (38.2% mentation of the intervention. Furthermore, while there was a small vs. 75.4%, respectively).26 However, HbA1c reductions during the but significant increase in HbA1c of 0.14% (95% CI: 0.05–0.23; titration period (baseline to week 12) were greater in the subgroup P = 0.003) within the first year of the intervention, mean HbA1c that experienced early hypoglycaemia (−1.46%) compared with those remained stable in the following year.45 who did not (−1.28%). A second trial comparing Gla-300 and IDeg has Results of these two studies suggest that while RCTs might show been completed (NCT03078478) and full results are expected to be lower hypoglycaemia risk and improved pharmacokinetic/pharmacody- published soon. However, this study required an important protocol namic profiles of long-acting insulins compared with intermediate- amendment to change the glucose meter used for titration; as such, acting insulins, such as NPH,30 these benefits may not translate to real- comparisons of the two second-generation BI analogues within the life clinical practice. Furthermore, the higher cost of long-acting BI ana- titration period are not possible.41,42 logues compared with human insulins may be an important factor to consider when selecting insulin therapies; for instance, one USA-based survey conducted in an urban diabetes centre indicated that 25% of 4.2 | Real-world evidence individuals with diabetes reported cost-related underuse of insulin, and this was associated with significantly poorer glycaemic control.46 Real-world evidence (RWE) is an important source of information on Real-world studies comparing first- and second-generation BIs how people titrate BI in everyday clinical practice. Despite the clinical using electronic health record data have also been conducted. The benefits favouring second-generation versus first-generation BIs, CONFIRM and DELIVER-D+ studies compared HbA1c reduction and including lower rates of hypoglycaemia, RWE suggests that patients hypoglycaemia risk in US patient records for individuals using either are still not achieving glycaemic targets during the initial 12 weeks of Gla-300 or IDeg, with both studies using propensity score matching treatment. For example, the DUNE study, a prospective, 12-week (PSM) to account for potential confounders; however, these studies real-world observational study in insulin-naïve and pretreated (within showed conflicting results.47,48 DELIVER-D+ showed similar HbA1c the preceding 12 months) individuals with T2D who initiated or reductions (Gla-300: 0.63 [SD 1.7]%, IDeg-100: 0.58 [1.6]%; switched BI therapy, showed that only 28% and 27% of these P = 0.488) and HbA1c <7% target achievement (Gla-300: 15.1%, 43 patients, respectively, achieved their individualized HbA1c targets. IDeg: 16.1%; P = 0.628) from baseline to 3–6 months’ follow-up.48 No Failure to achieve these targets could have been because of insuffi- significant between-treatment differences in hypoglycaemia incidence cient dose titration, as only modest increases in dose were observed or rates (hospitalizations or ED visits) were observed between (mean 0.10 U/kg in insulin-naïve patients and 0.06 U/kg in pretreated Gla-300 or IDeg following adjustment for baseline hypoglycaemia.48 patients). By comparison, a pooled analysis of 15 RCTs examining the By contrast, CONFIRM showed significantly greater HbA1c reduc- initiation of Gla-100 in insulin-naïve individuals showed mean tions with IDeg than Gla-300 (−1.48% vs. −1.22%; P = 0.03).47 Simi- 21 increases of >0.24 U/kg. larly, over the initial 180 days, the proportion of patients experiencing A recent retrospective observational study of 25 489 people with ≥1 hypoglycaemic event was significantly lower with IDeg than T2D in the USA assessed hypoglycaemia-related emergency depart- Gla-300 (P <0.01) and fewer patients discontinued treatment with ment (ED) visits or hospital admissions after initiation of long-acting IDeg than Gla-300 (13% vs. 21%; P <0.001).47 insulin analogues (1928; 8%) compared with NPH insulin (n = 23 561; The LIGHTNING study also compared the safety and effective- 92%).44 Results indicated no significant differences in rates of ness of first-generation (Gla-100 and IDet) and second-generation hypoglycaemia-related ED visits between individuals using NPH insulin (Gla-300 and IDeg) BI analogues using data from US electronic health (8.8 events per 1000 person-years) or long-acting insulin analogues records.49 Potential confounders were controlled using either PSM or 44 (11.9 events per 1000 person-years; P = 0.07). However, this study predictive modelling with machine learning techniques. Results of 14631326, 2020, 5, Downloaded from https://dom-pubs.pericles-prod.literatumonline.com/doi/10.1111/dom.13946 by Readcube (Labtiva Inc.), Wiley Online Library on [25/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 728 KHUNTI ET AL. predictive modelling indicated that rates of severe hypoglycaemia Providing enhanced digital educational tools or titration-support with Gla-300 (0.07 events per patient-year) were significantly lower devices can further empower patients to self-titrate their BI, as shown than with Gla-100 (0.14 events per patient-year; P <0.05) or IDet with the INNOVATE and AUTOMATIX trials (Table 1). INNOVATE (0.15 events per patient-year; P <0.05) in insulin-naïve individuals, but compared the efficacy and safety of Gla-100 administered with were not significantly lower versus IDeg (0.10 events per patient-year, physician-led titration versus self-titrated insulin titration facilitated P >0.05).49 Similar results were observed in the PSM analysis.49 It with a home-based web tool (LTHome).55 While the primary endpoint should be noted that CONFIRM, DELIVER-D+ and LIGHTNING did in INNOVATE was not met (non-inferiority was not shown for not specifically compare the safety and efficacy of different BI formu- LTHome self-titration vs. physician-managed titration for the compos- lations within the initial period of insulin titration, probably because of ite endpoint: four out of seven FPG readings within 5.0–7.2 mmol/L, the limitations of the electronic healthcare records datasets. Never- mean of three consecutive FPG measurements within 5.0–7.2 mmol/L, theless, data from these RWE studies add to the results observed and no severe hypoglycaemia), HbA1c reductions and incidence of in RCTs. hypoglycaemia were similar between groups. Additionally, LTHome There are limitations to consider when interpreting results from self-titration was associated with greater reductions in hypoglycaemia RWE studies. The lack of randomization and unselected patient fear scores and diabetes distress scores versus physician-managed titra- 50 populations may lead to potential biases and confounders. Fur- tion.55 The AUTOMATIX trial compared physician-led titration with a thermore, the data used are not collected or organized with the pur- device-supported titration system to facilitate self-titration for Gla-300. pose of supporting research, and as such, data may be inaccurate or The device-supported titration system provided automated titration incomplete50; this could lead to underreporting of events (eg, suggestions based on device-measured fasting SMPG readings from a hypoglycaemia episodes). Furthermore, the studies detailed above minimum of 3 consecutive days.56 Results showed that the device- did not capture data on how titration was performed, or the insulin supported titration was non-inferior to physician-led titration for the doses used, and did not present results by separate titration and primary endpoint (fasting SMPG target achievement of 5.0–7.2 mmol/L maintenance periods. Therefore, comparisons of clinical outcomes [90–130 mg/dL] after 16 weeks without severe hypoglycaemia). Addi- specifically within the titration period are not possible. Additionally, tionally, a greater proportion of patients achieved target fasting SMPG many RWE studies assessing hypoglycaemia utilize ED visits and without confirmed (≤3.9 mmol/L [≤70 mg/dL]) hypoglycaemia in hospitalizations to define hypoglycaemic events. However, this the device-supported versus physician-led titration arm. Impor- approach would not capture non-severe hypoglycaemia events, tantly, patient-reported outcome scores were similar between 51 which also have a large impact on people with diabetes, or severe groups, and the device-supported titration was rated as easy to episodes where the individual was not hospitalized or did not require use.56 A similar trial comparing device-supported versus physician- an ED visit. managed titration is currently ongoing in people with T2D receiving IDeg BI therapy. 57 Providing simpler titration algorithms can also facilitate patients in 4.3 | Self-titration and patient empowerment self-titrating their BI. For example, the TITRATION study, which compared self-titration of Gla-300 using either a simple insulin titration algorithm of Patient empowerment can also be achieved with titration tools 1 U/day dose increases (the INSIGHT study BI titration algorithm, that enable people to self-titrate their BI, with guidelines rec- Figure 3)58 or physician-titration with the EDITION algorithm33-35 in both ommending the use of evidence-based titration algorithms to insulin-pretreated or insulin-naïve people with T2D (Figure 3), showed that facilitate self-titration. 9,10 There have been several trials in which both titration groups achieved similar glycaemic outcomes without differ- self- and physician-managed titration utilizing simple paper-based titra- ences in hypoglycaemia or insulin dose increases.59 Additionally, the tion algorithms have been compared (Table 1). Three such trials are BEGIN: ONCE Simple Use trial compared simple versus stepwise titration ATLAS, AT.LANTUS and TAKE CONTROL, which compared self- versus algorithms using IDeg in insulin-naïve people with T2D (Figure 3).60 Both physician-managed titration with either Gla-100 or Gla-300. All three tri- titration algorithms provided similar reductions in HbA1c (−1.09% and als showed significantly greater reductions in HbA1c with self- versus −0.93% with simple and stepwise titration, respectively) with comparable 52-54 physician-led insulin titration (Table 1). While the incidence of confirmed (<3.1 mmol/L [<56 mg/dL]) hypoglycaemia rates (1.60 and 1.17 hypoglycaemia was slightly higher with the self- versus physician- events/patient-year of exposure, P = 0.43), comparable confirmed noctur- managed groups in the two trials that investigated Gla-100 titration nal hypoglycaemia rates (0.21 and 0.10 events/patient-year of exposure, (ATLAS and AT.LANTUS), both titration arms showed a similar incidence P = 0.20), similar insulin doses, and similar weight changes observed over of hypoglycaemia in TAKE CONTROL, where participants received the 26-week study.60 52 Gla-300. However, it should be noted that the definitions of The results of these studies show that self-titration did not hypoglycaemia varied between these studies. Results from TAKE increase the risk of hypoglycaemia and was still effective in achieving CONTROL also showed that a greater proportion of participants in the glycaemic control, while providing similar or better patient satisfaction self- versus physician-managed group achieved SMPG targets without compared with physician-managed titration. Use of digital education hypoglycaemia and had slightly greater improvements in emotional tools, titration-support devices or providing simpler titration algo- burden.52 rithms could further facilitate patients to self-titrate their BI. TABLE 1 Summary of randomized controlled trials comparing self-management versus physician-led management of titration TAKE CONTROL52 AT.LANTUS54 ATLAS53 INNOVATE55 AUTOMATIX56 KHUNTI ET AL. Study length, 24 24 24 12 16 weeks Location 10 European countries Europe, South America, Asia, Asia Canada Germany/UK Africa/Middle East Population Insulin-naïve and previously Insulin-naïve and previously Insulin-naïve, age 40–75 years, Insulin-naïve and previously Insulin-naïve and previously treated, age ≥18 years, treated, age ≥18 years, HbA1c ≥7.0% and ≤11.0% treated, age ≥18 and ≤75 years, treated, age ≥18 years, HbA1c ≥7.0% and ≤10.0% BMI <40 kg/m2, HbA1c >7.0% BMI ≤45 kg/m2, HbA1c >7.0% HbA1c ≥7.5% and ≤11.0% (prior BI) or ≥7.5% and ≤11.0% and <12.0% (BI-naïve) Type of Paper-based titration algorithm Paper-based titration algorithm Paper-based titration algorithm Self-titration web tool (LTHome) Self-titration device (MyStar titration DoseCoach) support Study drug Gla-300 Gla-100 Gla-100 Gla-100 Gla-300 Key results Significantly greater HbA1c Significantly greater HbA1c Significantly greater HbA1c Similar HbA1c reductions Similar HbA1c reductions reductions with self- reductions with self- reductions with self- observed between groups and a observed between groups. vs. physician-managed titration vs. physician-managed titration vs. physician-managed titration greater proportion of patients Numerically greater and a higher proportion of and a higher proportion of and a numerically higher achieving HbA1c of ≤7.0% in achievement of fasting SMPG people achieving HbA1c of people achieving HbA1c of proportion of patients achieving the self- vs. physician-managed target without severe <7.0%. Similar incidence of <7.0%. Significantly greater HbA1c of <7.0% without severe titration group. Lower hypoglycaemia with self- hypoglycaemia (all categories incidence of any hypoglycaemia hypoglycaemia. Similar achievement of the composite vs. physician-managed titration and BG thresholds reported)a in and symptomatic (<2.8 mmol/L incidence of severe primary outcome‡ in the self- (not significant). Slightly lower both groups. Slightly greater [<50 mg/dL]) hypoglycaemia in hypoglycaemia, but significantly vs. physician-managed titration incidence of any hypoglycaemia increase in insulin dose with the self- vs. physician-managed greater incidence of arm. Incidence of and confirmed (≤3.9 mmol/L self- vs. physician-managed titration group, but similar symptomatic (clinical symptoms hypoglycaemia (all categories [≤70 mg/dL]) or severe titration. incidence of nocturnal of hypoglycaemia regardless of reported)§ was similar in both hypoglycaemia, occurring either hypoglycaemia (occurring BG measurement) groups. at night (00:00–05:59 hours) or during sleep with BG of hypoglycaemia and nocturnal any time of day (24 hours) with <2.8 mmol/L [<50 mg/dL]). hypoglycaemia (occurring self (device)- vs. physician during sleep with BG of (routine)-managed titration. <2.8 mmol/L [<50 mg/dL]) with Greater dose increases with self- vs. physician-managed self- vs. physician-managed titration. Significantly greater titration. increase in insulin dose with self- vs. physician-managed titration. Abbreviations: BG, blood glucose; BI, basal insulin; BMI, body mass index; FPG, fasting plasma glucose; SMPG, self-measured plasma glucose. a Any hypoglycaemia, confirmed or severe at BG thresholds of ≤3.9 mmol/L (≤70 mg/dL) or <3.0 mmol/L (<54 mg/dL) and symptomatic, with all categories reported at any time of day (24 hours) or at night (00:00–05:59 hours); ‡primary composite outcome: (i) at least four out of seven FPG values within a 10-day period in the target range (5.0–7.2 mmol/L [90–130 mg/dL]); (ii) mean FPG for three consecutive prior FPG values within a 10-day period in the target range; (iii) no severe hypoglycaemia during the 7-10-day period; §overall, nocturnal, daytime, symptomatic or asymptomatic hypoglycaemia, time intervals and BG thresholds were not specified. 729 14631326, 2020, 5, Downloaded from https://dom-pubs.pericles-prod.literatumonline.com/doi/10.1111/dom.13946 by Readcube (Labtiva Inc.), Wiley Online Library on [25/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 14631326, 2020, 5, Downloaded from https://dom-pubs.pericles-prod.literatumonline.com/doi/10.1111/dom.13946 by Readcube (Labtiva Inc.), Wiley Online Library on [25/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 730 KHUNTI ET AL. 4.4 | Insulin titration in special populations therapy with or without concomitant BI.52,65 HbA1c and SMPG reductions were similar between age groups and the proportions Hypoglycaemia risk is increased in certain populations, such as those achieving the SMPG target (4.4–7.2 mmol/L [80–130 mg/dL]) without with renal impairment, established cardiovascular disease, long dura- confirmed (<3.0 mmol/L [<54 mg/dL]) or severe hypoglycaemia were tion of diabetes, impaired awareness of hypoglycaemia, and those higher in the older age group. The incidence and rate of with cognitive impairment.25,61 Additionally, certain populations (such hypoglycaemia was also similar between groups, showing that self- as older individuals) may be at increased risk from the consequences titration with Gla-300 was effective in this older population without of hypoglycaemia, such as falls/fractures and hospitalizations.62 While increasing the risk of hypoglycaemia.65 Similar results were observed insulin therapy must always be carefully balanced between optimizing in a post hoc analysis of the BRIGHT study, where Gla-300 provided glycaemic control and minimizing the risk of hypoglycaemia, it is an similar HbA1c reduction versus IDeg-100 in insulin-naïve older people especially sensitive issue in these high-risk populations. with T2D, and greater reductions versus IDeg-100 in those aged Studies comparing BI therapy use in high-risk populations have ≥70 years with no increased hypoglycaemia risk.66 These results sug- showed that simple titration algorithms can be effective in these patients. gest that the simple titration algorithm used in BRIGHT, along with The SWITCH 2 RCT investigated the use of IDeg versus Gla-100 the more stringent fasting SMPG titration target (4.4–5.6 mmol/L in people with poorly controlled T2D despite prior treatment with BI [80–100 mg/dL]), was effective in this older population, without with or without OADs and at least one hypoglycaemia risk factor: ≥1 increasing their risk of hypoglycaemia.66 severe hypoglycaemic episode within the last year (ADA definition); While these studies provide reassurance that simple titration moderate chronic renal failure (estimated glomerular filtration rate of algorithms can be used to titrate second-generation BI analogues in 30–59 mL/min/1.73 m2); hypoglycaemic symptom unawareness; populations at high risk of hypoglycaemia, it should be noted that min- exposure to insulin for >5 years; episode of hypoglycaemia (symptoms imizing hypoglycaemia requires a multifaceted approach that reaches and/or blood glucose level ≤3.9 mmol/L [≤70 mg/dL]) within the last beyond BI dose adjustments. Indeed, the consensus report of the 12 weeks.63 Insulin was adjusted weekly based on the mean of 3 days ADA and EASD proposed that the appropriate use of insulin (dose, prebreakfast blood glucose with a target of 4.0–5.0 mmol/L timing, targets) impacts the effectiveness and adverse effects of insu- (71–90 mg/dL) (Figure 3). In this population with a high risk of lin therapy more than the differences between formulations.10 Factors hypoglycaemia, IDeg was associated with a significant absolute that should be considered include treatment choices, patient educa- 9% reduction in overall symptomatic (<3.1 mmol/L [<56 mg/dL]) tion, and individualized glucose targets that account for hypoglycaemia (P < 0.001) and a 5.1% reduction in nocturnal symp- hypoglycaemia risk, lifestyle, activity levels and concomitant medica- tomatic (<3.1 mmol/L [<56 mg/dL]) hypoglycaemia (P = 0.001) com- tions.10,67 Patient education should include awareness of the times 63 pared with Gla-100. However, it should be noted that (eg, during the overnight fast and prebreakfast), daily situations (eg, SWITCH 2 included patients who were previously treated with insu- missed meals, exercise, alcohol intake) and other factors (eg, vulnera- lin; as such, extrapolation of the results to an insulin-naïve population ble/special populations, co-morbidities) that raise hypoglycaemia risk, may not be possible. Additionally, the SWITCH 2 trials employed a so that glucose monitoring can be increased and countermeasures stringent fasting SMPG titration target that is often not used in rou- taken, which in a busy practice may be best achieved by dedicated tine clinical practice, particularly in patients with an increased risk of diabetes nurses and educators.25 hypoglycaemia. The SENIOR study compared Gla-300 versus Gla-100 in both insulin-pretreated and insulin-naïve older individuals with T2D aged 5 | CONC LU SIONS ≥65 years (and also in a subgroup aged ≥75 years).64 A more relaxed fasting SMPG target of 5.0–7.2 mmol/L (90–130 mg/dL) was used in The initial period during insulin initiation and titration is a critical time SENIOR, in line with ADA guidelines for recommended targets in for successful glycaemic target achievement. Despite the well- older individuals (Figure 3).9 Glycaemic control was comparable evidenced benefit of early tight glycaemic control, there are still a between treatment groups, and incidence of anytime (24 hours) and number of barriers at the patient, physician and healthcare system nocturnal (00:00–05:59 hours) hypoglycaemia, and annualized event levels to initiating, intensifying and up-titrating BI therapy. There are rates of confirmed (≤3.9 mmol/L [≤70 mg/dL]) or severe also different approaches to optimizing BI titration in people with hypoglycaemia at any time or at night, were low and similar between T2D. It should be noted that this article was not a systematic review treatment groups. Overall, a trend towards lower annualized and, as such, may have omitted some trials showing use of novel event rates of hypoglycaemia with Gla-300 was observed; this titration algorithms or methods to improve self-management. between-treatment difference was more pronounced in the ≥75 years Additionally, for the purposes of brevity, this review focuses on the subgroup.64 recent ADA and EASD guidelines; however, there are other global A post hoc analysis of TAKE CONTROL compared the efficacy guidelines which provide similar recommendations. and safety of self- versus physician-managed titration of Gla-300 in Helping patients to effectively self-manage their own diabetes older (≥65 years of age) versus younger (<65 years of age) people with can provide similar or greater reductions in HbA1c with comparable T2D receiving treatment with ≥1 non-insulin antihyperglycaemic safety profiles to physician-managed care, often accompanied by 14631326, 2020, 5, Downloaded from https://dom-pubs.pericles-prod.literatumonline.com/doi/10.1111/dom.13946 by Readcube (Labtiva Inc.), Wiley Online Library on [25/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License KHUNTI ET AL. 731 improvements in treatment satisfaction, perceived self-management AUTHOR CONTRIBU TIONS efficacy, and reduced diabetes-related distress. Consequently, The authors were involved from the conception of the review article, empowering patients to self-manage their diabetes may help alleviate the generation of the review outline and all subsequent drafts. All many of the patient-related barriers to insulin therapy inertia and thus authors critically reviewed the manuscript and approved the final ver- may improve therapy adherence. Self-management can also be sion for submission. improved through the implementation of simple and easy titration algorithms (daily or weekly), which have been proven to result in FUNDING INF ORMATI ON glycaemic efficacy while helping to minimize hypoglycaemia risk. This review article was supported by Sanofi. There is currently no evidence for second-generation BI analogues improving treatment adherence compared with first-generation BI ana- OR CID logues. Further research is required to directly assess this relationship Kamlesh Khunti https://orcid.org/0000-0003-2343-7099 and to assess the cost-effectiveness of second-generation versus first- Lori Berard https://orcid.org/0000-0002-9695-2094 generation BIs. However, given that fear of hypoglycaemia is a major Didac Mauricio https://orcid.org/0000-0002-2868-0250 barrier that leads to insulin therapy inertia in patients and their healthcare providers, by reducing the risk of hypoglycaemia overall— RE FE RE NCE S particularly during the titration period when most insulin dose change 1. Skyler JS, Bergenstal R, Bonow RO, et al. Intensive glycemic control occurs—second-generation BI analogues may potentially help to and the prevention of cardiovascular events: implications of the improve treatment adherence and long-term glycaemic outcomes com- ACCORD, ADVANCE, and VA diabetes trials: a position statement of pared with first-generation BI analogues. the American Diabetes Association and a scientific statement of the American College of Cardiology Foundation and the American Heart Association. Diabetes Care. 2009;32:187-192. ACKNOWLEDGMENTS 2. Action to Control Cardiovascular Risk in Diabetes Study Group, K. K. acknowledges support from the NIHR Collaboration for Gerstein HC, Miller ME, et al. Effects of intensive glucose lowering in Leadership in Applied Health Research and Care East Midlands type 2 diabetes. N Engl J Med. 2008;358:2545-2559. 3. Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular (CLAHRC-EM) to NIHR Applied Research Collaboration East Midlands complications in veterans with type 2 diabetes. N Engl J Med. 2009; (NIHR ARC-EM). The views expressed are those of the authors and 360:129-139. not necessarily those of the NHS, the NIHR or the Department of 4. Hayward RA, Reaven PD, Wiitala WL, et al. Follow-up of glycemic Health and Social Care. control and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;372:2197-2206. This review article was supported by Sanofi. The authors received 5. ADVANCE Collaborative Group, Patel A, MacMahon S, et al. Inten- editorial/writing support in the preparation of this manuscript pro- sive blood glucose control and vascular outcomes in patients with vided by Hannah Brown, PhD, of Fishawack Communications Ltd, type 2 diabetes. N Engl J Med. 2008;358:2560-2572. funded by SANOFI. 6. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:1577-1589. CONF LICT OF IN TE RE ST 7. Paul SK, Klein K, Thorsted BL, Wolden ML, Khunti K. Delay in treat- S. B. H. — advisory board/consultant: Abbott, AstraZeneca, ment intensification increases the risks of cardiovascular events in Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, Sanofi; patients with type 2 diabetes. Cardiovasc Diabetol. 2015;14:100. 8. Khunti K, Gomes MB, Pocock S, et al. Therapeutic inertia in the treat- research support: Abbott, AstraZeneca, Boehringer Ingelheim, Eli Lilly, ment of hyperglycaemia in patients with type 2 diabetes: A systematic Janssen, Novo Nordisk, Sanofi. D. M. — advisory board: AstraZeneca, review. Diabetes Obes Metab. 2018;20:427-437. Ferrer, Merck, Novo Nordisk, Praxis Pharmaceutical, Sanofi; speakers 9. American Diabetes Association. Standards of Medical Care in Diabe- bureau: Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Menarini, tes 2019. Diabetes Care. 2019;42:S1-S193. Merck, Novartis, Novo Nordisk, Sanofi. K. K. — advisory board, con- 10. Davies MJ, D'Alessio DA, Fradkin J, et al. Management of Hyper- glycemia in Type 2 Diabetes, 2018. A Consensus Report by the sultant, and speakers bureau: Berlin-Chemie AG / Menarini Group, American Diabetes Association (ADA) and the European Associa- Novartis, Novo Nordisk, Sanofi, Eli Lilly, Servier, MSD; research sup- tion for the Study of Diabetes (EASD). Diabetes Care. 2018;41: port: Novartis, Novo Nordisk, Sanofi, Eli Lilly, Pfizer, Boehringer 2669-2701. Ingelheim, MSD, Roche. L. B. — consultancy: Eli Lilly, Sanofi, Novo 11. Khunti K, Damci T, Meneghini L, Pan CY, Yale JF, Group SS. Study of Nordisk, LifeScan, Abbott, BD, MontMed, Merck, Janssen, Once Daily Levemir (SOLVE): insights into the timing of insulin initia- tion in people with poorly controlled type 2 diabetes in routine clini- AstraZeneca, Boehringer Ingelheim; grants: MontMed; Honoraria: Eli cal practice. Diabetes Obes Metab. 2012;14:654-661. Lilly, Sanofi, Novo Nordisk, LifeScan, Abbott, BD, Merck, Janssen, 12. Mauricio D, Meneghini L, Seufert J, et al. Glycaemic control and AstraZeneca; lecture/other fees: Eli Lilly, Sanofi, Novo Nordisk, hypoglycaemia burden in patients with type 2 diabetes initiating basal LifeScan, Abbott, BD, Merck, Janssen, AstraZeneca. F. G. — advisory insulin in Europe and the USA. Diabetes Obes Metab. 2017;19:1155- 1164. board: AstraZeneca, Eli Lilly, Novo Nordisk, Roche Diabetes Care, 13. Stone MA, Charpentier G, Doggen K, et al. Quality of care of people Sanofi; consultant: Boehringer Ingelheim, LifeScan, Merck Sharp & with type 2 diabetes in eight European countries: findings from the Dohme, Sanofi, AstraZeneca, MedImmune, Roche Diabetes Care, Guideline Adherence to Enhance Care (GUIDANCE) study. Diabetes Sanofi; research support: Eli Lilly; LifeScan, Takeda. Care. 2013;36:2628-2638. 14631326, 2020, 5, Downloaded from https://dom-pubs.pericles-prod.literatumonline.com/doi/10.1111/dom.13946 by Readcube (Labtiva Inc.), Wiley Online Library on [25/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 732 KHUNTI ET AL. 14. Aschner P, Gagliardino JJ, Ilkova HM, et al. Poor Glycemic Control in 31. Chatterjee S, Khunti K, Davies MJ. Achieving glycaemic control with People with T1D and T2D—Results from the International Diabetes concentrated insulin in patients with type 2 diabetes. Drugs. 2019;79: Management Practices Study (IDMPS). Diabetes. 2018;67:1656. 173-186. 15. Russell-Jones D, Pouwer F, Khunti K. Identification of barriers to 32. Vijan S, Hayward RA, Ronis DL, Hofer TP. Brief report: the burden of insulin therapy and approaches to overcoming them. Diabetes Obes diabetes therapy: implications for the design of effective patient- Metab. 2018;20:488-496. centered treatment regimens. J Gen Intern Med. 2005;20:479-482. 16. Dalal MR, Kazemi M, Ye F, Xie L. Hypoglycemia after initiation of 33. Riddle MC, Bolli GB, Ziemen M, et al. New insulin glargine basal insulin in patients with type 2 diabetes in the United States: 300 units/mL versus glargine 100 units/mL in people with type 2 dia- implications for treatment discontinuation and healthcare costs and betes using basal and mealtime insulin: glucose control and hypogly- utilization. Adv Ther. 2017;34:2083-2092. cemia in a 6-month randomized controlled trial (EDITION 1). Diabetes 17. Peyrot M, Barnett AH, Meneghini LF, Schumm-Draeger PM. Factors Care. 2014;37:2755-2762. associated with injection omission/non-adherence in the Global Atti- 34. Yki-Jarvinen H, Bergenstal R, Ziemen M, et al. New insulin glargine tudes of Patients and Physicians in Insulin Therapy study. Diabetes 300 units/mL versus glargine 100 units/mL in people with type 2 dia- Obes Metab. 2012;14:1081-1087. betes using oral agents and basal insulin: glucose control and hypogly- 18. Berard L, Bonnemaire M, Mical M, Edelman S. Insights into optimal cemia in a 6-month randomized controlled trial (EDITION 2). Diabetes basal insulin titration in type 2 diabetes: Results of a quantitative sur- Care. 2014;37:3235-3243. vey. Diabetes Obes Metab. 2018;20:301-308. 35. Bolli GB, Riddle MC, Bergenstal RM, et al. New insulin glargine 19. Pastakia SD, Pekny CR, Manyara SM, Fischer L. Diabetes in sub- 300 U/ml compared with glargine 100 U/ml in insulin-naive people Saharan Africa - from policy to practice to progress: targeting the with type 2 diabetes on oral glucose-lowering drugs: a randomized existing gaps for future care for diabetes. Diabetes Metab Syndr Obes. controlled trial (EDITION 3). Diabetes Obes Metab. 2015;17:386-394. 2017;10:247-263. 36. European Medicines Agency. Toujeo 300 units/mL Summary of Prod- 20. European Medicines Agency. Guidelines on clinical investigation of uct Characteristics. https://www.medicines.org.uk/emc/product/ medicinal products in the treatment or prevention of diabetes 6938/smpc. Accessed October 24, 2019. mellitus 2012. https://www.ema.europa.eu/en/documents/scientific- 37. Ratner RE, Gough SC, Mathieu C, et al. Hypoglycaemia risk with insu- guideline/guideline-clinical-investigation-medicinal-products- lin degludec compared with insulin glargine in type 2 and type 1 dia- treatment-prevention-diabetes-mellitus-revision_en.pdf. Accessed betes: a pre-planned meta-analysis of phase 3 trials. Diabetes Obes April 29, 2019. Metab. 2013;15:175-184. 21. Owens DR, Traylor L, Dain MP, Landgraf W. Efficacy and safety of 38. Rosenstock J, Cheng A, Ritzel R, et al. More similarities than differ- basal insulin glargine 12 and 24 weeks after initiation in persons with ences testing insulin glargine 300 units/mL versus insulin degludec type 2 diabetes: a pooled analysis of data from treatment arms of 100 units/mL in insulin-naive type 2 diabetes: the randomized head- 15 treat-to-target randomised controlled trials. Diabetes Res Clin to-head BRIGHT trial. Diabetes Care. 2018;41:2147-2154. Pract. 2014;106:264-274. 39. Ritzel R, Cheng A, Rosenstock J, et al. The BRIGHT randomised study: 22. Ross SA. Breaking down patient and physician barriers to opti- similar glycaemic control and less confirmed hypoglycaemia with Gla- mize glycemic control in type 2 diabetes. Am J Med. 2013;126: 300 vs IDeg-100 during the initial titration period. Diabetes Technol S38-S48. Ther. 2019;21:A-42. 23. Ascher-Svanum H, Lage MJ, Perez-Nieves M, et al. Early discontinua- 40. Roussel R, Frias J, Westerbacka J, et al. Reaching ADA glycemic tar- tion and restart of insulin in the treatment of type 2 diabetes mellitus. gets without hypoglycemia during titration with Gla-300 and IDeg in Diabetes Ther. 2014;5:225-242. T2DM: exploratory analyses from BRIGHT. Diabetes. 2019;68:1090. 24. Khunti K, Nikolajsen A, Thorsted BL, Andersen M, Davies MJ, 41. ClinicalTrials.gov. A Trial Comparing the Efficacy and Safety of Insulin Paul SK. Clinical inertia with regard to intensifying therapy in people Degludec and Insulin Glargine 300 Units/mL in Subjects With Type with type 2 diabetes treated with basal insulin. Diabetes Obes Metab. 2 Diabetes Mellitus Inadequately Treated With Basal Insulin With or 2016;18:401-409. Without Oral Antidiabetic Drugs. https://clinicaltrials.gov/ct2/show/ 25. Amiel SA, Aschner P, Childs B, et al. Hypoglycaemia, cardiovascular NCT03078478. Accessed April 29, 2019. disease, and mortality in diabetes: epidemiology, pathogenesis, and 42. Philis-Tsimikas A, Stratton I, Norgard Troelsen L, Anker Bak B, management. Lancet Diabetes Endocrinol. 2019;7:385-396. Leiter LA. Efficacy and safety of degludec compared to glargine 26. Harris SB, Berard L, Westerbacka J, et al. Early hypoglycemia after ini- 300 units/mL in insulin-experienced patients with type 2 diabetes: tiation of second-generation basal insulin (BI) analogs: patient charac- trial protocol amendment (NCT03078478). J Diabetes Sci Technol. teristics and clinical outcomes. Diabetes. 2019;68:1095. 2019;13:498-506. 27. Frier BM, Landgraf W, Zhang M, Bolli GB, Owens DR. Hypoglycaemia 43. Meneghini LF, Mauricio D, Orsi E, et al. The Diabetes Unmet Need risk in the first 8 weeks of titration with insulin glargine 100 U/mL in with Basal Insulin Evaluation (DUNE) study in type 2 diabetes: previously insulin-naive individuals with type 2 diabetes mellitus. Dia- Achieving HbA1c targets with basal insulin in a real-world setting. betes Obes Metab. 2018;20:2894-2898. Diabetes Obes Metab. 2019;21:1429-1436. 28. Plank J, Bodenlenz M, Sinner F, et al. A double-blind, randomized, 44. Lipska KJ, Parker MM, Moffet HH, Huang ES, Karter AJ. Association dose-response study investigating the pharmacodynamic and phar- of initiation of basal insulin analogs vs neutral protamine hagedorn macokinetic properties of the long-acting insulin analog detemir. Dia- insulin with hypoglycemia-related emergency department visits or betes Care. 2005;28:1107-1112. hospital admissions and with glycemic control in patients with type 29. Lepore M, Pampanelli S, Fanelli C, et al. Pharmacokinetics and phar- 2 diabetes. JAMA. 2018;320:53-62. macodynamics of subcutaneous injection of long-acting human insu- 45. Luo J, Khan NF, Manetti T, et al. Implementation of a health plan pro- lin analog glargine, NPH insulin, and ultralente human insulin and gram for switching from analogue to human insulin and glycemic con- continuous subcutaneous infusion of insulin lispro. Diabetes. 2000; trol among medicare beneficiaries with type 2 diabetes. JAMA. 2019; 49:2142-2148. 321:374-384. 30. Heise T, Mathieu C. Impact of the mode of protraction of basal insu- 46. Herkert D, Vijayakumar P, Luo J, et al. Cost-related insulin underuse lin therapies on their pharmacokinetic and pharmacodynamic prop- among patients with diabetes. JAMA Intern Med. 2019;179:112-114. erties and resulting clinical outcomes. Diabetes Obes Metab. 2017; 47. Tibaldi J, Hadley-Brown M, Liebl A, et al. A comparative effectiveness 19:3-12. study of degludec and insulin glargine 300 U/mL in insulin-naive 14631326, 2020, 5, Downloaded from https://dom-pubs.pericles-prod.literatumonline.com/doi/10.1111/dom.13946 by Readcube (Labtiva Inc.), Wiley Online Library on [25/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License KHUNTI ET AL. 733 patients with type 2 diabetes. Diabetes Obes Metab. 2019;21: people with type 2 diabetes on either no oral glucose-lowering agents 1001-1009. or submaximal doses of metformin and/or sulphonylureas. The Cana- 48. Sullivan SD, Bailey TS, Roussel R, et al. Clinical outcomes in real-world dian INSIGHT (Implementing New Strategies with Insulin Glargine for patients with type 2 diabetes switching from first- to second- Hyperglycaemia Treatment) study. Diabet Med. 2006;23:736-742. generation basal insulin analogues: Comparative effectiveness of 59. Yale JF, Berard L, Groleau M, Javadi P, Stewart J, Harris SB. TITRA- insulin glargine 300 units/mL and insulin degludec in the DELIVER D+ TION: a randomized study to assess 2 treatment algorithms with new cohort study. Diabetes Obes Metab. 2018;20:2148-2158. insulin glargine 300 units/mL. Can J Diabetes. 2017;41:478-484. 49. Pettus J, Roussel R, Liz Zhou F, et al. Rates of hypoglycemia predicted 60. Philis-Tsimikas A, Brod M, Niemeyer M, Ocampo Francisco AM, in patients with type 2 diabetes on insulin glargine 300 U/ml versus Rothman J. Insulin degludec once-daily in type 2 diabetes: simple or step- first- and second-generation basal insulin analogs: the real-world wise titration (BEGIN: once simple use). Adv Ther. 2013;30:607-622. LIGHTNING study. Diabetes Ther. 2019;10:617-633. 61. Lee AK, Lee CJ, Huang ES, Sharrett AR, Coresh J, Selvin E. Risk fac- 50. Sherman RE, Anderson SA, Dal Pan GJ, et al. Real-world evidence - tors for severe hypoglycemia in black and white adults with diabetes: What is it and what can it tell us? N Engl J Med. 2016;375:2293- the Atherosclerosis Risk in Communities (ARIC) study. Diabetes Care. 2297. 2017;40:1661-1667. 51. Frier BM, Jensen MM, Chubb BD. Hypoglycaemia in adults with 62. Abdelhafiz AH, Rodriguez-Manas L, Morley JE, Sinclair AJ. Hypogly- insulin-treated diabetes in the UK: self-reported frequency and cemia in older people - a less well recognized risk factor for frailty. effects. Diabet Med. 2016;33:1125-1132. Aging Dis. 2015;6:156-167. 52. Russell-Jones D, Dauchy A, Delgado E, et al. Take Control: a random- 63. Wysham C, Bhargava A, Chaykin L, et al. Effect of insulin degludec vs ized trial evaluating the efficacy and safety of self- versus physician- insulin glargine U100 on hypoglycemia in patients with type 2 diabe- managed titration of insulin glargine 300 U/mL in patients with tes: the SWITCH 2 randomized clinical trial. JAMA. 2017;318:45-56. uncontrolled type 2 diabetes. Diabetes Obes Metab. 2019;21:1615- 64. Ritzel R, Harris SB, Baron H, et al. A randomized controlled trial com- 1624. paring efficacy and safety of insulin glargine 300 units/mL versus 53. Garg SK, Admane K, Freemantle N, et al. Patient-led versus 100 units/mL in older people with type 2 diabetes: results from the physician-led titration of insulin glargine in patients with uncontrolled SENIOR study. Diabetes Care. 2018;41:1672-1680. type 2 diabetes: a randomized multinational ATLAS study. Endocr 65. Strojek K, Bigot G, Bonnemaire M, et al. Self- vs. physician-led titra- Pract. 2015;21:143-157. tion of insulin glargine 300 U/mL (Gla-300)—improved or comparable 54. Davies M, Lavalle-Gonzalez F, Storms F, Gomis R, Group ALS. Initia- efficacy at week 24 without increased risk of hypoglycemia, tion of insulin glargine therapy in type 2 diabetes subjects sub- irrespective of age (<65 or =65 years)—TAKE CONTROL. Diabetes. optimally controlled on oral antidiabetic agents: results from the AT. 2018;67:303-OR. LANTUS trial. Diabetes Obes Metab. 2008;10:387-399. 66. Charbonnel B, Aroda V, Westerbacka J, et al. Differences in HbA1c 55. Bajaj HS, Venn K, Ye C, Aronson R. Randomized trial of long-acting reduction between insulin glargine 300 U/mL (Gla-300) and insulin insulin glargine titration web tool (LTHome) versus enhanced usual degludec 100 U/mL (IDeg-100) in adults ≥70 years of age with therapy of glargine titration (INNOVATE trial). Diabetes Technol Ther. T2DM in the BRIGHT trial. Diabetes. 2019;68:131-LB. 2016;18:610-615. 67. International Hypoglycaemia Study Group. Minimizing hypoglycemia 56. Davies M, Bain S, Charpentier G, et al. A randomized controlled, in diabetes. Diabetes Care. 2015;38:1583-1591. treat-to-target study evaluating the efficacy and safety of insulin glargine 300 U/mL (Gla-300) administered using either device- supported or routine titration in people with type 2 diabetes. J Diabetes Sci Technol. 2019;13:881-889. How to cite this article: Khunti K, Giorgino F, Berard L, 57. ClinicalTrials.gov. Insulin Degludec Titration Using Mobile Insulin Mauricio D, Harris SB. The importance of the initial period of Dosing System. https://clinicaltrials.gov/ct2/show/NCT03091712. basal insulin titration in people with diabetes. Diabetes Obes Accessed April 29, 2019. 58. Gerstein HC, Yale JF, Harris SB, Issa M, Stewart JA, Dempsey E. A Metab. 2020;22:722–733. https://doi.org/10.1111/dom. randomized trial of adding insulin glargine vs. avoidance of insulin in 13946