Diabetes Ther (2018) 9:927–949 https://doi.org/10.1007/s13300-018-0422-4 REVIEW A Review of Basal-Bolus Therapy Using Insulin Glargine and Insulin Lispro in the Management of Diabetes Mellitus . . Riccardo Candido Kathleen Wyne Ester Romoli Received: January 31, 2018 / Published online: April 13, 2018 The Author(s) 2018 Abstract: Basal-bolus therapy (BBT) refers to component, and generally provides similar the combination of a long-acting basal insulin glycemic control and rates of severe hypo- with a rapid-acting insulin at mealtimes. Basal glycemia to those achieved with insulin lispro insulin glargine 100 U/mL and prandial insulin administered by continuous subcutaneous lispro have been available for many years and insulin infusion (CSII). Studies evaluating BBT there is a substantial evidence base to support with insulin glargine plus insulin lispro in the efﬁcacy and safety of these agents when patients with T2DM also demonstrate the efﬁ- they are used in BBT or basal-plus therapy for cacy and safety of these insulins. Available data patients with type 1 or type 2 diabetes mellitus suggest that BBT with insulin glargine and (T1DM, T2DM). With the growing availability insulin lispro provides similar levels of efﬁcacy of alternative insulins for use in such regimens, and safety in pediatric and adult populations it seems timely to review the data regarding BBT with T1DM and in adult patients and those aged with insulin glargine 100 U/mL and insulin more than 65 years with T2DM. These insulin lispro. In patients with T1DM, BBT with insulin preparations also appear to be safe and effective glargine plus insulin lispro provides similar or for controlling T2DM in people of different better glycemic control and leads to less noc- ethnicities and in patients with T1DM or T2DM turnal hypoglycemia compared to BBT using and comorbidities. human insulin as the basal and/or prandial Funding: Eli Lilly and Company. Keywords: Basal-bolus therapy; Insulin Enhanced digital features To view enhanced digital features for this article go to https://doi.org/10.6084/ glargine; Insulin lispro; Lilly insulin glargine; m9.ﬁgshare.6040796. Type 1 diabetes mellitus; Type 2 diabetes mellitus R. Candido (&) Diabetes Centre District 3, Azienda Sanitaria Universitaria Integrata di Trieste, Via Puccini 48/50, INTRODUCTION 34100 Trieste, Italy e-mail: email@example.com Insulin treatment of type 1 (T1DM) and type 2 K. Wyne (T2DM) diabetes mellitus has progressed con- The Ohio State University Wexner Medical Center, siderably since the discovery of insulin in 1922 Columbus, OH 43210, USA  and its subsequent puriﬁcation and crystal- E. Romoli lization . Initially, only animal insulin was Eli Lilly Italia SPA, via A. Gramsci 731/733, 50019 available to diabetics, and animal insulin is Sesto Fiorentino, Italy 928 Diabetes Ther (2018) 9:927–949 associated with adverse effects such as insulin INSULIN LISPRO allergy, insulin resistance, and insulin lipodys- trophy [3–5]. However, in the 1980s, recombi- Structure, Pharmacokinetics, nant DNA technology enabled the development and Pharmacodynamics of synthetic human insulin, which replaced animal insulin as it was found to be less likely to The ﬁrst genetically engineered rapid-acting produce adverse effects and it could be mass- insulin analogue (RAIA) to become available produced. In the late 1980s and early 1990s, it was insulin lispro, which was approved for became apparent that better glucose control clinical use in Europe and the USA in 1996 . would require new insulin preparations with a The B26–30 region of the insulin molecule is faster onset and shorter duration of action, not critical for binding to the insulin receptor, enabling prandial insulin to be administered but it is important in mediating the formation closer to mealtimes, as well as long-acting of insulin dimers [9, 14]. The insulin lispro preparations with a ﬂatter time–action proﬁle molecule is created by reversing the normal and less variable bioavailability, including for- sequence of proline at position 28 of the B chain mulations suitable for once-daily dosing [6–9]. and lysine at position 29 (Fig. 1). This Molecular genetic techniques provided oppor- reversal causes a decreased tendency for self- tunities to create insulin analogues by changing association [13, 15, 16]; consequently, insulin the structure of the native protein and lispro has faster absorption, higher peak serum improving its therapeutic properties [8–10]. levels, and a shorter duration of action com- The crucial importance of an exogenous pared with regular human insulin (RHI) basal-bolus insulin supply to control blood [9, 13, 17, 18]. In patients with T1DM treated glucose concentrations in patients with abso- with multiple daily injections, insulin lispro can lute insulin deﬁciency disease (i.e., T1DM) is be associated with fewer hypoglycemic events well recognized. However, in T2DM, the ini- than RHI . Importantly, structural modiﬁ- tial relative insulin deﬁciency progresses with cations at these positions do not affect the the decline in b-cell function, which again receptor-binding domain of the molecule  makes a combination of basal and prandial or the afﬁnity for the insulin receptor . insulin the most effective insulin strategy Although the afﬁnity of insulin lispro for the [5, 11, 12]. insulin-like growth factor-1 (IGF-1) receptor is This article reviews the current evidence slightly higher than that of RHI, this difference concerning a widely used basal-bolus strategy in afﬁnity is not large enough to cause a dif- combining insulin glargine 100 U/mL with ference in cell-growth-stimulating activity . insulin lispro in patients with T1DM and Insulin lispro has essentially the same effect on T2DM. The review does not consider all insu- lipogenesis as RHI . lins and, as such, does not include other Pharmacokinetic (PK)/pharmacodynamic (PD) established or new insulins used in basal-bolus studies indicate that the action of insulin lispro regimens unless they have been directly starts within 15 min, peaks in approximately compared with insulin glargine 100 U/mL plus 40–90 min, and disappears within 2–4 h of sub- insulin lispro. An introductory summary of cutaneous (SC) injection [18, 20, 21]. key information about the individual agents After insulin lispro, two other RAIAs, insulin leads into a discussion of their combined use aspart and insulin glulisine, were developed. in basal-bolus therapy (BBT). In addition, the Although studies have shown some differences use of this BBT in special populations is con- in various PK parameters between RAIAs sidered. The information provided is based on [22–26], overall there do not appear to be sub- previously conducted and published studies stantial differences in their effectiveness at and does not contain any studies with human controlling postprandial glucose levels and participants or animals performed by any of blood glucose proﬁles [19, 23–28]. However, the authors. there are some differences in the indications Diabetes Ther (2018) 9:927–949 929 Fig. 1 Structure of insulin lispro. Ala alanine, Arg Leu leucine, Lys lysine, Phe phenylalanine, Pro proline, Ser arginine, Asn asparagine, Cys cysteine, Gln glutamine, serine, Thr threonine, Tyr tyrosine, Val valine Glu glutamic acid, Gly glycine, His histidine, Ile isoleucine, and the patient populations studied with the and RHI to provide true basal coverage, mean- three analogues [29–31]. ing that increased preprandial blood glucose concentrations were present in patients on insulin lispro. Supporting this theory, a clini- Efﬁcacy and Safety cally and statistically signiﬁcant decrease in HbA1c level was seen when insulin lispro was Insulin lispro is one of the most studied and used in conjunction with two or more daily widely used rapid-acting insulins. As expected injections (instead of one) of neutral protamine for a RAIA, insulin lispro signiﬁcantly improves Hagedorn (NPH) insulin [36–38]. postprandial blood glucose levels compared Insulin lispro is the only rapid-acting ana- with RHI when administered as prandial insulin logue which also has a 200 U/mL formulation. in conjunction with basal insulin, leading to a Insulin lispro 200 U/mL has the same PK/PD, lower rate of hypoglycemic events [32–35]. This efﬁcacy, and safety proﬁles as lispro 100 U/mL was observed even when insulin lispro was [39, 40], but the 200 U/mL pen had a lower glide administered immediately before meals and force and was preferred by patients [41, 42]. RHI was injected 30–45 min before meals. No differences have been reported between However, in most cases, the beneﬁcial effects of insulin lispro and RHI regarding the likelihood insulin lispro on postprandial blood glucose of allergic reactions, nonhypoglycemic adverse levels and frequency of hypoglycemic events events, or abnormal laboratory values were not accompanied by improvements in [34, 35, 43]. The immunogenicity of insulin glycosylated hemoglobin (HbA1c) compared lispro is similar to that of RHI , and anti- with RHI [33–35]. The most likely explanation bodies against insulin lispro rarely develop and for this is the inability of the long-acting insu- do not affect dose requirements . Interest- lins that were administered with insulin lispro ingly, there have been reports of patients with 930 Diabetes Ther (2018) 9:927–949 severe resistance to RHI due to antibody for- depots, increased bioavailability, and mainte- mation that was successfully overcome by nance of stability in acidic solutions [3, 50, 52]. switching to insulin lispro [44–47]. After SC injection, insulin glargine precipitates in SC tissues, which delays its absorption and prolongs its duration of action [51–53]. Insulin INSULIN GLARGINE glargine must not be mixed with other insulins, as it precipitates and the PK and PD proﬁles are Structure, Pharmacokinetics, altered. and Pharmacodynamics Insulin glargine generally behaves like RHI regarding insulin receptor binding, receptor Insulin glargine is a long-acting biosynthetic autophosphorylation, phosphorylation of human insulin analogue that was ﬁrst approved signaling elements, and promotion of mito- for use in patients with T1DM and T2DM in the genesis in muscle cells, apart from an USA and Europe in 2000 (Lantus insulin glar- increased binding afﬁnity for the IGF-1 gine) [48–50]. receptor in in-vitro (but not in cell-based) The structure of insulin glargine was models [54, 55]. The growth-promoting designed by substituting an asparagine residue activity of insulin glargine in muscle cells and with a glycine at position 21 of the A chain and its maximal metabolic activity do not differ elongating the B chain at the C-terminus by from the effects of native human insulin, but adding two arginine residues (Fig. 2)[50, 51]. the lipogenic activity of insulin glargine is Modiﬁcation of the B chain shifts the isoelectric slightly less than that of RHI . point of insulin glargine, while the glycine The PD properties of insulin glargine differ substitution stabilizes the hexamer structure, from those of RHI. Insulin glargine exerted a and contributes to delayed delivery from SC glucose-lowering effect for 24 h after a single Fig. 2 Structure of insulin glargine. Ala alanine, Arg leucine, Lys lysine, Phe phenylalanine, Pro proline, Ser arginine, Asn asparagine, Cys cysteine, Gln glutamine, Glu serine, Thr threonine, Tyr tyrosine, Val valine glutamic acid, Gly glycine, His histidine, Ile isoleucine, Leu Diabetes Ther (2018) 9:927–949 931 daily injection, without a pronounced plasma More recently, epidemiological studies sug- peak, and induced a smoother metabolic effect gested that insulin glargine might be associated than NPH insulin [3, 57]. Although it is recog- with an increased risk of cancer [69, 70], but this nized that the effect of NPH insulin can vary was not conﬁrmed by the ORIGIN trial, which with injection site, changes in injection site do showed that treatment with basal insulin glar- not alter the time–action proﬁle of insulin gine for more than 6 years had a neutral effect glargine [3, 52]. on cancers . Exposure to insulin glargine is very limited as it is rapidly metabolized, pri- marily to the metabolite M1 , which medi- Efﬁcacy and Safety ates most of the glucodynamic effects, has slightly lower receptor binding afﬁnity than One of the ﬁrst studies to evaluate insulin human insulin, and does not exceed the mito- glargine showed that once-daily injections of genic potential of human insulin . this analogue in patients with T1DM who were Insulin glargine 100 U/mL is regarded as a also receiving prandial RHI resulted in similar standard-of-care basal insulin . Recently, glycemic control to that provided by four daily Lilly insulin glargine (Abasaglar ), the ﬁrst injections of NPH insulin plus prandial RHI biosimilar insulin to receive marketing autho- (same total number of insulin units) . Sub- rization in the European Union, has become sequently, large, multicenter clinical trials in available . It has an identical primary patients with T1DM and T2DM generally amino-acid sequence to that of the insulin demonstrated that insulin glargine provided glargine reference product (Lantus insulin lower fasting blood glucose levels and less fre- glargine), and phase I and phase III studies (in quent hypoglycemic episodes than NPH insulin particular ELEMENT-1 and ELEMENT-2) have when administered alone or with premeal RHI demonstrated that Lilly insulin glargine has [3, 59–63]. similar PK/PD proﬁles, efﬁcacy, and safety to the Given that a reduced frequency of hypo- insulin glargine reference product [76–80]. glycemia was generally observed in these stud- ies, the target fasting blood glucose level can be lower than the target that has traditionally been BASAL-BOLUS THERAPY used with NPH insulin [62, 64]. Patients treated WITH INSULIN LISPRO with insulin glargine had less pharmacody- AND INSULIN GLARGINE namic variability than patients treated with NPH insulin , possibly because, unlike NPH IN ADULTS WITH DIABETES insulin , insulin glargine does not need to be resuspended prior to use. In patients with severe insulin deﬁciency, Phase III study data raised no signiﬁcant insulin therapy should replace both basal and safety concerns for insulin glargine [51, 60, 63]. prandial insulin requirements, matching the Retinopathy progression was noted in one study physiologic pattern of insulin secretion as clo- sely as possible . The basal-bolus approach in patients with T2DM . However, a review of all clinical trial data for insulin glargine involves multiple daily injections (MDI), with a long-acting insulin used as the basal insulin and concluded that the data did not support pro- gression of retinopathy in patients with either a rapid-acting insulin adminstered at mealtimes [81, 82]. Long-acting insulin analogues gener- T1DM or T2DM [60, 67]. Subsequently, a large, randomized trial in patients with T2DM ally reduce HbA1c to a similar extent to syn- demonstrated that, despite slightly more severe thetic human insulins, but may be associated diabetic retinopathy at baseline in the group with less nocturnal hypoglycemia [83–85]. treated with insulin glargine, the progression of RAIAs are often preferred over RHI for mealtime retinopathy was similar in insulin glargine- insulin administration because they are absor- treated patients and NPH-treated patients over a bed more rapidly, can be given nearer to the meal, their action better simulates the 5-year period . 932 Diabetes Ther (2018) 9:927–949 physiological insulin response to meals, and that most people with T1DM should receive they are associated with less hypoglycemia either MDI (C 3 prandial insulin injections and [83, 86, 87]. 1 or 2 basal insulin injections per day) or CSII Insulin glargine 100 U/mL and insulin lispro . have both been available for many years, have been widely studied, and can be considered Insulin Glargine Plus Insulin Lispro Versus ﬁrst-line options for use as the basal and bolus Human Insulin components, respectively, of BBT . A search BBT using insulin glargine 100 U/mL plus of the PubMed database up to October 3, 2017 insulin lispro was compared with BBT using was performed to identify papers about BBT other insulin combinations that utilized human involving insulin glargine 100 U/mL plus insu- insulin for the basal and/or prandial compo- lin lispro in patients with T1DM or T2DM that nent in seven studies in adults with T1DM, all were published in English. The search was lim- of which had randomized, open-label [93–97], ited to human data, and the following search or single-blind  designs (Table 1). Overall, string was used: ((basal insulin) OR (basal bolus these studies indicate that insulin glargine plus therapy) OR basal-plus OR basal-bolus OR basal insulin lispro provides similar or better glycemic bolus premixed) AND (insulin glargine OR control to and less nocturnal hypoglycemia Lantus OR ‘‘Lantus SoloStar’’ OR Basaglar OR than regimens including human insulin. Over- Abasaglar OR insulin lispro OR Humalog OR all, insulin glargine plus insulin lispro reduced basal g OR ﬂexpen OR Novorapid OR HbA1c by 0.1–1.0% (1–11 mmol/mol) com- LY2963016 OR (LY2963016 AND lispro)) OR pared with baseline, whereas the change seen (insulin glargine biosimilar) NOT Letter. Addi- with recombinant or synthetic human insulin tional papers were detected from bibliographies as the basal and/or prandial component ranged of the identiﬁed articles. Clinical trials, obser- from an increase of 0.1% (1 mmol/mol) to a vational studies, and review articles were con- reduction of 0.6% (7 mmol/mol) (Table 1). The sidered; trials could be of any duration and mean number of episodes of nocturnal hypo- could involve adult patients of any age or glycemia per month was 0.53–2.0 with insulin pediatric populations. Only studies in which glargine plus insulin lispro, compared with one treatment arm clearly comprised BBT with 0.55–3.6 for regimens including human insulin insulin glargine 100 U/mL plus insulin lispro (Table 1). (and no other insulin preparation) were Only one of these studies compared insulin retained. Comparisons with non-insulin ther- glargine plus insulin lispro with a combination apy were excluded. The initial search identiﬁed of two human insulin products in patients with 994 papers, of which 39 met the criteria for T1DM . In this randomized crossover study inclusion. The remainder of this section focuses (n = 56), insulin glargine plus insulin lispro on studies in adults; pediatric data are discussed provided better glycemic control than NPH later. insulin plus RHI, as indicated by a signiﬁcantly lower HbA1c after 16 weeks of treatment [7.5% Type 1 Diabetes Mellitus vs. 8.0% (59 vs. 64 mmol/mol); p \ 0.001], together with an 8% lower 24-h blood glucose AUC (p = 0.037). In addition, the rate of symp- Insulin is the cornerstone of treatment for tomatic nocturnal hypoglycemia was 44% lower patients with T1DM, with the initial dosage with insulin glargine plus insulin lispro than generally based on body weight (0.4–1.0 with the comparator regimen (0.66 vs. 1.18 U/kg/day total insulin) . Intensive insulin episodes/month; p \ 0.001) . Moreover, therapy (C 3 injections per day or CSII) recipients of insulin analogue therapy reported improves glycemic control and produces better greater satisfaction with treatment . long-term outcomes than 1–2 insulin injections The other studies (n = 34–619 patients) per day [89–91]. Consequently, American Dia- compared BBT with insulin glargine plus insulin betes Association (ADA) guidelines recommend lispro with BBT using either insulin glargine Diabetes Ther (2018) 9:927–949 933 Table 1 Clinical trials comparing basal-bolus therapy with insulin glargine 100 U/mL plus insulin lispro with other basal- bolus regimens in patients with type 1 diabetes mellitus Study design; treatment Treatment N Mean change from baseline Nocturnal duration (prior treatment, hypoglycemia HbA1c (%) Fasting blood as speciﬁed) (episodes per [mmol/mol] glucose mon ) (mmol/L) Comparisons with human insulin IGlar ? LIS vs. NPH ? RHI b b Ashwell R, OL, C, M; 16 wk IGlar ? LIS 56 NR NR 0.66 ± 0.02 b b et al. (No previous IGlar; insulin NPH ? RHI 56 NR NR 1.18 ± 0.02  [MDI] for C 1 year) b b NR NR p \ 0.001 IGlar vs. NPH c d,e Rossetti R, OL; 3 months IGlar ? LIS 17 - 0.4 [- 5] NR 2.0 ± 0.19 d,e et al.  (NPH ? LIS [MDI]) NPH ? LIS 17 ? 0.1 [? 1] NR 3.6 ± 0.4 d,e p \ 0.04 p \ 0.05 p \ 0.05 f d,e Porcellati R, OL; 1 year IGlar ? LIS 61 - 0.5 [- 6] NR 1.2 ± 0.2 et al.  f d,e (NPH ? LIS [MDI]) NPH ? LIS 60 0  NR 3.2 ± 0.3 f d,e p \ 0.05 NR p \ 0.05 g,h Fulcher R, SB, M; 30 wk IGlar ? LIS 62 - 1.0 - 3.46 0.22 et al.  [- 11] g,h (Insulin for C 1 year) NPH ? LIS 63 - 0.5 [- 6] - 2.34 0.37 g,h p \ 0.01 p \ 0.05 p =0.02 d,i Bolli et al. R, OL, M; 24 wk IGlar ? LIS 85 - 0.6 [- 7] - 1.56 0.18 ± 0.25 d,i  (NPH ? RHI or LIS NPH ? LIS 90 - 0.6 [- 7] - 0.54 0.16 ± 0.25 [MDI]) d,i NS p = 0.0064 p = 0.383 Raskin R, OL, M; 16 wk IGlar ? LIS 310 - 0.1 [- 1] - 2.33 ± 0.26 1114 et al.  (NPH ? LIS [MDI] NPH ? LIS 309 - 0.1 [- 1] - 0.69 ± 0.26 992 for C 3 months) NS p = 0.0001 p =0.06 LIS vs. RHI d,g Brunetti R, OL, M, NI; 16 wk IGlar ? LIS 193 NR NR 0.022 et al. d,g (NPH or IGlar ? prandial IGlar ? RHI 202 NR NR 0.021  insulin [MDI]) k k d,g NS NS p = 0.742 934 Diabetes Ther (2018) 9:927–949 Table 1 continued Study design; treatment Treatment N Mean change from baseline Nocturnal duration (prior treatment, hypoglycemia HbA1c (%) Fasting blood as speciﬁed) (episodes per [mmol/mol] glucose mon ) (mmol/L) Comparisons with other insulin analogues LIS vs. GLU Dreyer R, OL, M; 26 wk IGlar ? LIS 333 - 0.1 [- 1] NR 0.53 ± 0.84 et al. (Insulin for [ 1 year) IGlar ? GLU 339 - 0.1 [- 1] NR 0.55 ± 0.94  NS NR NR Kawamori R, OL, M, NI; 28 wk IGlar ? LIS 135 0.04 [0.5] NR 0.01 et al. (BBT for C 12 wk) IGlar ? GLU 132 0.01 [0.1] NR 0.00  l g NS NR p = 0.6637 BBT basal-bolus therapy, C crossover, CI conﬁdence interval, GLU insulin glulisine, HbA1c glycated hemoglobin, IGlar Lantus insulin glargine, LIS insulin lispro, M multicenter, MDI multiple daily injections, mon months, N number of patients, NI noninferiority, NPH neutral protamine Hagedorn insulin, NR not reported, NS not signiﬁcant, OL open-label, R randomized, RHI regular human insulin, SB single-blind, wk weeks Mean ± SE episodes of nocturnal hypoglycemia per patient per month during treatment period, unless indicated otherwise HbA1c value at 16 wk lower with IGlar ? LIS vs. NPH ? RHI [difference - 0.5% (6 mmol/mol), 95% CI - 0.7 to - 0.3% (- 8to - 3 mmol/mol), p \ 0.001]; fasting FBG value lower at 16 wk with IGlar ? LIS vs. NPH ? RHI (difference -1.5 mmol/L, 95% CI - 2.6 to - 0.5, p = 0.005) Data shown are for patients given IGlar at bedtime. Another group received IGlar at dinnertime; there were no signiﬁcant differences in HbA1c or hypoglycemia results between these two groups Mean number of episodes per month during the last month of treatment Hypoglycemia deﬁned as blood glucose \ 4.0 mmol/L irrespective of symptoms Mean daily blood glucose was lower with IGlar vs. NPH (7.6 ± 0.11 mmol/L vs. 8.1 ± 0.22 mmol/L, p \ 0.05) Severe nocturnal hypoglycemia Number of episodes per 100 patient days Serious nocturnal hypoglycemia (blood glucose \ 2.3 mmol/L) Number of episodes during entire treatment period (16 wk) Paper states treatments did not differ with respect to HbA1c and FBG at study end Non-inferiority of IGlar ? GLU versus IGlar ? LIS was demonstrated based on analysis of covariance of the change in HbA1c and using a prespeciﬁed non-inferiority margin (upper 95% CI limit) of 0.45% (5 mmol/mol); the between-group difference in least-squares mean change was 0.1% [1 mmol/mol; 95% CI - 0.1 to 0.2% (- 1 to 2 mmol/mol)] plus RHI or NPH insulin plus insulin lispro. nocturnal hypoglycemia  versus NPH insu- lin plus insulin lispro (mean episodes of noc- Insulin glargine plus insulin lispro provided better control of fasting blood glucose [95–99] turnal hypoglycemia per month 1.2–2.0 vs. and/or HbA1c [95, 96, 99] than NPH insulin 3.2–3.6; see Table 1 for individual study results). plus insulin lispro, and similar glycemic control to insulin glargine plus RHI . Half of these Insulin Glargine Plus Insulin Lispro Versus studies also found that BBT with insulin glar- Other Insulin Analogues gine plus insulin lispro reduced the frequency of When compared with BBT utilizing other insu- total nocturnal hypoglycemia [95, 96] or severe lin analogues in T1DM, BBT with insulin Diabetes Ther (2018) 9:927–949 935 Table 2 Clinical trials comparing basal-bolus therapy with insulin glargine 100 U/mL plus insulin lispro to continuous subcutaneous insulin infusion using insulin lispro in patients with type 1 diabetes mellitus Study design; duration Treatment N Mean change from baseline Severe hypoglycemia (prior treatment, as (episodes per patient HbA1c (%) Fasting blood speciﬁed) during treatment ) [mmol/mol] glucose (mmol/L) Lepore et al. OL; 1 year IGlar ? LIS 24 - 0.7  NR 0.21 ± 0.40  (NPH ? RHI or LIS LIS CSII 24 - 1.0 NR 0.17 ± 0.37 [MDI] for C 1 year) [- 11] NS NR NS Lepore et al. OL; 1 year IGlar ? LIS 16 NR NR 0.18  (NPH ? RHI or LIS LIS CSII 16 NR NR 0.12 [MDI] for C 1 year) b b NS NS NS Bolli et al. R, OL, M; 24 wk IGlar ? LIS 26 - 0.6 [- 7] - 2.7 35 ± 35  c (NPH-based MDI LIS CSII 24 - 0.7 [- 8] - 3.3 41 ± 43 regimen) NS NS p = 0.93 Bruttomesso R, OL, C, M; 4 mon IGlar ? LIS 39 - 0.1 [- 1] NR 0.1 ± 0.4 et al.  (LIS or ASP CSII LIS CSII 39 - 0.2 [- 2] NR 0.1 ± 0.3 for C 6 mon) NS NR p = 0.710 Ruiz-de- R, OL; 6 mon IGlar ? LIS 23 - 0.3 NR 0.05 ± 0.2 Adana [- 3] et al.  (IGlar ? LIS [MDI] LIS CSII 15 - 0.9 NR 0.29 ± 1 for 6 mon) [- 10] NR NR p = 0.08 ASP insulin aspart, C crossover, CSII continuous subcutaneous insulin infusion, IGlar Lantus insulin glargine, HbA1c glycated hemoglobin, LIS insulin lispro, M multicenter, MDI multiple daily injections, mon months, N number of patients, NPH neutral protamine Hagedorn insulin, NR not reported, NS not signiﬁcant, OL open-label, R randomized, RHI regular human insulin, wk weeks Total number of episodes per patient during study treatment. Severe hypoglycemia, unless indicated otherwise Values for changes in HbA1c and FBG were not reported, but paper stated that there were no signiﬁcant differences in the degree of improvement in HbA1c or fasting plasma glucose between the groups Overall incidence of hypoglycemia. There were also no signiﬁcant differences for nonsevere, nocturnal, symptomatic, or asymptomatic hypoglycemia events All patients underwent a 6-month period of IGlar ? LIS prior to randomization to receive CSII or continue with IGlar ? LIS. Baseline values were obtained after this initial 6-month period of IGlar ? LIS p = 0.03 for comparison of HbA1c values at endpoint [IGlar ? LIS 7.6% vs. CSII 7.0% (60 vs. 53 mmol/mol)] 936 Diabetes Ther (2018) 9:927–949 Table 3 Clinical trials comparing basal-bolus therapy with insulin glargine 100 U/mL plus insulin lispro to other insulin regimens in patients with type 2 diabetes mellitus Study design; duration Treatment N Mean change from baseline Nocturnal (prior treatment, as hypoglycemia HbA1c (%) Fasting blood speciﬁed) (episodes per year ) [mmol/mol] glucose (mmol/L) Comparisons with premixed insulin Rosenstock R, OL, M, NI; 24 wk IGlar ? LIS 187 - 2.1 - 1.88 6.17 ± 10.68 et al.  [- 23] (IGlar ? OAD LM 50/50 t.i.d 187 - 1.9 - 0.74 4.78 ± 7.15 for C 90 days) [- 20] c d p = 0.021 NR p = 0.139 Miser et al. R, OL, M, NI; 24 wk IGlar ? LIS 199 0.1  NR 3.0 ± 13.6  (Arm A) (IGlar ? OAD or LM LM 75/25 b.i.d. 200 0.0  NR 2.5 ± 7.0 75/25 ? OAD) (Arm A) NR NR p = 0.657 IGlar ? LIS 171 0.2 [2.2] NR 2.4 ± 6.1 (Arm B) LM 50/50 t.i.d. 174 0.2 [2.2] NR 2.5 ± 8.1 (Arm B) NR NR p = 0.949 Jia et al. R, OL, M, NI; 24 wk IGlar ? LIS 202 - 1.1 -1.2 0.05 ± 0.21  [- 12] (PMI [human insulin-, LM 50/50 197 - 1.1 -0.8 0.03 ± 0.09 LIS- or ASP-based] b.i.d ? LM [- 12] for C 6 mon) 75/25 o.d. NS p = 0.002 p = 0.235 Diabetes Ther (2018) 9:927–949 937 Table 3 continued Study design; duration Treatment N Mean change from baseline Nocturnal (prior treatment, as hypoglycemia HbA1c (%) Fasting blood speciﬁed) (episodes per year ) [mmol/mol] glucose (mmol/L) Comparison with other insulin analogues Koivisto R, OL, M, NI; 24 wk IGlar ? LIS 191 - 1.2 NR 0.09 et al.  [- 13] (OAD ? insulin) ILPS ? LIS 192 - 1.1 NR 0.13 [- 12] NR NR p = 0.2 ASP insulin aspart, b.i.d. twice daily, C crossover, CI conﬁdence interval, IGlar Lantus insulin glargine, HbA1c glycated hemoglobin, ILPS insulin lispro protamine suspension, LIS insulin lispro, LM 50/50 50% insulin lispro protamine sus- pension/50% insulin lispro, LM 75/25 75% insulin lispro protamine suspension/25% insulin lispro, M multicenter, mon months, N number of patients, NI noninferiority, NR not reported, NS not signiﬁcant, OAD oral antihyperglycemic drugs, o.d. once daily, OL open-label, PMI premixed insulin, R randomized, t.i.d. three times daily, wk weeks Mean ± SD number of episodes per patient per year unless indicated otherwise Evening dose could be changed to LM 75/25 if necessary; this occurred in 55% of patients Difference in HbA1c change from baseline to endpoint (BBT minus LM 50/50) - 0.2% [- 2 mmol/mol; 90% CI - 0.4 to - 0.1% (- 4 to 1 mmol/mol)]. Protocol-speciﬁed lower limit of CI for noninferiority was - 0.3%. Therefore, non- inferiority of LM 50/50 was not demonstrated p = 0.013 for comparison of fasting plasma glucose values at endpoint (IGlar ? LIS 8.2 mmol/L vs. LM 50/50 8.8 mmol/L) Substudy of DURABLE study. During a 6-month initiation phase, patients received IGlar once daily or LM 75/25 twice daily. Patients who did not achieve glycemic control then entered the 6-month intensiﬁcation substudy. Patients on IGlar entered intensiﬁcation arm A and patients on LM 75/25 entered intensiﬁcation arm B Noninferiority of LM 75/25 and LM 50/50 versus BBT was demonstrated based on HbA1c values at endpoint, with 95% CI of - 0.10 to 0.37% (- 1 to 4 mmol/mol) and - 0.25 to 0.25% (- 3 to 3 mmol/mol), respectively; the noninferiority margin was set at 0.4% (5 mmol/mol) Noninferiority of LM 50/50–LM 75/25 vs. IGlar ? LIS was demonstrated based on a noninferiority margin of 0.4% (5 mmol/mol); the between-group difference in least squares mean change was 0% [0 mmol/mol; 95% CI - 0.1 to 0.2% (- 1 to 2 mmol/mol)] Mean ± SD number of episodes per patient per 30 days Noninferiority of ILPS ? LIS vs. IGLar ? LIS was demonstrated based on analysis of covariance of the change in HbA1c and using a prespeciﬁed noninferiority margin (upper 95% CI limit) of 0.4% (5 mmol/mol); the between-group difference in least-squares mean change was 0.1% [1 mmol/mol; 95% CI - 0.1 to 0.3% (- 1 to 3 mmol/mol)] Insulin Glargine Plus Insulin Lispro Versus glargine 100 U/mL plus insulin lispro provided similar glycemic control and rates of hypo- Insulin Lispro CSII BBT with insulin glargine 100 U/mL plus insulin glycemia to insulin glargine plus insulin gluli- sine in randomized clinical trials (n = 672 and lispro was compared with CSII using insulin 267, respectively) (Table 1)[101, 102], and lispro in ﬁve open-label studies in patients with lower evening post-prandial glucose levels than T1DM (n = 32–50) (Table 2)[104–108]. The two insulin detemir plus insulin lispro in a crossover approaches provided similar glycemic control and frequency of severe hypoglycemia in most trial (n = 8), which could be due to insulin detemir having a shorter duration of action or a studies [104–106], although two reported better glycemic control with CSII [107, 108]. slower onset of action . 938 Diabetes Ther (2018) 9:927–949 Type 2 Diabetes Mellitus Among three studies evaluating full BBT (n = 374, 744, 402) (Table 3), two concluded that premixed insulin (insulin lispro mix 25/75 Pharmacological treatment for patients with or 50/50) was noninferior to BBT with insulin T2DM usually starts with a single oral antidiabetic glargine plus insulin lispro with respect to agent (OAD), generally metformin . If maxi- HbA1c levels in patients who had failed to mally titrated OAD monotherapy is inadequate, a achieve glycemic control on their initial insulin second oral agent, a glucagon-like peptide-1 (GLP- regimen (in combination with OADs) 1) receptor agonist or insulin, is added . The [114, 115]. The third study was unable to progressive decline in b-cell function that occurs demonstrate noninferiority for insulin lispro in T2DM means that most patients eventually mix 50/50 or 75/25, based on a difference in need exogenous insulin therapy in combination HbA1c change (BBT minus premixed) of - 0.2% with other therapies [87, 88]. [2 mmol/mol; 90% CI - 0.4 to - 0.1% (- 5to - 1 mmol/mol)] after 24 weeks, against a non- Treatment Intensiﬁcation Using Insulin inferiority margin of - 0.3% (3 mmol/mol) Insulin is usually added to ongoing treatment . In two of these studies, the total daily with metformin and/or other OADs and possibly insulin dose at study end was similar with both GLP-1 receptor agonist therapy. Rapid-acting approaches [114, 115]; in the third study, mean mealtime insulin may be used as the initial total insulin dose was higher in the BBT group insulin therapy in patients with T2DM [109, 110]. than in the premixed-insulin group at study However, it is generally more common to start end (146 vs. 123 units, p = 0.002) . Rates of with a single daily injection of basal insulin overall and nocturnal hypoglycemia and mean [81, 82, 88, 111]. If basal insulin alone does not weight gain were similar with both treatment provide adequate glycemic control, prandial approaches [113–115]. insulin can be added, either as a full basal-bolus The other four studies evaluated basal-plus regimen (basal insulin with bolus insulin admin- therapy or intensiﬁcation strategies involving istered at all meals) or in a stepwise fashion, one to three doses of insulin lispro (n = 476, starting with the largest meal (‘basal-plus’ ther- 426, 344, 484) [116–119]. In these studies, the apy) and then other meals, as necessary, to reach addition of an increasing number of prandial full BBT [11, 82, 111]. Alternatively, a GLP-1 insulin injections was effective and safe receptor agonist might be added to basal insulin [116–119]. Three studies found premixed insu- therapy as the next step [81, 88, 111, 112], or the lin was noninferior to basal-plus therapy with patient could be switched from basal insulin to insulin glargine plus insulin lispro premixed insulin (initially administered twice [116, 118, 119]. However, one study did not daily, progressing to three times daily if necessary) demonstrate noninferiority for insulin lispro [81, 88]. The intensiﬁcation option selected will mix 50/50, based on a change in HbA1c of depend on each patient’s clinical circumstances - 1.76% (- 19 mmol/mol) versus - 1.93% and preferences . (- 21 mmol/mol) with insulin glargine plus insulin lispro [between-group difference 0.17% Insulin Glargine Plus Insulin Lispro Versus (2 mmol/mol) for premixed minus basal-plus, Premixed Insulin 95% CI - 0.03 to 0.37 (- 0 to 4 mmol/mol); Seven studies, all using a randomized, con- noninferiority margin 0.3% (3 mmol/mol)] trolled, noninferiority design, compared insulin . In this study, HbA1c values were signiﬁ- glargine 100 U/mL plus insulin lispro with pre- cantly lower in the basal-plus group compared mixed insulin with the aim of establishing with the premixed insulin group at weeks 12 whether premixed insulin was noninferior to and 24 weeks, although not at week 36 (study BBT. Overall, study results did not suggest any end) . Total daily insulin doses, number of clinically relevant advantage of premixed insu- injections, rates of hypoglycemia, and weight lin over insulin glargine plus insulin lispro changes at study end were similar with both [113–119]. approaches in most studies [116–119], with the Diabetes Ther (2018) 9:927–949 939 exceptions that the total daily insulin dose and to self-titrate their bolus insulin lispro safely mean daily number of injections were greater using either of two simple algorithms, with , nocturnal hypoglycemia was more com- insulin lispro adjusted every other day based on mon , and weight gain was greater  the preprandial reading from the previous with premixed than BBT in one study each. 1–3 days . Glargine 1 Lispro Versus Other Insulin BASAL-BOLUS THERAPY Analogues WITH INSULIN LISPRO PLUS A randomized clinical trial (n =383) showed that INSULIN GLARGINE IN SPECIAL similar glycemic control was achieved with insulin glargine 100 U/ml plus insulin lispro BBT POPULATIONS and insulin lispro protamine suspension plus insulin lispro BBT in patients with T2DM who no Children and Adolescents longer achieved glycemic targets on insulin plus OAD treatment (Table 3). More than 82% The use of BBT with insulin glargine 100 U/mL of patients in each group received three insulin plus insulin lispro in pediatric patients has been lispro injections per day throughout the study evaluated in a few, mostly small, trials, includ- . In a small crossover study involving 12 ing two randomized open-label studies patients, BBT with insulin glargine plus insulin [122–124] and one noncomparative study . lispro was associated with lower pre- and post- Overall, these studies found that this regimen dinner glucose levels than BBT with insulin was effective and safe in children or adolescents detemir plus insulin lispro . with T1DM. In a crossover study involving adolescents Insulin Administration and Titration (aged 12–20 years, currently in puberty) with Protocols T1DM (n = 25) who were already receiving Various algorithms for starting and intensifying multiple injection regimens (not speciﬁed fur- insulin therapy in patients with T2DM are ther), BBT with insulin glargine plus insulin available, such as those provided by the ADA lispro was at least as effective as NPH insulin  and the American Association of Clinical plus RHI at maintaining glycemic control, and Endocrinologists/American College of was associated with a lower incidence of noc- Endocrinology (AACE/ACE) . turnal hypoglycemia . In the other ran- Only one of the studies evaluating full BBT domized study (n = 175), insulin glargine plus with insulin glargine 100 U/mL plus insulin insulin lispro was at least as effective as inter- lispro in patients with T2DM outlined the dos- mediate-acting NPH or lente insulin plus insu- ing algorithms used: insulin doses were adjusted lin lispro, and reduced glucose variability, in weekly based on mean preprandial blood glu- children and adolescents (aged 9–17 years) who cose level and, if a more aggressive approach had previously been receiving intermediate- was needed, total daily insulin requirement acting NPH or lente insulin [123, 124]. There . was no difference in the rates of hypoglycemia Studies that evaluated progression of insulin [blood glucose \ 2.00 mmol/L (\ 36 mg/dL) or therapy, but not necessarily full BBT, used var- severe hypoglycemia requiring assistance] ious algorithms based on fasting and/or between the groups in the overall analysis , preprandial blood glucose levels to adjust the but in an analysis of a subset who used contin- dosages of insulin glargine and insulin lispro uous glucose monitoring (n = 90), insulin glar- [117–119]. Importantly, patients can be trained gine plus insulin lispro reduced the amount of to self-titrate bolus insulin doses safely . In time spent with blood glucose the 24-week AUTONOMY study, patients on levels \ 2.22 mmol/L (\ 40 mg/dL) based on optimized basal insulin glargine who were such monitoring . Finally, a small (n = 35) starting to add insulin lispro therapy were able noncomparative study suggested that ﬂexible 940 Diabetes Ther (2018) 9:927–949 MDI using insulin glargine plus insulin lispro insulin lispro in patients with renal disease or (with the lispro dose adjusted according to hepatic disease. The product characteristic 2-hour postprandial blood glucose measure- summaries for insulin glargine and insulin lis- ments) improved glycemic control in preschool pro include the warning that insulin require- children who had previously been receiving ments may be lower in patients with renal or twice-daily ultralente insulin plus insulin lispro hepatic impairment due to reduced insulin . metabolism, and lower in patients with hepatic impairment due to a reduced capacity for glu- coneogenesis [31, 75], although in chronic Elderly Patients hepatic impairment, insulin requirements may increase due to greater insulin resistance . No studies speciﬁcally evaluating BBT with However, the summary of product characteris- insulin glargine 100 U/mL plus insulin lispro in tics for insulin lispro also states that renal and elderly patients (aged C 65 years) were identi- hepatic impairment do not affect the glucody- ﬁed, but two studies reported subgroup analyses namic response to insulin lispro . Studies in patients in this age group with T2DM showed that the PK and PD characteristics of [120, 121]. According to a post hoc subgroup insulin lispro were maintained in patients with analysis, BBT with either insulin lispro pro- T1DM and diabetic nephropathy  and that tamine suspension plus insulin lispro or insulin postprandial glucose levels and hypoglycemia glargine plus insulin lispro was effective and rates were lower with insulin lispro than with safe in patients aged [ 65 years (n = 89), with RHI in patients with T2DM and compensated mean reductions from baseline at 24 weeks in nonalcoholic liver disease . Insulin glar- HbA1c of - 1.0% (11 mmol/mol) and - 1.2% gine provided better glycemic control than NPH (13 mmol/mol), respectively; these reductions insulin in patients with T2DM on hemodialysis were similar to those achieved in the overall . Overall, insulin glargine and insulin lis- population [- 1.1% (11 mmol/mol) and - 1.2% pro appear to be suitable for use in patients with (13 mmol/mol), respectively] . The pro- renal or hepatic disease. portion of elderly patients reporting at least one No studies were identiﬁed that speciﬁcally hypoglycemic event was similar to that of the evaluated BBT with insulin glargine plus insulin overall population for both treatment groups lispro in patients with cardiovascular disease. . Subgroup analysis of the AUTONOMY However, in patients with T2DM, the glycemic study (n = 255/1112) showed that patients beneﬁts of insulin glargine were unaltered by aged C 65 years on basal insulin glargine were cardiovascular risk factors ; insulin glar- able to self-titrate insulin lispro doses safely to gine did not increase the risk of adverse car- achieve insulin intensiﬁcation . The per- diovascular outcomes in patients with pre- centages of patients aged C 65 years who existing cardiovascular disease or cardiovascular achieved HbA1c targets of B 7.0% risk factors in the ORIGIN study [130, 131]; and (53 mmol/mol) were 58.5% and 58.0% when RAIAs, including insulin lispro, had potentially insulin lispro was self-titrated every day or every more favorable effects on cardiovascular risk 3 days, respectively, and were similar to the factors such as dyslipidemia and biomarkers of percentages achieving this goal in the total inﬂammation or atherosclerosis compared with population. There was no signiﬁcant difference RHI . in the rate of hypoglycemia between algorithm Two randomized, open-label studies (n = 60, groups among either the overall population or 140) evaluated BBT with insulin glargine plus elderly patients . insulin lispro in hospitalized patients with dia- betes [133, 134]. In patients with T2DM on a Patients with Comorbidities general medicine ward, BBT with insulin glar- gine plus insulin lispro permitted better adher- Studies have not been published that speciﬁ- ence to target insulin timing with respect to cally evaluated BBT with insulin glargine plus meals and reduced the percentage of patient Diabetes Ther (2018) 9:927–949 941 days in which hypoglycemia \ 70 mg/dL support the efﬁcacy and safety of these agents as occurred when compared with NPH insulin plus BBT or basal-plus therapy in patients with RHI . In patients with T2DM undergoing T1DM and T2DM. surgery, BBT using insulin glargine plus insulin Clinical studies indicate that in patients with lispro provided effective glycemic control, with T1DM, BBT with insulin glargine plus insulin no signiﬁcant difference in postoperative glu- lispro provides similar or better glycemic con- cose levels or in overall hypoglycemic episodes trol, and less nocturnal hypoglycemia, than BBT compared with insulin detemir plus insulin involving human insulin as the basal and/or aspart . prandial component. Moreover, in patients with T1DM, BBT with insulin glargine 100 U/mL plus insulin lispro generally provides a Other Patient Populations similar level of glycemic control to that achieved with insulin lispro CSII, with similar Most trials involving insulin glargine plus rates of severe hypoglycemia. insulin lispro were conducted in Europe or the In patients with T2DM receiving basal insu- USA. However, ethnicity can affect the response lin, intensiﬁcation of insulin therapy can gen- of patients with T2DM to insulin therapy . erally be achieved by either initiating BBT or Studies and subgroup analyses have shown that progressing to basal-plus therapy and then full BBT or basal-plus therapy with insulin glargine BBT with prandial cover for all meals. Progres- plus insulin lispro can provide effective gly- sion of insulin therapy can be achieved using cemic control in South American  and East various algorithms based on fasting and/or Asian populations [115, 137] with T2DM. preprandial blood glucose levels to adjust the Finally, no studies appear to have speciﬁcally dosages of insulin glargine and insulin lispro. evaluated BBT with insulin glargine plus insulin Algorithms for starting and intensifying insulin lispro in pregnant women with diabetes; how- therapy are provided by the ADA  and the ever, available data for the individual agents AACE/ACE . Simple algorithms for the suggest that both are safe for use in pregnancy titration of prandial insulin lispro can facilitate [138, 139]. patient self-management of insulin therapy. Most studies evaluating BBT with insulin glar- gine plus insulin lispro in patients with T2DM CONCLUSIONS evaluated the noninferiority of premixed insu- lin versus BBT. These studies found that pre- With the growing availability of alternative mixed insulin does not appear to provide any insulins for use in BBT, it is timely that this advantage over this BBT with respect to gly- article reviews the current evidence regarding cemic control or rates of hypoglycemia. BBT combining insulin glargine 100 U/mL with One of the key factors to be considered with insulin lispro in patients with T1DM and T2DM, insulin therapy is the need to achieve a balance including its use in special populations (chil- between maintaining good glycemic control dren, elderly, pregnant women, patients with and minimizing the risk of hypoglycemic epi- comorbidities, and people of different sodes. Studies such as AUTONOMY  ethnicities). demonstrate that, if well titrated, insulin ther- Insulin glargine 100 U/mL and insulin lispro apy enables glycemic targets to be reached have both been available for many years, have safely and simply. been studied extensively, and are widely used as Pooled analyses of studies involving insulin the basal and bolus components, respectively, glargine or insulin lispro showed that these of BBT. Insulin lispro was the ﬁrst rapid-acting agents provided similar levels of efﬁcacy and insulin analogue to become available and has safety in elderly and young patients. In addi- been evaluated in a wide range of patients, and tion, insulin glargine plus insulin lispro is safe insulin glargine is regarded as a standard-of-care and effective in people of different ethnicities, basal insulin. Given the length of their avail- and these insulins appear to be suitable for use ability, a substantial evidence base exists to 942 Diabetes Ther (2018) 9:927–949 in other special populations such as pregnant Data Availability. Data sharing is not women and patients with comorbidities. applicable to this article, as no datasets were In conclusion, BBT remains a relevant option generated or analyzed during the current study. for patients with T1DM and those with T2DM Open Access. This article is distributed requiring insulin treatment. In particular, the under the terms of the Creative Commons widely used combination of insulin glargine Attribution-NonCommercial 4.0 International 100 U/mL plus insulin lispro has established License (http://creativecommons.org/licenses/ efﬁcacy and safety, and should be considered a by-nc/4.0/), which permits any non- ﬁrst-line option in patients for whom BBT reg- commercial use, distribution, and reproduction imens are being considered. in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, ACKNOWLEDGEMENTS and indicate if changes were made. Funding. Sponsorship for this study and article processing charges were funded by Eli REFERENCES Lilly and Company. All authors had full access to all of the data in this study and take complete 1. Banting FG, Best CH, Collip JB, Campbell WR, responsibility for the integrity of the data and Fletcher AA. 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