Introduction
Insulin treatment of type 1 (T1DM) and type 2 (T2DM) diabetes mellitus has progressed considerably since the discovery of insulin in 1922 [
1] and its subsequent purification and crystallization [
2]. Initially, only animal insulin was available to diabetics, and animal insulin is associated with adverse effects such as insulin allergy, insulin resistance, and insulin lipodystrophy [
3‐
5]. However, in the 1980s, recombinant DNA technology enabled the development of synthetic human insulin, which replaced animal insulin as it was found to be less likely to produce adverse effects and it could be mass-produced. In the late 1980s and early 1990s, it became apparent that better glucose control would require new insulin preparations with a faster onset and shorter duration of action, enabling prandial insulin to be administered closer to mealtimes, as well as long-acting preparations with a flatter time–action profile and less variable bioavailability, including formulations suitable for once-daily dosing [
6‐
9]. Molecular genetic techniques provided opportunities to create insulin analogues by changing the structure of the native protein and improving its therapeutic properties [
8‐
10].
The crucial importance of an exogenous basal-bolus insulin supply to control blood glucose concentrations in patients with absolute insulin deficiency disease (i.e., T1DM) is well recognized. However, in T2DM, the initial relative insulin deficiency progresses with the decline in β-cell function, which again makes a combination of basal and prandial insulin the most effective insulin strategy [
5,
11,
12].
This article reviews the current evidence concerning a widely used basal-bolus strategy combining insulin glargine 100 U/mL with insulin lispro in patients with T1DM and T2DM. The review does not consider all insulins and, as such, does not include other established or new insulins used in basal-bolus regimens unless they have been directly compared with insulin glargine 100 U/mL plus insulin lispro. An introductory summary of key information about the individual agents leads into a discussion of their combined use in basal-bolus therapy (BBT). In addition, the use of this BBT in special populations is considered. The information provided is based on previously conducted and published studies and does not contain any studies with human participants or animals performed by any of the authors.
Basal-Bolus Therapy with Insulin Lispro and Insulin Glargine in Adults with Diabetes
In patients with severe insulin deficiency, insulin therapy should replace both basal and prandial insulin requirements, matching the physiologic pattern of insulin secretion as closely as possible [
81]. The basal-bolus approach involves multiple daily injections (MDI), with a long-acting insulin used as the basal insulin and a rapid-acting insulin adminstered at mealtimes [
81,
82]. Long-acting insulin analogues generally reduce HbA1c to a similar extent to synthetic human insulins, but may be associated with less nocturnal hypoglycemia [
83‐
85]. RAIAs are often preferred over RHI for mealtime insulin administration because they are absorbed more rapidly, can be given nearer to the meal, their action better simulates the physiological insulin response to meals, and they are associated with less hypoglycemia [
83,
86,
87].
Insulin glargine 100 U/mL and insulin lispro have both been available for many years, have been widely studied, and can be considered first-line options for use as the basal and bolus components, respectively, of BBT [
87]. A search of the PubMed database up to October 3, 2017 was performed to identify papers about BBT involving insulin glargine 100 U/mL plus insulin lispro in patients with T1DM or T2DM that were published in English. The search was limited to human data, and the following search string was used: ((basal insulin) OR (basal bolus therapy) OR basal-plus OR basal-bolus OR basal bolus premixed) AND (insulin glargine OR Lantus OR “Lantus SoloStar” OR Basaglar OR Abasaglar OR insulin lispro OR Humalog OR basal g OR flexpen OR Novorapid OR LY2963016 OR (LY2963016 AND lispro)) OR (insulin glargine biosimilar) NOT Letter. Additional papers were detected from bibliographies of the identified articles. Clinical trials, observational studies, and review articles were considered; trials could be of any duration and could involve adult patients of any age or pediatric populations. Only studies in which one treatment arm clearly comprised BBT with insulin glargine 100 U/mL plus insulin lispro (and no other insulin preparation) were retained. Comparisons with non-insulin therapy were excluded. The initial search identified 994 papers, of which 39 met the criteria for inclusion. The remainder of this section focuses on studies in adults; pediatric data are discussed later.
Type 1 Diabetes Mellitus
Insulin is the cornerstone of treatment for patients with T1DM, with the initial dosage generally based on body weight (0.4–1.0 U/kg/day total insulin) [
88]. Intensive insulin therapy (≥ 3 injections per day or CSII) improves glycemic control and produces better long-term outcomes than 1–2 insulin injections per day [
89‐
91]. Consequently, American Diabetes Association (ADA) guidelines recommend that most people with T1DM should receive either MDI (≥ 3 prandial insulin injections and 1 or 2 basal insulin injections per day) or CSII [
92].
Insulin Glargine Plus Insulin Lispro Versus Human Insulin
BBT using insulin glargine 100 U/mL plus insulin lispro was compared with BBT using other insulin combinations that utilized human insulin for the basal and/or prandial component in seven studies in adults with T1DM, all of which had randomized, open-label [
93‐
97], or single-blind [
98] designs (Table
1). Overall, these studies indicate that insulin glargine plus insulin lispro provides similar or better glycemic control to and less nocturnal hypoglycemia than regimens including human insulin. Overall, insulin glargine plus insulin lispro reduced HbA1c by 0.1–1.0% (1–11 mmol/mol) compared with baseline, whereas the change seen with recombinant or synthetic human insulin as the basal and/or prandial component ranged from an increase of 0.1% (1 mmol/mol) to a reduction of 0.6% (7 mmol/mol) (Table
1). The mean number of episodes of nocturnal hypoglycemia per month was 0.53–2.0 with insulin glargine plus insulin lispro, compared with 0.55–3.6 for regimens including human insulin (Table
1).
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
Comparisons with human insulin |
IGlar + LIS vs. NPH + RHI |
| R, OL, C, M; 16 wk | IGlar + LIS | 56 | NRb | NRb | 0.66 ± 0.02 |
(No previous IGlar; insulin [MDI] for ≥ 1 year) | NPH + RHI | 56 | NRb | NRb | 1.18 ± 0.02 |
| | | NRb | NRb | p < 0.001 |
IGlar vs. NPH |
| R, OL; 3 months | IGlarc + LIS | 17 | − 0.4 [− 5] | NR | 2.0 ± 0.19d,e |
(NPH + LIS [MDI]) | NPH + LIS | 17 | + 0.1 [+ 1] | NR | 3.6 ± 0.4d,e |
| | | p < 0.04 | p < 0.05 | p < 0.05d,e |
| R, OL; 1 year | IGlar + LIS | 61 | − 0.5 [− 6] | NRf | 1.2 ± 0.2d,e |
(NPH + LIS [MDI]) | NPH + LIS | 60 | 0 [0] | NRf | 3.2 ± 0.3d,e |
| | | p < 0.05 | NRf | p < 0.05d,e |
| R, SB, M; 30 wk | IGlar + LIS | 62 | − 1.0 [− 11] | − 3.46 | 0.22g,h |
(Insulin for ≥ 1 year) | NPH + LIS | 63 | − 0.5 [− 6] | − 2.34 | 0.37g,h |
| | | p < 0.01 | p < 0.05 | p = 0.02g,h |
| R, OL, M; 24 wk | IGlar + LIS | 85 | − 0.6 [− 7] | − 1.56 | 0.18 ± 0.25d,i |
(NPH + RHI or LIS [MDI]) | NPH + LIS | 90 | − 0.6 [− 7] | − 0.54 | 0.16 ± 0.25d,i |
| | | NS | p = 0.0064 | p = 0.383d,i |
| R, OL, M; 16 wk | IGlar + LIS | 310 | − 0.1 [− 1] | − 2.33 ± 0.26 | 1114j |
(NPH + LIS [MDI] for ≥ 3 months) | NPH + LIS | 309 | − 0.1 [− 1] | − 0.69 ± 0.26 | 992j |
| | | NS | p = 0.0001 | p = 0.06j |
LIS vs. RHI |
| R, OL, M, NI; 16 wk | IGlar + LIS | 193 | NR | NR | 0.022d,g |
(NPH or IGlar + prandial insulin [MDI]) | IGlar + RHI | 202 | NR | NR | 0.021d,g |
| | | NSk | NSk | p = 0.742d,g |
Comparisons with other insulin analogues |
LIS vs. GLU |
| R, OL, M; 26 wk | IGlar + LIS | 333 | − 0.1 [− 1] | NR | 0.53 ± 0.84 |
(Insulin for > 1 year) | IGlar + GLU | 339 | − 0.1 [− 1] | NR | 0.55 ± 0.94 |
| | | NS | NR | NR |
| R, OL, M, NI; 28 wk | IGlar + LIS | 135 | 0.04 [0.5] | NR | 0.01g |
(BBT for ≥ 12 wk) | IGlar + GLU | 132 | 0.01 [0.1] | NR | 0.00g |
| | | NSl | NR | p = 0.6637g |
Only one of these studies compared insulin glargine plus insulin lispro with a combination of two human insulin products in patients with T1DM [
93]. In this randomized crossover study (
n = 56), insulin glargine plus insulin lispro provided better glycemic control than NPH insulin plus RHI, as indicated by a significantly lower HbA1c after 16 weeks of treatment [7.5% 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 symptomatic nocturnal hypoglycemia was 44% lower with insulin glargine plus insulin lispro than with the comparator regimen (0.66 vs. 1.18 episodes/month;
p < 0.001) [
93]. Moreover, recipients of insulin analogue therapy reported greater satisfaction with treatment [
94].
The other studies (
n = 34–619 patients) compared BBT with insulin glargine plus insulin lispro with BBT using either insulin glargine plus RHI or NPH insulin plus insulin lispro. Insulin glargine plus insulin lispro provided better control of fasting blood glucose [
95‐
99] and/or HbA1c [
95,
96,
99] than NPH insulin plus insulin lispro, and similar glycemic control to insulin glargine plus RHI [
100]. Half of these studies also found that BBT with insulin glargine plus insulin lispro reduced the frequency of total nocturnal hypoglycemia [
95,
96] or severe nocturnal hypoglycemia [
99] versus NPH insulin plus insulin lispro (mean episodes of nocturnal hypoglycemia per month 1.2–2.0 vs. 3.2–3.6; see Table
1 for individual study results).
Insulin Glargine Plus Insulin Lispro Versus Other Insulin Analogues
When compared with BBT utilizing other insulin analogues in T1DM, BBT with insulin glargine 100 U/mL plus insulin lispro provided similar glycemic control and rates of hypoglycemia to insulin glargine plus insulin glulisine in randomized clinical trials (
n = 672 and 267, respectively) (Table
1) [
101,
102], and lower evening post-prandial glucose levels than insulin detemir plus insulin lispro in a crossover trial (
n = 8), which could be due to insulin detemir having a shorter duration of action or a slower onset of action [
103].
Insulin Glargine Plus Insulin Lispro Versus Insulin Lispro CSII
BBT with insulin glargine 100 U/mL plus insulin lispro was compared with CSII using insulin lispro in five open-label studies in patients with T1DM (
n = 32–50) (Table
2) [
104‐
108]. The two approaches provided similar glycemic control and frequency of severe hypoglycemia in most studies [
104‐
106], although two reported better glycemic control with CSII [
107,
108].
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
| OL; 1 year | IGlar + LIS | 24 | − 0.7 [8] | NR | 0.21 ± 0.40 |
(NPH + RHI or LIS [MDI] for ≥ 1 year) | LIS CSII | 24 | − 1.0 [− 11] | NR | 0.17 ± 0.37 |
| | | NS | NR | NS |
| OL; 1 year | IGlar + LIS | 16 | NR | NR | 0.18 |
(NPH + RHI or LIS [MDI] for ≥ 1 year) | LIS CSII | 16 | NR | NR | 0.12 |
| | | NSb | NSb | NS |
| R, OL, M; 24 wk | IGlar + LIS | 26 | − 0.6 [− 7] | − 2.7 | 35 ± 35c |
(NPH-based MDI regimen) | LIS CSII | 24 | − 0.7 [− 8] | − 3.3 | 41 ± 43c |
| | | NS | NS | p = 0.93c |
| R, OL, C, M; 4 mon | IGlar + LIS | 39 | − 0.1 [− 1] | NR | 0.1 ± 0.4 |
(LIS or ASP CSII for ≥ 6 mon) | LIS CSII | 39 | − 0.2 [− 2] | NR | 0.1 ± 0.3 |
| | | NS | NR | p = 0.710 |
Ruiz-de-Adana et al. [ 108] | R, OL; 6 mon | IGlar + LIS | 23 | − 0.3 [− 3]d | NR | 0.05 ± 0.2 |
(IGlar + LIS [MDI] for 6 mon) | LIS CSII | 15 | − 0.9 [− 10]d | NR | 0.29 ± 1 |
| | | NRe | NR | p = 0.08 |
Type 2 Diabetes Mellitus
Pharmacological treatment for patients with T2DM usually starts with a single oral antidiabetic agent (OAD), generally metformin [
88]. If maximally titrated OAD monotherapy is inadequate, a second oral agent, a glucagon-like peptide-1 (GLP-1) receptor agonist or insulin, is added [
88]. The progressive decline in β-cell function that occurs in T2DM means that most patients eventually need exogenous insulin therapy in combination with other therapies [
87,
88].
Treatment Intensification Using Insulin
Insulin is usually added to ongoing treatment with metformin and/or other OADs and possibly GLP-1 receptor agonist therapy. Rapid-acting mealtime insulin may be used as the initial insulin therapy in patients with T2DM [
109,
110]. However, it is generally more common to start with a single daily injection of basal insulin [
81,
82,
88,
111]. If basal insulin alone does not provide adequate glycemic control, prandial insulin can be added, either as a full basal-bolus regimen (basal insulin with bolus insulin administered at all meals) or in a stepwise fashion, starting with the largest meal (‘basal-plus’ therapy) and then other meals, as necessary, to reach full BBT [
11,
82,
111]. Alternatively, a GLP-1 receptor agonist might be added to basal insulin therapy as the next step [
81,
88,
111,
112], or the patient could be switched from basal insulin to premixed insulin (initially administered twice daily, progressing to three times daily if necessary) [
81,
88]. The intensification option selected will depend on each patient’s clinical circumstances and preferences [
81].
Insulin Glargine Plus Insulin Lispro Versus Premixed Insulin
Seven studies, all using a randomized, controlled, noninferiority design, compared insulin glargine 100 U/mL plus insulin lispro with premixed insulin with the aim of establishing whether premixed insulin was noninferior to BBT. Overall, study results did not suggest any clinically relevant advantage of premixed insulin over insulin glargine plus insulin lispro [
113‐
119].
Among three studies evaluating full BBT (
n = 374, 744, 402) (Table
3), two concluded that premixed insulin (insulin lispro mix 25/75 or 50/50) was noninferior to BBT with insulin glargine plus insulin lispro with respect to HbA1c levels in patients who had failed to achieve glycemic control on their initial insulin regimen (in combination with OADs) [
114,
115]. The third study was unable to demonstrate noninferiority for insulin lispro mix 50/50 or 75/25, based on a difference in HbA1c change (BBT minus premixed) of − 0.2% [2 mmol/mol; 90% CI − 0.4 to − 0.1% (− 5 to − 1 mmol/mol)] after 24 weeks, against a noninferiority margin of − 0.3% (3 mmol/mol) [
113]. In two of these studies, the total daily insulin dose at study end was similar with both approaches [
114,
115]; in the third study, mean total insulin dose was higher in the BBT group than in the premixed-insulin group at study end (146 vs. 123 units,
p = 0.002) [
113]. Rates of overall and nocturnal hypoglycemia and mean weight gain were similar with both treatment approaches [
113‐
115].
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
Comparisons with premixed insulin |
| R, OL, M, NI; 24 wk | IGlar + LIS | 187 | − 2.1 [− 23] | − 1.88 | 6.17 ± 10.68 |
(IGlar + OAD for ≥ 90 days) | LM 50/50 t.i.db | 187 | − 1.9 [− 20] | − 0.74 | 4.78 ± 7.15 |
| | | p = 0.021c | NRd | p = 0.139 |
| R, OL, M, NI; 24 wk | IGlar + LIS (Arm A)e | 199 | 0.1 [1] | NR | 3.0 ± 13.6 |
(IGlar + OAD or LM 75/25 + OAD) | LM 75/25 b.i.d. (Arm A)e | 200 | 0.0 [0] | NR | 2.5 ± 7.0 |
| | | NRf | NR | p = 0.657 |
| IGlar + LIS (Arm B)e | 171 | 0.2 [2.2] | NR | 2.4 ± 6.1 |
| LM 50/50 t.i.d. (Arm B)e | 174 | 0.2 [2.2] | NR | 2.5 ± 8.1 |
| | | NRf | NR | p = 0.949 |
| R, OL, M, NI; 24 wk | IGlar + LIS | 202 | − 1.1 [− 12] | −1.2 | 0.05 ± 0.21h |
(PMI [human insulin-, LIS- or ASP-based] for ≥ 6 mon) | LM 50/50 b.i.d + LM 75/25 o.d. | 197 | − 1.1 [− 12] | −0.8 | 0.03 ± 0.09h |
| | | NSg | p = 0.002 | p = 0.235 |
Comparison with other insulin analogues |
| R, OL, M, NI; 24 wk | IGlar + LIS | 191 | − 1.2 [− 13] | NR | 0.09h |
(OAD + insulin) | ILPS + LIS | 192 | − 1.1 [− 12] | NR | 0.13h |
| | | NRi | NR | p = 0.2 |
The other four studies evaluated basal-plus therapy or intensification strategies involving one to three doses of insulin lispro (
n = 476, 426, 344, 484) [
116‐
119]. In these studies, the addition of an increasing number of prandial insulin injections was effective and safe [
116‐
119]. Three studies found premixed insulin was noninferior to basal-plus therapy with insulin glargine plus insulin lispro [
116,
118,
119]. However, one study did not demonstrate noninferiority for insulin lispro mix 50/50, based on a change in HbA1c of − 1.76% (− 19 mmol/mol) versus − 1.93% (− 21 mmol/mol) with insulin glargine plus insulin lispro [between-group difference 0.17% (2 mmol/mol) for premixed minus basal-plus, 95% CI − 0.03 to 0.37 (− 0 to 4 mmol/mol); noninferiority margin 0.3% (3 mmol/mol)] [
117]. In this study, HbA1c values were significantly lower in the basal-plus group compared with the premixed insulin group at weeks 12 and 24 weeks, although not at week 36 (study end) [
117]. Total daily insulin doses, number of injections, rates of hypoglycemia, and weight changes at study end were similar with both approaches in most studies [
116‐
119], with the exceptions that the total daily insulin dose and mean daily number of injections were greater [
117], nocturnal hypoglycemia was more common [
118], and weight gain was greater [
116] with premixed than BBT in one study each.
Glargine + Lispro Versus Other Insulin Analogues
A randomized clinical trial (
n = 383) showed that similar glycemic control was achieved with insulin glargine 100 U/ml plus insulin lispro BBT and insulin lispro protamine suspension plus insulin lispro BBT in patients with T2DM who no longer achieved glycemic targets on insulin plus OAD treatment (Table
3) [
120]. More than 82% of patients in each group received three insulin lispro injections per day throughout the study [
120]. In a small crossover study involving 12 patients, BBT with insulin glargine plus insulin lispro was associated with lower pre- and post-dinner glucose levels than BBT with insulin detemir plus insulin lispro [
103].
Insulin Administration and Titration Protocols
Various algorithms for starting and intensifying insulin therapy in patients with T2DM are available, such as those provided by the ADA [
88] and the American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE) [
111].
Only one of the studies evaluating full BBT with insulin glargine 100 U/mL plus insulin lispro in patients with T2DM outlined the dosing algorithms used: insulin doses were adjusted weekly based on mean preprandial blood glucose level and, if a more aggressive approach was needed, total daily insulin requirement [
113].
Studies that evaluated progression of insulin therapy, but not necessarily full BBT, used various algorithms based on fasting and/or preprandial blood glucose levels to adjust the dosages of insulin glargine and insulin lispro [
117‐
119]. Importantly, patients can be trained to self-titrate bolus insulin doses safely [
121]. In the 24-week AUTONOMY study, patients on optimized basal insulin glargine who were starting to add insulin lispro therapy were able to self-titrate their bolus insulin lispro safely using either of two simple algorithms, with insulin lispro adjusted every other day based on the preprandial reading from the previous 1–3 days [
121].
Conclusions
With the growing availability of alternative insulins for use in BBT, it is timely that this article reviews the current evidence regarding BBT combining insulin glargine 100 U/mL with insulin lispro in patients with T1DM and T2DM, including its use in special populations (children, elderly, pregnant women, patients with comorbidities, and people of different ethnicities).
Insulin glargine 100 U/mL and insulin lispro have both been available for many years, have been studied extensively, and are widely used as the basal and bolus components, respectively, of BBT. Insulin lispro was the first rapid-acting insulin analogue to become available and has been evaluated in a wide range of patients, and insulin glargine is regarded as a standard-of-care basal insulin. Given the length of their availability, a substantial evidence base exists to support the efficacy and safety of these agents as BBT or basal-plus therapy in patients with T1DM and T2DM.
Clinical studies indicate that in patients with T1DM, BBT with insulin glargine plus insulin lispro provides similar or better glycemic control, and less nocturnal hypoglycemia, than BBT involving human insulin as the basal and/or prandial component. Moreover, in patients with T1DM, BBT with insulin glargine 100 U/mL plus insulin lispro generally provides a similar level of glycemic control to that achieved with insulin lispro CSII, with similar rates of severe hypoglycemia.
In patients with T2DM receiving basal insulin, intensification of insulin therapy can generally be achieved by either initiating BBT or progressing to basal-plus therapy and then full BBT with prandial cover for all meals. Progression of insulin therapy can be achieved using various algorithms based on fasting and/or preprandial blood glucose levels to adjust the dosages of insulin glargine and insulin lispro. Algorithms for starting and intensifying insulin therapy are provided by the ADA [
88] and the AACE/ACE [
111]. Simple algorithms for the titration of prandial insulin lispro can facilitate patient self-management of insulin therapy. Most studies evaluating BBT with insulin glargine plus insulin lispro in patients with T2DM evaluated the noninferiority of premixed insulin versus BBT. These studies found that premixed insulin does not appear to provide any advantage over this BBT with respect to glycemic control or rates of hypoglycemia.
One of the key factors to be considered with insulin therapy is the need to achieve a balance between maintaining good glycemic control and minimizing the risk of hypoglycemic episodes. Studies such as AUTONOMY [
121] demonstrate that, if well titrated, insulin therapy enables glycemic targets to be reached safely and simply.
Pooled analyses of studies involving insulin glargine or insulin lispro showed that these agents provided similar levels of efficacy and safety in elderly and young patients. In addition, insulin glargine plus insulin lispro is safe and effective in people of different ethnicities, and these insulins appear to be suitable for use in other special populations such as pregnant women and patients with comorbidities.
In conclusion, BBT remains a relevant option for patients with T1DM and those with T2DM requiring insulin treatment. In particular, the widely used combination of insulin glargine 100 U/mL plus insulin lispro has established efficacy and safety, and should be considered a first-line option in patients for whom BBT regimens are being considered.