IN BRIEF Titratable fixed-ratio combinations (FRCs) of a basal insulin and a glucagon-like peptide-1 (GLP-1) receptor agonist are new therapeutic options for people with type 2 diabetes. Two FRCs—insulin degludec/liraglutide and insulin glargine/lixisenatide—have been approved for use in the United States. The two components in these FRCs target different aspects of diabetes pathophysiology, working in a complementary manner to decrease blood glucose while mitigating the side effects associated with each component (hypoglycemia and weight gain with insulin and gastrointestinal side effects with GLP-1 receptor agonists). This article reviews these products and key considerations for their use.

The burden of diabetes on individuals and society continues to grow. The worldwide prevalence of diabetes was estimated to be 422 million in 2014 (1), with ∼30 million people (>9% of the total population) having the disease. In the United States, 1.5 million adults received a new diagnosis of diabetes in 2015 (2).

The U.K. Prospective Diabetes Study in type 2 diabetes and the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study in type 1 diabetes showed that early achievement of target glucose levels reduces the long-term risk of microvascular and macrovascular complications, even when A1C increases over time (3,4). Guidelines recommend lowering A1C to <7.0% or ≤6.5% for most patients, although less stringent goals may be advised based on individual patient factors (5,6).

Improvements in the clinical management of type 2 diabetes and diabetes-associated complications have substantially reduced rates of cardiovascular disease, stroke, kidney failure, and amputations (7). However, despite the availability of detailed guidelines and an expanding range of therapeutic options to reduce hyperglycemia, between 2007 and 2010, almost half (47.5%) of patients with diabetes in the United States failed to attain an A1C <7.0% (8).

The reasons behind this failure are multifactorial; however, clinical inertia on the part of both clinicians and patients, resulting in delay in treatment intensification at every stage of disease progression, is an important contributing factor (9,10). Once patients are no longer achieving their target A1C on basal insulin, options for intensifying therapy add to the complexity of day-to-day management. The need for additional injections (up to three per day plus the single basal insulin injection if prandial insulin is added) contributes to poor adherence (11) and may also deter patients and physicians from intensifying therapy.

Fixed-ratio combinations (FRCs) of a basal insulin and a glucagon-like peptide-1 (GLP-1) receptor agonist may help to address gaps in care for basal insulin treatment intensification by targeting both fasting plasma glucose (FPG) and postprandial plasma glucose (PPG), simplifying treatment regimens, and mitigating gastrointestinal side effects and weight gain associated with insulin, with no increased risk of hypoglycemia, both of which affect patients’ willingness to intensify and adhere to treatment. Early use of multiple agents targeting the various pathophysiologic abnormalities of the disease may also have a beneficial effect in the early management of type 2 diabetes (12).

Multiple clinical trials support the benefit of combining basal insulin and a GLP-1 receptor agonist for the treatment of type 2 diabetes (1315). A proof-of-concept study showed that twice-daily administration of exenatide plus basal insulin resulted in A1C improvement comparable to that observed with basal-bolus insulin, but yielded a greater reduction in some measures of glycemic variability, weight, and some cardiometabolic risk markers (16).

Several clinical trials investigated the addition of lixisenatide in patients with type 2 diabetes inadequately controlled on basal insulin therapy with or without metformin and/or other oral antidiabetes drugs (OADs) (1719). Patient populations included those newly initiated on insulin glargine 100 units/mL (U100), patients on established basal insulin therapy with or without metformin, and patients on established basal insulin therapy with or without OADs who required additional control. The addition of lixisenatide consistently improved A1C and PPG excursions, with body weight benefits and without an increase in hypoglycemia risk compared to basal insulin therapy alone (17,18). Compared to insulin glulisine once or three times daily, administration of lixisenatide resulted in similar A1C reductions with a greater reduction in PPG excursions, weight loss, and less hypoglycemia (19).

Another study compared once-daily insulin aspart to liraglutide added to insulin degludec and metformin in patients with type 2 diabetes inadequately controlled after 1 year of treatment. Liraglutide improved glycemic control, with body weight reduction and less hypoglycemia and with more patients achieving a composite endpoint of A1C <7.0% without weight gain or confirmed hypoglycemia compared to insulin aspart (20). Further evidence for the potential benefits of basal insulin and GLP-1 receptor agonist combination therapy showed that albiglutide added to insulin glargine U100 with or without OADs resulted in noninferior A1C control associated with weight loss and lower hypoglycemia risk compared to the addition of insulin lispro three times daily to insulin glargine U100 with or without OADs (21).

In November 2016, two titratable FRCs of a long-acting basal insulin and a once-daily GLP-1 receptor agonist were approved by the U.S. Food and Drug Administration (FDA). These products offer a once-daily alternative for intensifying type 2 diabetes therapy (as an adjunct to diet and exercise) when glycemia is inadequately controlled with basal insulin or the GLP-1 receptor agonist component used alone (22,23).

iGlarLixi is a combination of insulin glargine U100 with lixisenatide. Insulin glargine U100 is a mainstay of long-acting basal insulin therapy and was first approved for clinical use in 2000. Its pharmacologic effects are well characterized; once-daily insulin glargine U100 results in glucose-lowering activity for up to 24 hours, with blood glucose values of 130 mg/dL maintained until 15 hours and then slightly increasing to ∼140 mg/dL between 16 and 24 hours (24). Lixisenatide is a once-daily, shorter-acting GLP-1 receptor agonist recently approved in the United States for the treatment of patients with type 2 diabetes as an adjunct to diet and exercise to improve glycemic control. It has a half-life of 2–3 hours and acts mainly by delaying gastric emptying, exerting a pronounced PPG-lowering effect with a lesser effect on FPG at doses as low as 2.5 µg (2527). Although lixisenatide has a shorter half-life, it retains the ability to reduce PPG with once-daily dosing through reduction of PPG exposure after meals. Unlike longer-acting GLP-1 receptor agonists, its effects on gastric emptying or PPG levels do not disappear because they do not seem to be subjected to tachyphylaxis (28).

IDegLira combines insulin degludec 100 units/mL (U100) with liraglutide. Insulin degludec, a longer-acting, once-daily basal insulin analog that received approval for the treatment of diabetes in the United States in 2015, shows glucose-lowering activity for >42 hours, no pronounced peak, and even exposure over a 24-hour period once at steady state (29,30). The long-acting, once-daily GLP-1 receptor agonist liraglutide was approved in the United States in 2010 for the treatment of patients with type 2 diabetes as an adjunct to diet and exercise to improve glycemic control. It shows activity over a range of concentrations and has a longer half-life (11–15 hours) (31), as well as a smaller effect on gastric emptying and reduction in PPG excursions, but a greater effect on FPG, than lixisenatide (27,32).

Both iGlarLixi and IDegLira have been studied in several phase 3 clinical trials (Table 1). It is important to point out that these trials are not directly comparable because of differences in design, titration schemes, and glycemic targets and that currently there are no head-to-head comparisons of FRCs.

iGlarLixi was studied in two phase 3 clinical trials for the intensification of treatment in insulin-naive (LixiLan-O) and insulin-experienced (LixiLan-L) populations (33,34). LixiLan-O evaluated patients with type 2 diabetes inadequately controlled with metformin alone or combined with another OAD, whereas LixiLan-L enrolled patients with diabetes inadequately controlled with basal insulin (with or without up to two OADs).

Both trials included an initial run-in phase, during which all OADs except for metformin were discontinued. In LixiLan-O, the metformin dose was optimized during the 4-week run-in phase, and patients were then randomized to receive lixisenatide (maintenance dose of 20 µg/day), insulin glargine U100 (up to 60 units/day), or iGlarLixi (up to 60 units insulin glargine U100/20 µg lixisenatide per day) for 30 weeks. In LixiLan-L, patients continuing on or switching to insulin glargine U100 had their daily dose optimized during a 6-week run-in period and were then randomized to receive insulin glargine U100 (up to 60 units/day) or iGlarLixi (up to 60 units insulin glargine U100/20 µg lixisenatide per day) with or without metformin for 30 weeks. At the end of the run-in phase, A1C levels were reduced by 0.1% in LixiLan-O and 0.4% in LixiLan-L.

iGlarLixi consistently led to significantly greater A1C reductions than the comparators. In LixiLan-O, A1C reductions were −1.6, −1.3, and −0.9% in patients treated with iGlarLixi, insulin glargine U100, and lixisenatide, respectively; in LixiLan-L, reductions were −1.1 and −0.6% for patients treated with iGlarLixi and insulin glargine U100, respectively. A larger proportion of patients treated with iGlarLixi achieved a target A1C of <7.0% across studies (LixiLan-O: 73.7% for iGlarLixi vs. 59.4% for insulin glargine U100 and 33.0% for lixisenatide; LixiLan-L: 54.9% for iGlarLixi vs. 29.6% for insulin glargine U100; P < 0.0001 vs. insulin glargine U100 in both trials and vs. lixisenatide in LixiLan-O). The incidence of symptomatic hypoglycemia (≤70 mg/dL) with iGlarLixi was similar to that of basal insulin (25.6 and 40.0% vs. 23.6 and 42.5% in LixiLan-O and LixiLan-L, respectively), although it was higher than with lixisenatide alone (6.4% in LixiLan-O). iGlarLixi also mitigated the weight gain seen with insulin glargine U100 in both trials (LixiLan-O: −0.3 and +1.1 kg for iGlarLixi and insulin glargine U100, respectively; LixiLan-L: −0.7 and +0.7 kg for iGlarLixi and insulin glargine U100, respectively) (Table 1). The incidence of gastrointestinal adverse events (AEs) was lower with iGlarLixi than with lixisenatide alone (nausea: 9.6 vs. 24.0%, respectively, in LixiLan-O) (33), but higher than with insulin alone (nausea: 9.6 vs. 3.6%, respectively, in LixiLan-O; 10.4 vs. 0.5%, respectively, in LixiLan-L), and resulted in very low treatment discontinuation rates (0.4% due to nausea or vomiting and 0.2% due to diarrhea in LixiLan-O; 1.1% due to nausea in LixiLan-L) (33,34).

The DUAL series of phase 3 clinical trials looked at the use of IDegLira for intensifying treatment in a range of patient populations: insulin-naive (DUAL I and IV), insulin experienced (DUAL II, V, and VII), and those already on a GLP-1 receptor agonist (DUAL III). Treatment with IDegLira reduced A1C across the studies (ranging from −1.3 to −1.9%), and these reductions were consistently greater than those seen with the comparators (−0.9 to −1.4% with insulin degludec in DUAL I and II, −1.3% with liraglutide in DUAL I, −1.13% with insulin glargine U100 in DUAL V, and −0.5% with placebo in DUAL IV). In addition, a larger proportion of patients treated with IDegLira achieved a target A1C <7.0% than with the comparators (60–81% for IDegLira, 23–65% for insulin degludec, 60% for liraglutide, 47% for insulin glargine U100, and 28.8% for placebo). In DUAL VII, IDegLira was noninferior to insulin glargine U100 plus insulin aspart (up to 4 times a day) in controlling A1C, and a similar proportion of patients achieved glycemic targets (Table 1) (3540).

The reported incidence of hypoglycemia (severe hypoglycemia events and episodes of hypoglycemia with plasma glucose ≤56 mg/dL regardless of symptoms) was lower with IDegLira (24–41.7%) than with basal insulin comparators (25–49.1%), but higher than with placebo (17.1%) or liraglutide (7%) (35,3739). However, a re-analysis of hypoglycemia rates conducted by the FDA, using the American Diabetes Association definition of documented symptomatic hypoglycemia (typical symptoms accompanied by plasma glucose concentration ≤70 mg/dL) showed comparable hypoglycemia rates for IDegLira and insulin degludec (41).

IDegLira also led to less weight loss or to weight gain (−2.7 to +2.0 kg) compared to the insulin comparator (0 to +1.8 kg) in many of the trials. Compared to treatment with a sulfonylurea alone in DUAL IV, IDegLira resulted in a slight weight gain (+0.5 kg), whereas sulfonylurea therapy resulted in weight loss (−1.0 kg) (Table 1). The incidence of gastrointestinal AEs was higher with IDegLira than with basal insulin and placebo comparators, but lower than with GLP-1 receptor agonist comparators (incidence of nausea: IDegLira, 6.5–9.4%; basal insulin, 1.1–4.0%; GLP-1 receptor agonist, 20%) and did not lead to any patients discontinuing treatment in DUAL II (35,37,39).

Rare cases of allergic reactions to both iGlarLixi and IDegLira or their GLP-1 receptor agonist components have been reported in clinical trials and after commercialization (42,43).

Combination products such as FRCs have the potential to improve blood glucose control and adherence while simplifying patients’ treatment regimens compared to the use of multiple agents. In addition, they present less potential for clinical inertia and have decreased side effects compared to insulin or a GLP-1 receptor agonist alone.

Basal insulin therapy aims to provide consistent, flat, long-acting insulin levels to mimic the constant physiological release of hormone that regulates endogenous glucose levels. Basal insulin acts in a nonglucose-dependent manner predominantly on FPG levels and has less of an effect on PPG.

Long-acting GLP-1 receptor agonists also primarily affect FPG, whereas short-acting agents in this class have a greater effect on PPG (44,45). The lesser effect on PPG exerted by longer-acting GLP-1 receptor agonists may be the result of continuous stimulation of the GLP-1 receptor, which attenuates the effect on gastric emptying via tachyphylaxis at the level of the vagal nerve (44) and is supported by clinical studies showing greater reductions in PPG and PPG excursions for shorter-acting compared to longer-acting agents (46,47). Shorter-acting GLP-1 receptor agonists are therefore used in FRCs to complement the mechanism of action of basal insulin. GLP-1 receptor agonists have also been shown to reduce PPG increments in a dose-dependent manner, stimulate glucose-dependent insulin secretion, suppress glucagon secretion, inhibit gastric acid secretion and emptying, and increase satiety, with potential reductions in caloric intake (48).

Treatment with insulin is generally associated with an increase in body weight (an A1C decrease of 2.5% from baseline was associated with an increase in body weight of 5 kg during 1 year in one study) and risk of hypoglycemia (5,6,49,50), but the use of an insulin/GLP-1 receptor agonist combination product appears to mitigate the side effects of its individual components. In clinical trials, both weight gain and the incidence of hypoglycemia with FRCs were found to be comparable to or lower than with basal insulin (average weight loss of 0.5 kg with iGlarLixi vs. weight gain of 0.9 kg with insulin glargine U100 in the LixiLan trials and average weight loss of 1.5 kg with IDegLira vs. weight gain of 1.1 kg with insulin degludec in DUAL I, II, and V) (Table 1). In addition, the incidence of gastrointestinal AEs was lower with FRCs compared to a GLP-1 receptor agonist alone (33−39), which constitutes an additional advantage because reductions in AEs and tolerability issues may also help to increase medication adherence (51).

Experience with fixed-dose oral combination drugs in other therapeutic areas (e.g., combinations of antihypertensive agents or bronchodilators/corticosteroids) shows positive impacts on efficacy and adherence compared to their free-drug components (5255). In addition, the use of complex type 2 diabetes treatment regimens, involving multiple combinations of several oral and/or injectable agents, has been shown to be associated with intentional and accidental nonadherence to treatment (11,56). In a real-world study of patients treated with basal insulin and a GLP-1 receptor agonist, only 17% were persistent with treatment (defined as the absence of a prescription gap of at least 90 days for either agent) during a 12-month period (57). Simple, once-daily regimens thus have the potential to improve adherence and outcomes and may also encourage more timely treatment intensification for patients and clinicians who are deterred by more complicated regimens.

Disadvantages of combination therapy include the potential increase in direct costs of medications. The total direct and indirect costs of diabetes in the United States were $245 billion in 2012, with average medical expenditures for people with diabetes of$13,700 annually (2). Thus, the burden of treatment costs for patients is an important factor to consider in treatment decision-making (5,6). However, if current fixed-dose oral combinations are a guide, the cost of FRCs may be lower than the cost of the components taken separately (58); iGlarLixi is currently sold for a price comparable to that of its GLP-1 receptor agonist component lixisenatide (59). Indirect costs must also be considered, including lost productivity and quality-of-life issues related to hypoglycemia and weight gain or worsening diabetes associated with delay of insulin therapy (6,60), which may be mitigated by earlier intensive treatment and offset by the use of FRCs.

Finally, injectable therapy is often perceived as a hurdle for patients on oral therapies. However, results from the Perspectives in Diabetes Care surveys show that there is a disconnect between patient and physician perceptions, with many patients in fact willing to do more to achieve their target A1C (57%) and a smaller proportion of clinicians believing the same (19%) (61). Based on their experience with oral fixed-dose combinations, clinicians and patients may have the impression that injectable FRCs are inflexible for dose adjustments and will limit their ability to titrate to target. Therefore, it is important to note that these are fixed-ratio, but not fixed-dose, combinations: both components are titratable based on patients’ insulin needs, with the GLP-1 receptor agonist component increasing in ratio to the insulin dose and so still providing flexibility in dosing.

FRCs are administered using modified insulin pens that contain a pre-mixed fixed-ratio supply of the basal insulin and GLP-1 receptor agonist components, such that as the insulin dose is adjusted, the GLP-1 receptor agonist dose also changes according to the fixed ratio. FRC doses are guided by the insulin dose component, following titration schedules similar to those used for titrating insulin (42,43). When initiating therapy, it is important for clinicians to inform their patients that, as with basal insulin, they will be starting at a low dose and titrating upward or downward to achieve their individual FPG goal, and it may be helpful to inform them about their anticipated final dose. This enables patients to know that they are not failing when they move away from the starting dose and that this is part of the normal treatment pattern (62).

When switching to either FRC from basal insulin, back-titration from the previous insulin dose is required for most patients; this may lead to transient increases in FPG that do not affect A1C reduction. Patients should also be alerted to this possibility so that they are prepared for any changes after switching.

### iGlarLixi

iGlarLixi (Soliqua 100/33, Sanofi) has been approved for use in the United States in a modified Sanofi SoloStar pen, which delivers 3 units of insulin glargine U100 to 1 µg of lixisenatide and ranges from 15 units/5 µg to 60 units/20 µg (43). It is indicated to improve glycemic control in adults with type 2 diabetes inadequately controlled on basal insulin (<60 units) or lixisenatide. iGlarLixi should be administered within 1 hour before the first meal of the day. In patients who are on lixisenatide, iGlarLixi is initiated at a starting dose of 15 units. For those switching from basal insulin, the starting dose of iGlarLixi is based on the previous dose of basal insulin; in patients receiving doses <30 units, the starting iGlarLixi dose will be 15 units, and in those receiving doses of 30–60 units, the starting iGlarLixi dose will be 30 units. Upward or downward titration is done according to the insulin glargine U100 dose, with dose changes of 2–4 units weekly. Initiation and titration dosing is described in Figure 1.

In the LixiLan clinical trials, the mean daily dose of basal insulin after 30 weeks of treatment in the FRC arm was 40 units (0.45 units/kg) in insulin-naive and 47 units (0.54 units/kg) for insulin-experienced patients (33,34). Furthermore, in both trials the final mean basal insulin daily dose was similar for patients in the iGlarLixi group and the insulin glargine U100 group (LixiLan-O: 39.8 vs. 40.3 units; LixiLan-L: 46.67 vs. 46.71 units for the FRC vs. the basal insulin arms, respectively; data on file). There was an insulin dose limit of 60 units in both arms of the two LixiLan trials (33,34).

Although iGlarLixi has been approved in a 3:1 ratio of insulin glargine U100 to lixisenatide in the United States, the LixiLan trials were conducted using pens delivering 3:1 and 2:1 ratios (33,34), and these two pen options may be available in other regions of the world. Regardless of presentation, iGlarLixi pens should be stored in the refrigerator at a temperature between 2 and 8°C before opening. Once opened, they should be kept at room temperature (<25°C) and disposed of after 28 days (43).

### IDegLira

IDegLira (Xultophy 100/3.6, Novo Nordisk) is available in one prefilled pen at a ratio of 1 unit insulin degludec to 0.036 mg liraglutide and is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes inadequately controlled on basal insulin (<50 units/day) or liraglutide (≤1.8 mg/day). IDegLira can be administered daily at the same time each day and does not need to be taken with a meal. The recommended starting dose is 16 units, which can be titrated upward or downward by 2 units every 3–4 days. The maximum dose of IDegLira is 50 units insulin degludec/1.8 mg liraglutide (42). Initiation and titration dosing is described in Figure 1.

In the DUAL clinical trials, the dose of IDegLira was 38 dose steps (one dose step was equivalent to 1 unit of insulin degludec plus 0.036 mg liraglutide) for insulin-naive patients (35) and 41–45 dose steps for insulin-experienced patients (37,39). The mean insulin dose was 28% lower at week 26 with IDegLira than with insulin degludec (38 vs. 53 units) in insulin-naive patients in DUAL I, where there was no maximum dose limit for insulin degludec (35) and similar for both drugs (45 units) in insulin-experienced patients in DUAL II, where the insulin degludec dose was capped at 50 units in both arms (39). The predominant effect of liraglutide on FPG versus PPG is likely responsible for the insulin-sparing effect observed with IDegLira. In addition, the design of the DUAL studies, which, unlike the LixiLan program, did not include a run-in phase in which basal insulin was titrated or stabilized, may also explain the lower insulin dose observed in the IDegLira arm.

Unopened IDegLira pens should be stored in the refrigerator at a temperature of 2–8°C. After opening, the pens should be kept at room temperature between 15 and 30°C or in the refrigerator at 2–8°C and disposed of after 21 days (42).

Clinicians should provide information to manage patients’ expectations regarding the scope and duration of expected AEs. AEs seen in the clinical trials for FRCs were predominantly gastrointestinal in nature; nausea, vomiting, and diarrhea were experienced by 6.5–10.4%, 2.5–4%, and 3.1–9% patients, respectively. Across the studies, these AEs were generally transient, with a greater incidence during the first 8–12 weeks, and resulted in treatment discontinuation rates of ∼0–1% (3339). The slow dose increase of the GLP-1 receptor agonist component is believed to lead to a reduction in gastrointestinal AEs compared to GLP-1 receptor agonist therapy alone (33,35).

Strategies used for minimizing gastrointestinal side effects when initiating a GLP-1 receptor agonist are also appropriate for FRCs. These include advising patients to stop eating when they feel full and suggesting that they eat slowly and avoid administering their dose before a large or high-fat meal (63,64). The risk of hypoglycemia is comparable to that associated with basal insulin, so it is important to provide patients with appropriate strategies to avoid and treat hypoglycemia.

Two FRC products, iGlarLixi and IDegLira, have recently been approved in the United States. FRCs are currently indicated for patients with type 2 diabetes inadequately controlled on basal insulin or lixisenatide (for iGlarLixi) or liraglutide (for IDegLira). Some patients may particularly benefit from FRC therapy, such as those for whom the weight gain seen with insulin alone would be a problem and who would benefit from the weight neutrality/weight loss seen with FRCs. For patients in whom increased treatment complexity is an issue, the use of a single co-formulation with once-daily injection provides a simple, user-friendly method of treatment intensification, which may help improve adherence. The potential to achieve greater A1C-lowering efficacy with less weight gain than seen with insulin, fewer gastrointestinal AEs than with GLP-1 receptor agonists, and no increase in risk of hypoglycemia are key attributes of FRCs.

The contents of this article and the opinions expressed within it are those of the authors, and it was the decision of the authors to submit the manuscript article for publication. The authors received writing/editorial support in the preparation of this manuscript, which was provided by Nicola Truss, PhD, and Patricia Fonseca, PhD, of Excerpta Medica.

N.S. has participated in advisory boards for AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Intarcia, Novartis, Sanofi, and Teva and has acted as a speaker for AstraZeneca and Boehringer Ingelheim. D.H. has participated in advisory boards for Eli Lilly and Company, Novo Nordisk, and Sanofi, and has acted as a speaker for Eli Lilly and Company/Boehringer Ingelheim, Janssen, Novo Nordisk, and Sanofi. M.L.M. has participated in advisory boards and/or has acted as a speaker for Janssen, Novo Nordisk, and Sanofi. J.R.W. has participated in advisory boards for Novo Nordisk and Sanofi and has acted as a consultant to Becton-Dickenson. No other potential conflicts of interest relevant to this article were reported.

All authors contributed to the discussion and reviewed/edited the manuscript originally drafted by a professional editorial service. N.S. is the guarantor of this work and, as such, had full access to all the data in the study and takes full responsibility for the integrity of the data and the accuracy of the data analysis.

1.
World Health Organization
.
Global report on diabetes: executive summary
.
2.
Centers for Disease Control and Prevention
.
National Diabetes Statistics Report, 2017: Estimates of Diabetes and Its Burden in the United States
.
Atlanta, Ga
.,
U.S. Department of Health and Human Services
,
2017
3.
Holman
RR
,
Paul
SK
,
Angelyn Bethel
M
,
Matthews
DR
,
Neil
HAW
.
10-year follow-up of intensive glucose control in type 2 diabetes
.
N Engl J Med
2008
;
359
:
1577
1589
4.
Nathan
DM
,
Bayless
M
,
Cleary
P
, et al
.;
DCCT/EDIC Research Group. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study at 30 years: advances and contributions
.
Diabetes
2013
;
62
:
3976
3986
5.
Inzucchi
SE
,
Bergenstal
RM
,
Buse
JB
, et al
.
Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach. Update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes
.
Diabetes Care
2015
;
38
:
140
149
6.
Garber
AJ
,
Abrahamson
MJ
,
Barzilay
JI
, et al
.
Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm – 2017: executive summary
.
Endocr Pract
2017
;
23
:
207
238
7.
Gregg
EW
,
Li
Y
,
Wang
J
, et al
.
Changes in diabetes-related complications in the United States, 1990–2010
.
N Engl J Med
2014
;
370
:
1514
1523
8.
Stark Casagrande
S
,
JE
,
Saydah
SH
,
Rust
KF
,
Cowie
CC
.
The prevalence of meeting A1C, blood pressure, and LDL goals among people with diabetes, 1988–2010
.
Diabetes Care
2013
;
36
:
2271
2279
9.
Khunti
K
,
Nikolajsen
A
,
Thorsted
BL
,
Andersen
M
,
Davies
MJ
,
Paul
SK
.
Clinical inertia with regard to intensifying therapy in people with type 2 diabetes treated with basal insulin
.
Diabetes Obes Metab
2016
;
18
:
401
409
10.
Khunti
K
,
Wolden
ML
,
Thorsted
BL
,
Andersen
M
,
Davies
MJ
.
Clinical inertia in people with type 2 diabetes
.
Diabetes Care
2013
;
36
:
3411
3417
11.
Peyrot
M
,
Rubin
RR
,
Kruger
DF
,
Travis
LB
.
Correlates of insulin injection omission
.
Diabetes Care
2010
;
33
:
240
245
12.
DeFronzo
RA
,
Eldor
R
,
Abdul-Ghani
M
.
Pathophysiologic approach to therapy in patients with newly diagnosed type 2 diabetes
.
Diabetes Care
2013
;
36
(
Suppl. 2
):
S127
S138
13.
Vora
J
.
Combining incretin-based therapies with insulin
.
Diabetes Care
2013
;
36
(
Suppl. 2
):
S226
S232
14.
Ahrén
B
.
Insulin plus incretin: a glucose-lowering strategy for type 2 diabetes
.
World J Diabetes
2014
;
5
:
40
51
15.
Berlie
H
,
Hurren
KM
,
Pinelli
NR
.
Glucagon-like peptide-1 receptor agonists as add-on therapy to basal insulin in patients with type 2 diabetes: a systematic review
.
Diabetes Metab Syndr Obes
2012
;
5
:
165
174
16.
FLAT-SUGAR Trial Investigators
.
Glucose variability in a 26-week randomized comparison of mealtime treatment with rapid-acting insulin versus GLP-1 agonist in participants with type 2 diabetes at high cardiovascular risk
.
Diabetes Care
2016
;
39
:
973
981
17.
Riddle
MC
,
Aronson
R
,
Home
P
, et al
.
Adding once-daily lixisenatide for type 2 diabetes inadequately controlled by established basal insulin: a 24-week, randomized, placebo-controlled comparison (GetGoal-L)
.
Diabetes Care
2013
;
36
:
2489
2496
18.
Riddle
MC
,
Forst
T
,
Aronson
R
, et al
.
Adding once-daily lixisenatide for type 2 diabetes inadequately controlled with newly initiated and continuously titrated basal insulin glargine: a 24-week, randomized, placebo-controlled comparison (GetGoal-Duo 1)
.
Diabetes Care
2013
;
36
:
2497
2503
19.
Rosenstock
J
,
Guerci
B
,
Hanefeld
M
, et al
.;
GetGoal Duo-2 Trial Investigators. Prandial options to advance basal insulin glargine therapy: testing lixisenatide plus basal insulin versus insulin glulisine either as basal-plus or basal-bolus in type 2 diabetes: the GetGoal Duo-2 trial
.
Diabetes Care
2016
;
39
:
1318
1328
20.
Mathieu
C
,
Rodbard
HW
,
Cariou
B
, et al.;
BEGIN: VICTOZA ADD-ON (NN1250-3948) Study Group
.
A comparison of adding liraglutide versus a single daily dose of insulin aspart to insulin degludec in subjects with type 2 diabetes (BEGIN: VICTOZA ADD-ON)
.
Diabetes Obes Metab
2014
;
16
:
636
644
21.
Rosenstock
J
,
Fonseca
VA
,
Gross
JL
, et al.;
Harmony 6 Study Group
.
Advancing basal insulin replacement in type 2 diabetes inadequately controlled with insulin glargine plus oral agents: a comparison of adding albiglutide, a weekly GLP-1 receptor agonist, versus thrice-daily prandial insulin lispro
.
Diabetes Care
2014
;
37
:
2317
2325
22.
Novo Nordisk
.
Novo Nordisk receives FDA approval for Xultophy 100/3.6 (insulin degludec and liraglutide injection)
.
23.
Sanofi
.
Sanofi receives FDA approval of Soliqua 100/33 for the treatment of adults with type 2 diabetes
.
24.
Lepore
M
,
Pampanelli
S
,
Fanelli
C
, et al
.
Pharmacokinetics and pharmacodynamics of subcutaneous injection of long-acting human insulin analog glargine, NPH insulin, and ultralente human insulin and continuous subcutaneous infusion of insulin lispro
.
Diabetes
2000
;
49
:
2142
2148
25.
Becker
RH
,
Stechl
J
,
Msihid
J
,
Kapitza
C
.
Lixisenatide resensitizes the insulin-secretory response to intravenous glucose challenge in people with type 2 diabetes: a study in both people with type 2 diabetes and healthy subjects
.
Diabetes Obes Metab
2014
;
16
:
793
800
26.
Becker
RH
,
Stechl
J
,
Steinstraesser
A
,
Golor
G
,
Pellissier
F
.
Lixisenatide reduces postprandial hyperglycaemia via gastrostatic and insulinotropic effects
.
Diabetes Metab Res Rev
2015
;
31
:
610
618
27.
Meier
JJ
,
Rosenstock
J
,
Hincelin-Méry
A
, et al
.
Contrasting effects of lixisenatide and liraglutide on postprandial glycemic control, gastric emptying, and safety parameters in patients with type 2 diabetes on optimized insulin glargine with or without metformin: a randomized, open-label trial
.
Diabetes Care
2015
;
38
:
1263
1273
28.
Lorenz
M
,
Pfeiffer
C
,
Steinsträsser
A
, et al
.
Effects of lixisenatide once daily on gastric emptying in type 2 diabetes: relationship to postprandial glycemia
.
Regul Pept
2013
;
185
:
1
8
29.
Heise
T
,
Nosek
L
,
Bøttcher
SG
,
Hastrup
H
,
Haahr
H
.
Ultra-long-acting insulin degludec has a flat and stable glucose-lowering effect in type 2 diabetes
.
Diabetes Obes Metab
2012
;
14
:
944
950
30.
Vora
J
,
Cariou
B
,
Evans
M
, et al
.
Clinical use of insulin degludec
.
Diabetes Res Clin Pract
2015
;
109
:
19
31
31.
Elbrønd
B
,
Jakobsen
G
,
Larsen
S
, et al
.
Pharmacokinetics, pharmacodynamics, safety, and tolerability of a single-dose of NN2211, a long-acting glucagon-like peptide 1 derivative, in healthy male subjects
.
Diabetes Care
2002
;
25
:
1398
1404
32.
Davidson
JA
.
Differential effects of prandial and non-prandial GLP-1 receptor agonists in type 2 diabetes therapy
.
2015
;
127
:
827
841
33.
Rosenstock
J
,
Aronson
R
,
Grunberger
G
, et al
.;
LixiLan-O Trial Investigators. Benefits of LixiLan, a titratable fixed-ratio combination of insulin glargine plus lixisenatide versus insulin glargine and lixisenatide monocomponents in type 2 diabetes inadequately controlled on oral agents: the LixiLan-O randomized trial
.
Diabetes Care
2016
;
39
:
2026
2035
34.
Aroda
VR
,
Rosenstock
J
,
Wysham
C
, et al
.
Efficacy and safety of LixiLan, a titratable fixed-ratio combination of insulin glargine plus lixisenatide in type 2 diabetes inadequately controlled on basal insulin and metformin: the LixiLan-L randomized trial
.
Diabetes Care
2016
;
39
:
1972
1980
35.
Gough
SCL
,
Bode
B
,
Woo
V
, et al.;
NN9068-3697 (DUAL-I) Trial Investigators
.
Efficacy and safety of a fixed-ratio combination of insulin degludec and liraglutide (IDegLira) compared with its components given alone-results of a phase 3, open-label, randomised, 26-week, treat-to-target trial in insulin-naïve patients with type 2 diabetes
.
Lancet Diabetes Endocrinol
2014
;
2
:
885
893
36.
Linjawi
S
,
Bode
B
,
Chaykin
LB
, et al
.
The efficacy of IDegLira (insulin degludec/liraglutide combination) in adults with type 2 diabetes inadequately controlled with a GLP-1 receptor agonist and oral therapy: DUAL III randomized clinical trial
.
Diabetes Ther
2017
;
8
:
101
114
37.
Lingvay
I
,
Pérez Manghi
F
,
García-Hernández
P
, et al.;
DUAL V Investigators
.
Effect of insulin glargine up-titration vs insulin degludec/liraglutide on glycated haemoglobin in patients with uncontrolled type 2 diabetes: the DUAL V randomized clinical trial
.
JAMA
2016
;
315
:
898
907
38.
Rodbard
HW
,
Bode
BW
,
Harris
SB
, et al.;
DUAL IV Investigators
.
Safety and efficacy of insulin degludec/liraglutide (IDegLira) added to sulphonylurea alone or to sulphonylurea and metformin in insulin-naïve people with type 2 diabetes: the DUAL IV trial
.
Diabet Med
2017
;
34
:
189
196
39.
Buse
JB
,
Vilsbøll
T
,
Thurman
J
, et al.;
NN9068-3912 (DUAL-II) Trial Investigators
.
Contribution of liraglutide in the fixed-ratio combination of insulin degludec and liraglutide (IDegLira)
.
Diabetes Care
2014
;
37
:
2926
2933
40.
Billings
LK
,
Doshi
A
,
Gouet
D
, et al
.
Efficacy and safety of insulin degludec/liraglutide (IDegLira) vs. basal-bolus (BB) therapy in patients with type 2 diabetes (T2D): DUAL VII trial
.
Diabetes
2017
;
66
(
Suppl. 1
):
A36
41.
.
FDA briefing document: Endocrinologic and Metabolic Drugs Advisory Committee meeting (EMDAC)
.
42.
Novo Nordisk
.
Xultophy [prescribing information]
.
November 2016. Available from http://www.novo-pi.com/xultophy10036.pdf. Accessed 28 September 2017
43.
Sanofi
.
Soliqua [prescribing information]
.
August 2017. Available from http://products.sanofi.us/Soliqua100-33/Soliqua100-33.pdf. Accessed 16 October 2017
44.
Werner
U
.
Effects of the GLP-1 receptor agonist lixisenatide on postprandial glucose and gastric emptying--preclinical evidence
.
J Diabetes Complications
2014
;
28
:
110
114
45.
Meier
JJ
.
GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus
.
Nat Rev Endocrinol
2012
;
8
:
728
742
46.
Buse
JB
,
Rosenstock
J
,
Sesti
G
, et al.;
.
Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6)
.
Lancet
2009
;
374
:
39
47
47.
Kapitza
C
,
Forst
T
,
Coester
HV
,
Poitiers
F
,
Ruus
P
,
Hincelin-Méry
A
.
Pharmacodynamic characteristics of lixisenatide once daily versus liraglutide once daily in patients with type 2 diabetes insufficiently controlled on metformin
.
Diabetes Obes Metab
2013
;
15
:
642
649
48.
Fineman
MS
,
Cirincione
BB
,
Maggs
D
,
Diamant
M
.
GLP-1 based therapies: differential effects on fasting and postprandial glucose
.
Diabetes Obes Metab
2012
;
14
:
675
688
49.
Yki-Järvinen
H
.
Combination therapies with insulin in type 2 diabetes
.
Diabetes Care
2001
;
24
;
758
767
50.
Holman
RR
,
Thorne
KI
,
Farmer
AJ
, et al.;
4-T Study Group
.
Addition of biphasic, prandial, or basal insulin to oral therapy in type 2 diabetes
.
N Engl J Med
2007
;
357
:
1716
1730
51.
Pollack
MF
,
Purayidathil
FW
,
Bolge
SC
,
Williams
SA
.
Patient-reported tolerability issues with oral antidiabetic agents: associations with adherence; treatment satisfaction and health-related quality of life
.
Diabetes Res Clin Pract
2010
;
87
:
204
210
52.
Gupta
AK
,
S
,
Poulter
NR
.
Compliance, safety, and effectiveness of fixed-dose combinations of antihypertensive agents: a meta-analysis
.
Hypertension
2010
;
55
:
399
407
53.
Page
C
,
Cazzola
M
.
Bifunctional drugs for the treatment of asthma and chronic obstructive pulmonary disease
.
Eur Respir J
2014
;
44
:
475
482
54.
Tan
RA
,
Corren
J
.
Clinical utility and development of the fluticasone/formoterol combination formulation (Flutiform) for the treatment of asthma
.
Drug Des Devel Ther
2014
;
8
:
1555
1561
55.
Incorvaia
C
,
Montagni
M
,
Makri
E
,
Ridolo
E
.
New combinations in the treatment of COPD: rationale for aclidinium-formoterol
.
Ther Clin Risk Manag
2016
;
12
:
209
215
56.
de Vries
ST
,
Keers
JC
,
Visser
R
, et al
.
Medication beliefs, treatment complexity, and non-adherence to different drug classes in patients with type 2 diabetes
.
J Psychosomat Res
2014
;
76
:
134
138
57.
Fan
T
,
Lingohr-Smith
M
,
Lin
J
.
Real-world medication persistence and outcomes associated with basal insulin and glucagon-like peptide receptor agonist free-dose combination therapy in patients with type 2 diabetes in the U.S.
Clinicoecon Outcomes Res
2017
;
9
:
19
29
58.
Lavernia
F
,
SE
,
Shubrook
JH
.
Use of oral combination therapy for type 2 diabetes in primary care: meeting individualized patient goals
.
2015
;
127
:
808
817
59.
GoodRx
.
Available from https://www.goodrx.com. Accessed 28 September 2017
60.
American Diabetes Association
.
Economic costs of diabetes in the U.S. in 2012
.
Diabetes Care
2013
;
36
:
1033
1046
61.
American Assocication of Clinical Endocrinologists
.
Surveys find adults with type 2 diabetes are more willing to take action to achieve A1C targets quicker than physicians and other medical professionals perceive
.
62.
Simon
AC
,
Gude
WT
,
Holleman
F
,
Hoekstra
JB
,
Peek
N
.
Diabetes patients’ experiences with the implementation of insulin therapy and their perceptions of computer-assisted self-management systems for insulin therapy
.
J Med Internet Res
2014
;
16
:
e235
63.
Reid
TS
.
Practical use of glucagon-like peptide-1 receptor agonist therapy in primary care
.
Clin Diabetes
2013
;
31
;
148
157
64.
Freeman
JS
.
Optimizing outcomes for GLP-1 agonists
.
J Am Osteopath Assoc
2011
;
111
(
Suppl. 1
):
eS15
eS20