Delayed treatment intensification is common in U.S. patients with type 2 diabetes uncontrolled on basal insulin. Concerns about weight gain, hypoglycemia, increased regimen complexity, and additional copayments may lead to reluctance to initiate prandial insulin. IDegLira is a titratable, fixed-ratio coformulation that combines the advantages of insulin degludec and the glucagon-like peptide 1 receptor agonist liraglutide in a single once-daily injection and mitigates the side effects associated with each component. Clinical trials have demonstrated that IDegLira improves glycemic control without the increased risk of hypoglycemia and weight gain observed with basal insulin up-titration and the addition of prandial insulin, and this is achieved using twice-weekly titration. Clinical trials and real-world studies have also shown that IDegLira has the potential to reduce therapeutic and titration inertia. However, better outcomes could be achieved with IDegLira initiation in suitable patients with timely titration and by providers sharing their experience with this combination product. This review describes considerations for initiation, titration, and intensification of IDegLira in patients previously receiving basal insulin.

In the United States, many patients with type 2 diabetes do not attain an A1C <7.0% with basal insulin (1,2), and this is often due to insufficient titration and delays in treatment intensification (35). The reasons for this therapeutic inertia include concerns about weight gain, hypoglycemia, and increased regimen complexity/ treatment burden (6,7) and have been reviewed in detail elsewhere (8).

A possibly lesser-known form of therapeutic inertia is “over-basalization,” or, the continued up-titration of basal insulin despite a lack of improvement in glycemic control with this regimen (911). As type 2 diabetes progresses, some patients will become so insulin resistant that continued up-titration of basal insulin is not matched by a proportional improvement in fasting plasma glucose (FPG) or A1C. American Diabetes Association (ADA) guidelines suggest that, if insulin is appropriately titrated and doses reach >0.5 units/kg/day without achieving glycemic targets, an additional strategy for intensifying treatment should be considered rather than continuing to up-titrate basal insulin (12). Patients experiencing recurrent hypoglycemia on basal insulin are often over-basalized or are using a secretagogue in conjunction with basal insulin. Discontinuation of secretagogue therapy on initiation of insulin therapy is recommended to avoid the increased risk of hypoglycemia associated with concomitant use (12), but that does not address the problems arising from excess basal insulin.

The optimal time for adding a mealtime insulin rather than up-titrating the basal dose for such patients is unknown. However, it has been suggested that a large decrease in glucose values between bedtime and morning (sometimes called the “BeAm value”) may be an indicator of insufficient postprandial control and over-basalization (13).

There is a clinical need for alternative treatment options for patients whose diabetes is uncontrolled on basal insulin. In this review, we introduce IDegLira, a fixed-ratio combination (FRC) of insulin degludec and the glucagon-like peptide 1 (GLP-1) receptor agonist liraglutide; consider whether it would be an appropriate treatment option for patients whose diabetes is uncontrolled on basal insulin; and discuss the practicalities of initiating and titrating IDegLira in clinical practice.

IDegLira is a titratable FRC of insulin degludec and liraglutide (14). The benefits of combining basal insulin with GLP-1 receptor agonist therapy have been reviewed in detail elsewhere (1517). In particular, this combination affords good control of postprandial glucose and FPG, predominantly provided by the GLP-1 receptor agonist and the basal insulin component, respectively (15). In addition, the joint use of these two agents has a dose-sparing effect, thereby minimizing unwanted side effects such as gastrointestinal (GI) adverse events with GLP-1 receptor agonists and weight gain with insulin (18,19). The lower rate of GI adverse events observed with IDegLira compared with liraglutide can also be explained by the more gradual titration of liraglutide as part of the IDegLira FRC (14,20,21). Furthermore, the favorable effect of IDegLira on weight compared with other insulin regimens is likely to be related to the effects of liraglutide on satiety (22).

The safety and efficacy of IDegLira have been studied in the phase 3 Dual Action of Liraglutide and Insulin Degludec in Type 2 Diabetes (DUAL) clinical trial program. Here, we will focus on the trials involving patients whose diabetes was uncontrolled on basal insulin. These trials compared IDegLira to ≤50 units degludec (DUAL II) (23), continued up-titration of insulin glargine 100 units/mL (IGlar U100) (DUAL V) (24), and basal-bolus therapy (IGlar U100 and insulin aspart) (DUAL VII) (25).

Key results from these trials are summarized in Figure 1. A1C reductions with IDegLira were greater than with basal insulin and similar to basal-bolus therapy (Figure 1A), and a high percentage of patients using IDegLira achieved an A1C <7% (Figure 1B). The rate of confirmed hypoglycemia was 57% lower with IDegLira than with continued up-titration with IGlar U100 and 89% lower with IDegLira than with basal-bolus therapy (Figure 1C). Hypoglycemia rates were similar for IDegLira and degludec (DUAL II), probably because the dose of degludec was capped at 50 units (because this trial assessed the contribution of the liraglutide component of IDegLira) (23), whereas in the two trials using IGlar U100, the basal insulin dose was not capped, and hypoglycemia rates were lower with IDegLira (24,25). Mean change in body weight is shown in Figure 1D. In all three trials, patients randomized to IDegLira achieved weight loss after 26 weeks, whereas degludec resulted in no change of weight; IGlar U100 resulted in weight gain (1.8 kg), as did basal-bolus therapy (2.6 kg).

FIGURE 1

Key results from the DUAL research program trials comparing IDegLira to basal insulin (2325). For DUAL II, hypoglycemia was defined as episodes confirmed by a plasma glucose value <56 mg/dL (regardless of symptoms) and severe episodes (requiring assistance of another person); for DUAL V, confirmed hypoglycemic episodes were defined as episodes in which plasma glucose was biochemically confirmed as <56 mg/dL, with or without symptoms or for which the patient required assistance; and for DUAL VII, hypoglycemic events were defined as either severe, according to the ADA classification (requiring assistance of another person to take corrective actions), or symptomatic (blood glucose–confirmed <56 mg/dL accompanied by glycopenic symptoms). ns, nonsignificant; RR, rate ratio.

FIGURE 1

Key results from the DUAL research program trials comparing IDegLira to basal insulin (2325). For DUAL II, hypoglycemia was defined as episodes confirmed by a plasma glucose value <56 mg/dL (regardless of symptoms) and severe episodes (requiring assistance of another person); for DUAL V, confirmed hypoglycemic episodes were defined as episodes in which plasma glucose was biochemically confirmed as <56 mg/dL, with or without symptoms or for which the patient required assistance; and for DUAL VII, hypoglycemic events were defined as either severe, according to the ADA classification (requiring assistance of another person to take corrective actions), or symptomatic (blood glucose–confirmed <56 mg/dL accompanied by glycopenic symptoms). ns, nonsignificant; RR, rate ratio.

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In a post hoc analysis, the odds of achieving a clinically relevant triple composite end point of A1C <7% without hypoglycemia and without weight gain were significantly higher with IDegLira in all three trials (at least 38% of patients using IDegLira achieved this composite, compared with no more than 12.2% of patients who up-titrated basal insulin or who used basal-bolus therapy) (2325). More IDegLira-treated patients in DUAL trials V and VII also achieved the triple composite end point when incorporating higher A1C targets (<7.5%, <8%, ≤9%) that might be used either in some clinical practice settings in which more stringent targets are not suitable or by quality metrics such as the Healthcare Effectiveness Data and Information Set (26). Specifically, in DUAL VII, the odds of achieving an A1C <7.5% or <8% with no weight gain and without hypoglycemia were 10 times higher for IDegLira compared with basal-bolus therapy (27).

In a DUAL V post hoc analysis, Lingvay et al. (28) demonstrated that, across different categories of baseline A1C, FPG, and BMI levels, estimated treatment differences for change in A1C and body weight all significantly favored IDegLira over IGlar U100 up-titration (Table 1); the clinical benefits of IDegLira were achieved in patients with different degrees of glycemic and metabolic control.

TABLE 1

Estimated Treatment Differences Over 26 weeks in A1C and Body Weight Across Baseline Categories of A1C, FPG, and BMI in Patients Intensifying Treatment With IDegLira Versus Up-Titration of Insulin Glargine in the DUAL V Trial

End Point Measured
Patient Characteristic at BaselineA1C, %Change in Body Weight, kg
A1C category   
≤7.5% –0.48 (–0.73 to –0.23), P = 0.0002 –2.26 (–3.35 to –1.17), P <0.0001 
>7.5 to ≤8.5% –0.55 (–0.80 to –0.31), P <0.0001 –2.84 (–3.68 to –2.01), P <0.0001 
>8.5–10% –0.68 (–0.93 to –0.42), P <0.0001 –4.21 (–5.17 to –3.24), P <0.0001 
FPG category (mg/dL)   
<129.7 –0.75 (–0.99 to –0.51), P <0.0001 –3.08 (–4.10 to –2.06), P <0.0001 
≥129.7 –0.52 (–0.70 to –0.34), P <0.0001 –3.32 (–4.00 to –2.64), P <0.0001 
BMI category (kg/m2  
<30 –0.68 (–0.94 to –0.42), P <0.0001 –3.40 (–4.32 to –2.49), P <0.0001 
≥30 to <35 –0.52 (–0.76 to –0.28), P <0.0001 –2.75 (–3.63 to –1.87), P <0.0001 
≥35–40 –0.59 (–0.83 to –0.34), P <0.0001 –3.65 (–4.91 to –2.39), P <0.0001 
End Point Measured
Patient Characteristic at BaselineA1C, %Change in Body Weight, kg
A1C category   
≤7.5% –0.48 (–0.73 to –0.23), P = 0.0002 –2.26 (–3.35 to –1.17), P <0.0001 
>7.5 to ≤8.5% –0.55 (–0.80 to –0.31), P <0.0001 –2.84 (–3.68 to –2.01), P <0.0001 
>8.5–10% –0.68 (–0.93 to –0.42), P <0.0001 –4.21 (–5.17 to –3.24), P <0.0001 
FPG category (mg/dL)   
<129.7 –0.75 (–0.99 to –0.51), P <0.0001 –3.08 (–4.10 to –2.06), P <0.0001 
≥129.7 –0.52 (–0.70 to –0.34), P <0.0001 –3.32 (–4.00 to –2.64), P <0.0001 
BMI category (kg/m2  
<30 –0.68 (–0.94 to –0.42), P <0.0001 –3.40 (–4.32 to –2.49), P <0.0001 
≥30 to <35 –0.52 (–0.76 to –0.28), P <0.0001 –2.75 (–3.63 to –1.87), P <0.0001 
≥35–40 –0.59 (–0.83 to –0.34), P <0.0001 –3.65 (–4.91 to –2.39), P <0.0001 

Adapted from ref. 28. Values are estimated treatment difference (95% CI) between IDegLira and IGlar U100.

The benefit of a simple, once-daily IDegLira regimen is reflected in the greater improvements observed in patient-reported outcomes with IDegLira versus comparators in DUAL V and DUAL VII (24,29). Improvements in scores on the Treatment-Related Impact Measure for Diabetes were significantly greater with IDegLira than with IGlar U100 (24) or basal-bolus therapy (29) for all domains and total scores. The greatest improvements were in the diabetes management and treatment burden domains (24,29). The patient-reported outcomes results from DUAL V are partly attributable to the reduced treatment complexity of IDegLira versus basal-bolus therapy in terms of the number of daily injections and the number of dose adjustments (30). Despite IDegLira being initiated at 16 units compared with continued titration of IGlar U100 from pre-trial doses (mean 33 units), the mean number of basal insulin dose adjustments was similar in the IDegLira (16.6) and basal-bolus (17.1) groups during 26 weeks of treatment. Furthermore, in the basal-bolus treatment arm, 153 patients (66.5%) required three or more daily bolus insulin injections, and the mean number of bolus insulin adjustments required during 26 weeks of treatment was 200.1 (30).

Adherence to trial protocols and titration algorithms is closely monitored in clinical trials, and the above-described results are unlikely to be replicated in clinical practice. However, greater satisfaction with IDegLira compared with basal-bolus therapy is consistent with physicians’ experience of real-world IDegLira use in Europe, according to the results of a multicenter survey (31); the authors observed greater patient adherence with IDegLira compared with other intensification strategies involving multiple daily injections.

GLP-1 receptor agonist therapy is associated with GI side effects at initiation (12). Overall, the incidences of GI adverse events, including nausea, vomiting, and diarrhea, were generally low across the DUAL trials and largely restricted to the first few weeks of treatment (14). GI adverse events were reported in fewer insulin degludec–treated patients but more liraglutide-treated patients compared with patients treated with IDegLira (20). This observation is likely related to the slower and more gradual liraglutide titration as a constituent of IDegLira treatment (32).

The U.S. Food and Drug Administration requires an assessment of cardiovascular (CV) safety for all new diabetes drugs (33). Although a CV outcomes trial has not been conducted for IDegLira, such trials have been carried out on its individual components of degludec (34) and liraglutide (35). The DEVOTE (Trial Comparing Cardiovascular Safety of Insulin Degludec Versus Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events) trial demonstrated insulin degludec’s noninferiority to IGlar U100 for the primary composite outcome of first occurrence of CV death, nonfatal myocardial infarction (MI), or nonfatal stroke (34). Additionally, a post hoc analysis demonstrated that patients treated with degludec or IGlar U100 plus liraglutide had significantly fewer major adverse CV events compared with patients who did not receive liraglutide (36). Using the same primary composite outcome, the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) trial confirmed superiority of liraglutide versus placebo in terms of incidence of major adverse CV events, with fewer deaths from CV or any cause and numerically lower rates of nonfatal MI, nonfatal stroke, and hospitalization for heart failure (35). Post hoc analyses of the LEADER trial suggested that participants also using basal insulin benefitted from the relative cardioprotection of liraglutide versus placebo (37). Meanwhile, post hoc analyses of the DUAL II, V, and VII trials found that, compared with basal insulin treatment, patients treated with IDegLira demonstrated a general improvement in CV risk markers, including systolic blood pressure, LDL cholesterol levels, and brain natriuretic peptide (38). It should be noted that these positive CV outcome data have been observed with the liraglutide 1.8-mg dose (35); patients receiving IDegLira would need to be receiving the maximum dose to achieve this dose of liraglutide (14).

Real-world evidence on IDegLira use in U.S. patients has not yet been published, but two studies from Europe have provided some insight (39,40). The larger of the studies was a retrospective chart review of 611 patients from 61 centers in five countries (40). Before switching to IDegLira, patients were on a variety of injectable and oral medications, used alone or in combination. Most patients (71.8%) switched to IDegLira because of a lack of efficacy of their previous regimen, whereas 26.5% switched because of concerns about weight gain on their previous regimen. After 6 months, significant A1C reductions were observed regardless of the baseline regimen, and rates of hypoglycemia were low. Mean changes in body weight were generally small, and the only statistically significant change was a 2.4-kg decrease in weight for patients changing from multiple daily insulin injections. At 6 months, 45 patients (7.4%) had discontinued IDegLira, but 69% of those discontinuations were because of changes in reimbursement that occurred in Germany. In the second study, which was conducted at a single center in Switzerland, 61 patients switching to IDegLira (mostly from regimens of insulin plus oral antidiabetic drugs) experienced a decrease of 1.7% in A1C (39). After 6 months, there was a mean loss of 1.9 kg body weight, and there were no episodes of severe hypoglycemia. Six patients (9.8%) discontinued IDegLira because of GI side effects.

Finally, research has consistently linked cost with medication nonadherence (41). In terms of out-of-pocket costs for patients, IDegLira has the advantage of providing two branded drugs for just one copayment, rather than the two separate copayments that would be required if degludec and liraglutide were initiated sequentially, for example. It is important to note that IDegLira is more expensive than other antidiabetic drug classes, which means that insurance coverage can be a practical barrier for providers and patients, but short- and long-term cost-effectiveness analyses demonstrate that its higher cost is offset by its greater efficacy (4249). Short-term analyses in the United States have reported lower or equivalent annual costs of achieving A1C targets or the composite end point of A1C targets without weight gain and/or hypoglycemia with IDegLira versus basal insulin (IGlar U100) or basal-bolus therapy (IGlar U100 plus insulin aspart four or more times per day) (42,46). Greater differences in favor of IDegLira were observed when the avoidance of weight gain/hypoglycemia was factored in (42,46). Moreover, long-term cost-effectiveness analyses using models that account for insulin dosing, hypoglycemia rates, and the development of diabetes-related complications have reported that IDegLira is cost-effective compared with IGlar U100, the combination of basal insulin and liraglutide administered separately, or basal-bolus therapy (43,4749).

Administration

The IDegLira 100/3.6 pen provides 100 units/mL degludec and 3.6 mg/mL liraglutide. Each unit of IDegLira contains 1 unit degludec and 0.036 mg liraglutide, and the pen can deliver doses from 10 to 50 units with each injection (14).

IDegLira should be administered once daily subcutaneously into the thigh, upper arm, or abdomen and at the same time each day, with or without food. IDegLira can be given at any time of the day, and the choice of dose timing can be individualized for each patient. Basal insulin is traditionally dosed in the evening (50), so patients switching from basal insulin may prefer to continue with that routine. In our experience, administration in the evening may be preferable for patients who have previously experienced GI side effects with initiation of GLP-1 receptor agonist therapy, but not for patients who usually have good blood glucose readings at bedtime (and thus may be more likely to omit or underestimate the dose required if IDegLira is given at bedtime). Treatment should be discussed with patients, and dose timing should be individualized to their needs and preferences (51,52).

Starting Dose

The IDegLira label states that it should be initiated at 10 units (10 units degludec plus 0.36 mg liraglutide) in patients transferring from oral antidiabetic drugs and at 16 units (16 units degludec plus 0.58 mg liraglutide) in patients transferring from basal insulin or a GLP-1 receptor agonist (14). This review is focused on patients who are transferring from basal insulin therapy.

Initially, such patients may be skeptical that 16 units of IDegLira will be sufficient to maintain or improve glycemic control. In such cases, it is important to refer patients to findings from clinical trials. For example, a post hoc analysis of the DUAL V trial demonstrated that, compared with IGlar U100 up-titration, IDegLira resulted in significantly greater reductions in A1C and body weight and lower hypoglycemia rates at a lower end-of-trial insulin dose, regardless of pre-trial IGlar U100 dose. Importantly, across all pretrial insulin dose groups (20 to <30, ≥30 to <40, and ≥40 to ≤50 units/day), there were no clinically relevant increases in self-monitoring of blood glucose (SMBG) levels and no withdrawals due to hyperglycemia with IDegLira during the first 8 weeks (53). Although not recommended nor studied, we have had success with patients coming from >50 units basal insulin, with some achieving glycemic targets soon after switching to IDegLira.

Titration

The outcomes observed in DUAL V and VII trials were achieved using twice-weekly titration of IDegLira, based on the mean of three consecutive daily fasting SMBG values, to a fasting glucose target of 72–90 mg/dL (24,25). We have found that pointing out that the mean insulin dose in these trials approached 40 units by week 12 can be a helpful frame of reference for patients. To achieve the best outcomes, IDegLira should be adjusted every 3–4 days by 2 units upward or downward as required, based on metabolic needs, SMBG measurements, and glycemic targets, until the desired FPG is achieved. To minimize the risk of hypo- or hyperglycemia, additional titration may be needed with changes in physical activity, meal patterns, renal or hepatic function, or during acute illness. It is often difficult for patients to exactly adhere to regimens used in clinical trials (8). In a prospective, observational, single-center, Swiss study investigating the effectiveness of IDegLira initiation in 61 patients, titrating IDegLira by 4 units once weekly, according to individualized fasting blood glucose targets, resulted in favorable outcomes (39).

If patients miss a dose, they should resume, as prescribed, with the next scheduled dose. However, if >3 days have elapsed since the previous dose, it is recommended to revert to the initial starting dose to mitigate any GI symptoms. Several resources are available for patients on the Novo Nordisk IDegLira website, such as a video showing how to use the IDegLira pen and adjust the dose. Patients may find these resources helpful in mitigating confusion about dosing and refreshing their knowledge (54). We have also found it beneficial to ensure prompt follow-up after IDegLira initiation (e.g., ask patients to contact the clinic after 2–3 weeks if they are struggling to control their blood glucose and routinely have patients return to the clinic 6 weeks after initiating IDegLira). This level of support for patients can overcome barriers to treatment intensification and improve their glycemic control.

What to Do If Patients Need Further Intensification?

When the addition of an oral antidiabetic drug to IDegLira therapy fails to improve glycemic control, we recommend considering a prandial insulin regimen. Patients may need to discontinue IDegLira and switch to multiple daily injections of basal and prandial insulin with or without a GLP-1 receptor agonist. The safety and efficacy of IDegLira in combination with prandial insulin has not been studied (14). Patients who continue to experience postprandial glucose excursions while taking the maximum dose of IDegLira may benefit from the addition of prandial insulin.

Titration in Clinical Practice

Compared with other insulin regimens, IDegLira provides improved glycemic control without increased risk of hypoglycemia and weight gain in a simple, once-daily regimen. By combining degludec and liraglutide in a single pen, it also allows two branded drugs to be initiated with a single copayment. Therefore, IDegLira is an attractive alternative to other intensification strategies for patients who are reluctant to take more than one injection per day or are concerned about additional costs, weight gain, or hypoglycemia.

The titration schedule relies on frequent self-titration at home, which may be a barrier to achieving good glycemic control, particularly for patients with low health literacy. These patients may need assistance and education to understand effective titration of the medication. Good communication between health care professionals and patients is crucial to alleviate patient concerns and offer potential solutions (8). Pharmacists and specialist nurses are well positioned to assist patients with titration.

An example from our clinical practice in which IDegLira initiation and titration, as recommended, was successful is a 56-year-old man with diabetes inadequately controlled on IGlar U100 and metformin. His A1C was 8.2%, and he was administering 45 units of IGlar U100 at bedtime but would frequently omit or adjust the IGlar U100 dose when his bedtime blood glucose reading was <100 mg/dL due to fear of nocturnal hypoglycemia. When considering intensification options, he had concerns about taking multiple daily injections and about the cost of additional medications; he was therefore pleased to learn that IDegLira required only one copayment and could be administered once daily. Three months after switching to 16 units of IDegLira (dosed in the morning) and increasing the dose by 2 units every 3 days until his fasting blood glucose readings were consistently <130 mg/dL, his IDegLira dose was 32 units, and his A1C had improved to 6.9%.

It is crucial to emphasize the importance of timely titration to patients so they achieve the best outcomes with treatment, and the above-mentioned case exemplifies success with this approach. However, our experience with patients in regular clinical practice has also demonstrated the virtues of tailoring the approach to IDegLira initiation and titration to individual patients. For example, patients with a recurrent history of hypoglycemia start on 16 units of IDegLira as recommended, but some patients may benefit from titrating once weekly, initially in increments of 1 unit. Fear of hypoglycemia could also be allayed in these patients with education about the lower rates of hypoglycemia observed with IDegLira compared with up-titration of basal insulin in clinical trials (24).

Some patients may be wary of decreasing their dose of insulin when starting IDegLira if they have previously experienced persistent hyperglycemia on a much higher dose of insulin. An example from our clinical practice is a 49-year-old woman who was receiving 45 units/day of IGlar U100 in combination with 2 g/day of metformin but had poor glycemic control with an A1C of 8.3% and fasting blood glucose levels between 130 and 150 mg/dL. Stressing the importance of twice-weekly titration and reassuring her that most patients had an IDegLira dose approaching 40 units after 3 months empowered her to titrate effectively, and she was encouraged by experiencing an improvement in her fasting blood glucose levels after 2 weeks. She ultimately required 38 units, demonstrating the insulin dose–sparing properties of IDegLira.

Taken together, these examples demonstrate the importance of having an initial discussion with patients regarding what they can expect and the important points to bear in mind when switching to IDegLira.

In our experience, IDegLira is an effective choice for patients languishing in poor glycemic control with basal insulin because it provides the benefits of good glycemic control with a low risk of weight gain and hypoglycemia at a lower basal insulin dose than with other insulin regimens. Additionally, its once-daily administration and simple titration algorithm are conducive to medication adherence and use in primary care settings. Real-world experience of IDegLira use demonstrates the importance of both reassuring patients so they are empowered to titrate IDegLira as required to achieve optimal outcomes and of tailoring initiation and titration of IDegLira to individual patient circumstances. By sharing our experience, we hope to have outlined important considerations when using IDegLira in clinical practice.

Acknowledgments

Medical writing and submission support were provided by Victoria Atess, Gary Patronek, and Helen Marshall of Watermeadow Medical, an Ashfield company, part of UDG Healthcare PLC.

Funding

Medical writing and submission support for this manuscript were funded by Novo Nordisk. Novo Nordisk also reviewed the manuscript for medical accuracy.

Duality of Interest

M.W. has received research support from Eli Lilly, Gan and Lee, Janssen, Mylan, Novo Nordisk, Sanofi, and Shire; is on advisory panels for Eli Lilly, Novo Nordisk, and Sanofi; and is on speakers’ bureaus for Amgen, AstraZeneca, Eli Lilly, Janssen, Mannkind, Merck, Novo Nordisk, Sanofi, and Shire. No other potential conflicts of interest relevant to this article were reported.

Author Contributions

Both authors made substantial contributions to the design and interpretation of data and the drafting of the manuscript and approved the final version. M.W. is the guarantor of this work and, as such, takes responsibility for the integrity and accuracy of this review.

1.
Dalal
MR
,
Grabner
M
,
Bonine
N
,
Stephenson
JJ
,
DiGenio
A
,
Bieszk
N
.
Are patients on basal insulin attaining glycemic targets? Characteristics and goal achievement of patients with type 2 diabetes mellitus treated with basal insulin and physician-perceived barriers to achieving glycemic targets
.
Diabetes Res Clin Pract
2016
;
121
:
17
26
2.
Curtis
B
,
Lage
MJ
.
Glycemic control among patients with type 2 diabetes who initiate basal insulin: a retrospective cohort study
.
J Med Econ
2014
;
17
:
21
31
3.
Schwab
P
,
Saundankar
V
,
Bouchard
J
, et al
Early treatment revisions by addition or switch for type 2 diabetes: impact on glycemic control, diabetic complications, and healthcare costs
.
BMJ Open Diabetes Res Care
2016
;
4
:
e000099
4.
Mocarski
M
,
Yeaw
J
,
Divino
V
, et al
Slow titration and delayed intensification of basal insulin among patients with type 2 diabetes
.
J Manag Care Spec Pharm
2018
;
24
:
390
400
5.
Berard
L
,
Bonnemaire
M
,
Mical
M
,
Edelman
S
.
Insights into optimal basal insulin titration in type 2 diabetes: results of a quantitative survey
.
Diabetes Obes Metab
2018
;
20
:
301
308
6.
Peyrot
M
,
Perez-Nieves
M
,
Ivanova
J
, et al
Correlates of basal insulin persistence among insulin-naive people with type 2 diabetes: results from a multinational survey
.
Curr Med Res Opin
2017
;
33
:
1843
1851
7.
Brod
M
,
Pfeiffer
KM
,
Barnett
AH
,
Berntorp
K
,
Vilsboll
T
,
Weissenberger
B
.
Perceptions of diabetes control among physicians and people with type 2 diabetes uncontrolled on basal insulin in Sweden, Switzerland, and the United Kingdom
.
Curr Med Res Opin
2016
;
32
:
981
989
8.
Russell-Jones
D
,
Pouwer
F
,
Khunti
K
.
Identification of barriers to insulin therapy and approaches to overcoming them
.
Diabetes Obes Metab
2018
;
20
:
488
496
9.
Johnson
EL
,
Frias
JP
,
Trujillo
JM
.
Anticipatory guidance in type 2 diabetes to improve disease management: next steps after basal insulin
.
Postgrad Med
2018
;
130
:
365
374
10.
Meece
J
.
Basal insulin intensification in patients with type 2 diabetes: a review
.
Diabetes Ther
2018
;
9
:
877
890
11.
LaSalle
JR
,
Berria
R
.
Insulin therapy in type 2 diabetes mellitus: a practical approach for primary care physicians and other health care professionals
.
J Am Osteopath Assoc
2013
;
113
:
152
162
12.
Davies
MJ
,
D’Alessio
DA
,
Fradkin
J
, et al
Management of hyperglycemia in type 2 diabetes, 2018: a consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)
.
Diabetes Care
2018
;
41
:
2669
2701
13.
Zisman
A
,
Morales
F
,
Stewart
J
,
Stuhr
A
,
Vlajnic
A
,
Zhou
R
.
BeAM value: an indicator of the need to initiate and intensify prandial therapy in patients with type 2 diabetes mellitus receiving basal insulin
.
BMJ Open Diabetes Res Care
2016
;
4
:
e000171
14.
Xultophy 100/3.6 (insulin degludec and liraglutide injection) [prescribing information]. Plainsboro, N.J., Novo Nordisk
,
February 2019
15.
Cohen
ND
,
Audehm
R
,
Pretorius
E
,
Kaye
J
,
Chapman
LH
,
Colagiuri
S
.
The rationale for combining GLP-1 receptor agonists with basal insulin
.
Med J Aust
2013
;
199
:
246
249
16.
Holst
JJ
,
Vilsbøll
T
.
Combining GLP-1 receptor agonists with insulin: therapeutic rationales and clinical findings
.
Diabetes Obes Metab
2013
;
15
:
3
14
17.
Valentine
V
,
Goldman
J
,
Shubrook
JH
.
Rationale for, initiation and titration of the basal insulin/GLP-1RA fixed-ratio combination products IDegLira and IGlarLixi for the management of type 2 diabetes
.
Diabetes Ther
2017
;
8
:
739
752
18.
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
19.
Goldenberg
RM
,
Berard
L
.
Adding prandial GLP-1 receptor agonists to basal insulin: a promising option for type 2 diabetes therapy
.
Curr Med Res Opin
2018
;
34
:
1
10
20.
Gough
SC
,
Bode
B
,
Woo
V
, et al
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-naive patients with type 2 diabetes
.
Lancet Diabetes Endocrinol
2014
;
2
:
885
893
21.
Novo
Nordisk
.
Xultophy summary of product characteristics
.
Bagsvaerd, Denmark
,
Novo Nordisk
,
2018
22.
van Can
J
,
Sloth
B
,
Jensen
CB
,
Flint
A
,
Blaak
EE
,
Saris
WH
.
Effects of the once-daily GLP-1 analog liraglutide on gastric emptying, glycemic parameters, appetite and energy metabolism in obese, non-diabetic adults
.
Int J Obes (Lond)
2014
;
38
:
784
793
23.
Buse
JB
,
Vilsbøll
T
,
Thurman
J
, et al
Contribution of liraglutide in the fixed-ratio combination of insulin degludec and liraglutide (IDegLira)
.
Diabetes Care
2014
;
37
:
2926
2933
24.
Lingvay
I
,
Pérez Manghi
F
,
Garcia-Hernandez
P
, et al
Effect of insulin glargine up-titration vs insulin degludec/liraglutide on glycated hemoglobin levels in patients with uncontrolled type 2 diabetes: the DUAL V randomized clinical trial
.
JAMA
2016
;
315
:
898
907
25.
Billings
LK
,
Doshi
A
,
Gouet
D
, et al
Efficacy and safety of IDegLira versus basal-bolus insulin therapy in patients with type 2 diabetes uncontrolled on metformin and basal insulin: the DUAL VII randomized clinical trial
.
Diabetes Care
2018
;
41
:
1009
1016
26.
NCQA
.
Disease management performance measures for comprehensive diabetes care
.
Available from
www.ncqa.org/hedis/measures/comprehensive-diabetes-care.
Accessed 15 July 2019
27.
Egede
LE
,
Bargiota
A
,
Cannon
AJ
, et al
Patients with type 2 diabetes treated with IDegLira have a greater chance of achieving glycated hemoglobin (HbA1c) targets without hypoglycemia and weight gain than with basal insulin or basal–bolus therapy, irrespective of HbA1c target
.
Presented at the Academy of Managed Care Pharmacy Annual Meeting
,
23
–26 April 2018
,
Boston, Mass
.
28.
Lingvay
I
,
Harris
S
,
Jaeckel
E
,
Chandarana
K
,
Ranthe
MF
,
Jodar
E
.
Insulin degludec/liraglutide (IDegLira) was effective across a range of dysglycaemia and body mass index categories in the DUAL V randomized trial
.
Diabetes Obes Metab
2018
;
20
:
200
205
29.
Billings
LK
,
Doshi
A
,
Gouet
D
, et al
Patient-reported outcomes (PROs) in insulin degludec/liraglutide (IDegLira) vs. basal-bolus (BB) therapy in patients (pts) with type 2 diabetes (T2D): DUAL VII trial [Abstract 124-LB]
.
Diabetes
2017
;
66
(
Suppl. 1
):
LB32
30.
Miller
EM
,
Jodar
E
,
Khunti
K
, et al
The clinical benefits of IDegLira in DUAL VII were achieved while using a simple regimen with fewer injections and dose adjustments compared with basal-bolus therapy
.
Diabetologia
2018
;
61
(
Suppl. 1
):
S83
31.
Drummond
R
,
Baru
A
,
Dutkiewicz
M
,
Basse
A
,
Tengmark
BO
.
Physicians’ real-world experience with IDegLira: results of a European survey
.
BMJ Open Diabetes Res Care
2018
;
6
:
e000531
32.
Aroda
V
,
Jaeckel
E
,
Jarlov
H
,
Abrahamsen
TJ
,
Vilsbøll
T
.
Incidence of gastrointestinal side effects similar between IDegLira and non-GLP-1RA comparators [Abstract 1009-P]
.
Diabetes
2015
;
64
(
Suppl. 1
):
A257
33.
U.S. Department of Health and Human Services
,
U.S. Food and Drug Administration
,
Center for Drug Evaluation and Research. Guidance for industry: diabetes mellitus: evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. Silver Spring
, Md.,
U.S. Food and Drug Administration
,
2008
34.
Marso
SP
,
McGuire
DK
,
Zinman
B
, et al
Efficacy and safety of degludec versus glargine in type 2 diabetes
.
N Engl J Med
2017
;
377
:
723
732
35.
Marso
SP
,
Daniels
GH
,
Brown-Frandsen
K
, et al
Liraglutide and cardiovascular outcomes in type 2 diabetes
.
N Engl J Med
2016
;
375
:
311
322
36.
Brown-Frandsen
K
,
Emerson
SS
,
McGuire
DK
, et al
Lower rates of cardiovascular events and mortality associated with liraglutide use in patients treated with basal insulin: A DEVOTE subanalysis (DEVOTE 10)
.
Diabetes Obes Metab
;
2019
;
21
:
1437
1444
37.
Tack
C
,
Jacob
S
,
DeSouza
C
, et al
Liraglutide effects in insulin-treated patients in LEADER
.
Diabetes
2018
;
67
(
Suppl. 1
):
A117
38.
Vilsbøll
T
,
Blevins
TC
,
Jodar
E
, et al
Fixed-ratio combination of insulin degludec and liraglutide (IDegLira) improves cardiovascular risk markers in patients with type 2 diabetes uncontrolled on basal insulin
.
Diabetes Obes Metab
2019
;
21
:
1506
1512
39.
Sofra
D
.
Glycemic control in a real-life setting in patients with type 2 diabetes treated with IDegLira at a single Swiss center
.
Diabetes Ther
2017
;
8
:
377
384
40.
Price
H
,
Bluher
M
,
Prager
R
,
Phan
TM
,
Thorsted
BL
,
Schultes
B
.
Use and effectiveness of a fixed-ratio combination of insulin degludec/liraglutide (IDegLira) in a real-world population with type 2 diabetes: results from a European, multicentre, retrospective chart review study
.
Diabetes Obes Metab
2018
;
20
:
954
962
41.
Briesacher
BA
,
Gurwitz
JH
,
Soumerai
SB
.
Patients at-risk for cost-related medication nonadherence: a review of the literature
.
J Gen Intern Med
2007
;
22
:
864
871
42.
Billings
LK
,
Mocarski
M
,
Slothuus
U
,
Hunt
B
,
Valentine
W
,
Jodar
E
.
Evaluation of the short-term cost-effectiveness of insulin degludec/liraglutide (IDegLira) vs. basal-bolus therapy in the USA [Abstract 981-P]
.
Diabetes
2017
;
66
(
Suppl. 1
):
A254
43.
Dempsey
M
,
Mocarski
M
,
Langer
J
,
Hunt
B
.
Long-term cost-effectiveness analysis shows that IDegLira is associated with improved outcomes and lower costs compared with insulin glargine U100 plus insulin aspart in the US
.
J Med Econ
2018
;
21
:
1110
1118
44.
Dempsey
M
,
Mocarski
M
,
Langer
J
,
Hunt
B
.
Ideglira is associated with improved short-term clinical outcomes and cost savings compared with insulin glargine U100 plus insulin aspart in the U.S
.
Endocr Pract
2018
;
24
:
796
804
45.
Drummond
R
,
Malkin
S
,
Du Preez
M
,
Lee
XY
,
Hunt
B
.
The management of type 2 diabetes with fixed-ratio combination insulin degludec/liraglutide (IDegLira) versus basal-bolus therapy (insulin glargine U100 plus insulin aspart): a short-term cost-effectiveness analysis in the UK setting
.
Diabetes Obes Metab
2018
;
20
:
2371
2378
46.
Hunt
B
,
Mocarski
M
,
Valentine
WJ
,
Langer
J
.
Evaluation of the short-term cost-effectiveness of IDegLira versus continued up-titration of insulin glargine U100 in patients with type 2 diabetes in the USA
.
Adv Ther
2017
;
34
:
954
965
47.
Hunt
B
,
Mocarski
M
,
Valentine
WJ
,
Langer
J
.
IDegLira versus insulin glargine U100: a long-term cost-effectiveness analysis in the US setting
.
Diabetes Ther
2017
;
8
:
531
544
48.
Hunt
B
,
Mocarski
M
,
Valentine
WJ
,
Langer
J
.
Evaluation of the long-term cost-effectiveness of IDegLira versus liraglutide added to basal insulin for patients with type 2 diabetes failing to achieve glycemic control on basal insulin in the USA
.
J Med Econ
2017
;
20
:
663
670
49.
Davies
MJ
,
Glah
D
,
Chubb
B
,
Konidaris
G
,
McEwan
P
.
Cost effectiveness of IDegLira vs. alternative basal insulin intensification therapies in patients with type 2 diabetes mellitus uncontrolled on basal insulin in a UK setting
.
Pharmacoeconomics
2016
;
34
:
953
966
50.
Joshi
S
,
Joshi
P
.
A review of insulin and insulin regimens in type 2 diabetes
.
S Afr Fam Pract
2009
;
51
:
97
102
51.
Kaku
K
,
Eid
MA
.
Safety, efficacy, and early clinical experience of insulin degludec in Japanese people with diabetes mellitus: a first-year report from Japan
.
J Diabetes Investig
2015
;
6
:
610
619
52.
Brod
M
,
Rana
A
,
Barnett
AH
.
Adherence patterns in patients with type 2 diabetes on basal insulin analogues: missed, mistimed and reduced doses
.
Curr Med Res Opin
2012
;
28
:
1933
1946
53.
Meneghini
LF
,
Jaeckel
E
,
Leiter
LA
, et al
Converting to insulin degludec/liraglutide (IDegLira) is efficacious regardless of pretrial insulin dose in patients with type 2 diabetes (T2D) uncontrolled on insulin glargine U100 (IGlar) [Abstract 1093-P]
.
Diabetes
2017
;
66
(
Suppl. 1
):
A289
54.
Novo
Nordisk
.
Starting Xultophy
.
Available from
www.xultophy10036.com/starting-xultophy10036/your-first-weeks.html.
Accessed October 2018
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