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GLP-1 receptor agonist and basal insulin co-therapy in type 2 diabetes: Clinical evidence and practicalities of use

Gwen Hall, Colin Kenny
,

Many people with type 2 diabetes in the UK are not reaching glycaemic treatment targets. A treatment regimen combining a basal insulin and a glucagon-like peptide-1 (GLP-1) receptor agonist (RA) can result in improved glycaemic control and may encourage weight loss and provide potential advantages in terms of reducing hypoglycaemia risk. There may be transient gastrointestinal side effects with GLP-1 RAs; however, these can be reduced using slow titration and through dietary adjustments. New GLP-1 RA and basal insulin products, such as once-daily fixed-ratio combinations, may potentially lead to further improvements in efficacy, tolerability and convenience of their co-use.

Owing to the progressive nature of the condition, many people with type 2 diabetes will eventually require insulin therapy; however, insulin initiation is often substantially delayed in UK clinical practice (Blak et al, 2012a; Khunti et al, 2013). In those people who have started basal insulin therapy, many are not achieving adequate glycaemic control (Dale et al, 2010; Blak et al, 2012a; Blak et al, 2012b). Despite elevated HbA1c levels, intensification of basal insulin therapy with meal-time or pre-mixed insulins appears infrequent (Blak et al, 2012b). Combining basal insulin and glucagon-like peptide-1 (GLP-1) receptor agonist (RA) therapies is a treatment approach that may help overcome the inertia with basal insulin initiation alone or insulin intensification. This article reviews the potential benefits of this treatment combination in people with type 2 diabetes and addresses the practicalities of implementing such an approach in primary care.

Brief overview of GLP-1 RAs
GLP-1 RAs improve glycaemic control by stimulating insulin secretion and inhibiting glucagon secretion in response to elevated glucose levels, such as post-meal hyperglycaemia (Baggio and Drucker, 2007). As a result of this glucose-dependent mechanism of action, rates of hypoglycaemia are very low with GLP-1 RA treatment, except when combined with sulphonylurea or insulin treatment (Nauck et al, 2009; Marre et al, 2009). Treatment with GLP-1 RA therapy is also generally associated with clinically significant weight loss, the extent of which varies with each agent (Vilsbøll et al, 2012). The most common side effect with GLP-1 RA therapy is transient gastrointestinal (GI) adverse events, although these usually subside within 12 weeks of treatment (MacConell et al, 2012) and with practical meal adjustments (Hicks et al, 2014).

There are currently five GLP-1 RAs available for use in the UK: exenatide once weekly (Bydureon®), exenatide twice daily (Byetta®), liraglutide (Victoza®), lixisenatide (Lyxumia®) and – the most recent addition – dulaglutide once weekly (Trulicity®). An overview of these agents is presented in Table 1.

Rationale for combining GLP-1 RAs and basal insulin
While the licences of some of the GLP-1 RAs may have been updated only relatively recently to include combination with basal insulin therapy, the concept is not new to the UK. In audits of both exenatide (2007) and liraglutide (2009) by the Association of British Clinical Diabetologists, the combination was extensively used off-licence in secondary care, with this being reported in almost 40% of people treated with a GLP-1 RA (Ryder and Thong, 2012). The most recent clinical guidelines for management of type 2 diabetes from NICE (2009) and SIGN (2010) do not include recommendations for this combination; the NICE guideline, which, at the time of writing, is undergoing an update, recommended further studies. However, in 2012, the American Diabetes Association and the European Association for the Study of Diabetes released a joint position statement recommending GLP-1 RA and basal insulin combination therapy for people not meeting glycaemic targets on dual therapy with either metformin and a GLP-1 RA or metformin and basal insulin (Inzucchi et al, 2012). This was reinforced in the recent update of this statement (Inzucchi et al, 2015).

Combining a basal insulin with a GLP-1 RA provides people with the complementary actions of the two products, as shown in a recently published systematic review and meta-analysis, which found that use of the combination in type 2 diabetes can help achieve adequate glycaemic control with no increased risk of hypoglycaemia or weight gain (Eng et al, 2014). While both classes of drug are effective at lowering blood glucose levels, basal insulin primarily acts on fasting plasma glucose (FPG), while short-acting GLP-1 RAs target postprandial glucose (PPG) and long-acting GLP-1 RAs have effects on both FPG and PPG (Drucker et al, 2008). It has been shown that fasting hyperglycaemia has the most impact on HbA1c when diabetes is poorly controlled while postprandial hyperglycaemia is the major contributor in people nearing HbA1c goals (Monnier et al, 2003). Additionally, insulin therapy often results in weight gain and an increased risk of hypoglycaemic events, while treatment with GLP-1 RAs can be associated with weight loss without increased risk of hypoglycaemia (Inzucchi et al, 2015).

Evidence to support the combination of basal insulin and GLP-1 RA therapy
There are two approaches to using a GLP-1 RA in combination with a basal insulin; adding a basal insulin to existing GLP-1 RA therapy or adding a GLP-1 RA to basal insulin therapy, both of which have been studied in phase III trials.

Adding a basal insulin to GLP-1 RA therapy
Two studies have demonstrated that adding basal insulin to GLP-1 RA therapy significantly reduces HbA1c and with a low rate of hypoglycaemia (0.29 and 0.57 events per patient-year for liraglutide in combination with insulin detemir and insulin degludec, respectively; DeVries et al, 2012; Aroda et al, 2014). In this sequence, there was either no change in mean body weight or a small increase. Box 1 presents a case illustrating the rationale for the addition of a basal insulin to the treatment regimen of a person with sub-optimally controlled type 2 diabetes who is already taking a GLP-1 RA.

Adding a GLP-1 RA to basal insulin therapy
The addition of a GLP-1 RA to basal insulin therapy can significantly improve HbA1c levels without increasing the risk of hypoglycaemia, and the addition of a GLP-1 RA to basal insulin is also commonly associated with clinically significant weight loss (Buse et al, 2011; Riddle et al, 2013a; Riddle et al, 2013b; Ahmann et al, 2014; Mathieu et al, 2014; Rosenstock et al, 2014a). See Box 2 for an example of how a GLP-1 RA may be added to basal insulin therapy.

Why is this combination particularly relevant in primary care?
Owing to the improvements in glycaemic control with a low risk of hypoglycaemia when adding a basal insulin to existing GLP-1 RA therapy (DeVries et al, 2012; Aroda et al, 2014), this approach presents primary care clinicians with a potentially attractive option for appropriate people with diabetes. Additionally, while intensifying basal insulin treatment by adding in a prandial or pre-mixed insulin often requires referral to secondary care, which may lead to increased costs and delays due to longer waiting times (Cuddihy et al, 2011), we feel that the addition of a GLP-1 RA to basal insulin is more suitable for a primary care setting.

Furthermore, intensification of basal insulin with a GLP-1 RA may be more acceptable to people with diabetes than the addition of prandial insulin injections owing to the more favourable weight profile and reduced likelihood of hypoglycaemic events with the GLP-1 RA (Mathieu et al, 2014; Rosenstock et al, 2014a). Basal insulin intensification with a GLP-1 RA has also been shown to be associated with reduced hospitalisation rates and lower all-cause costs compared with intensification using prandial insulin, in a US setting (Dalal et al, 2015).

Practical tips for using the combination
Adjusting prior medication doses
To reduce the risk of hypoglycaemia when adding a GLP-1 RA to basal insulin, a reduction in basal insulin dose should be considered (Table 1). In clinical studies, protocols have generally specified a reduction of around 20–25% of the prior dose in people with HbA1c <69 mmol/mol (<8.5%) at initiation (Viswanathan et al, 2007; Buse et al, 2011). In addition – again, owing to the risk of hypoglycaemia – for people treated with a GLP-1 RA or basal insulin in combination with a sulphonylurea, withdrawal, or at least a dose reduction, of the sulphonylurea should be considered prior to intensifying therapy with a basal insulin or GLP-1 RA (see Table 1).

Timing of injections
Injections should be administered as recommended in each product’s prescribing information, with regards to timing and frequency. Basal insulin and GLP-1 RA injections can be administered at the same time and in the same general area of the body; however, we strongly recommend that they are not administered at the same injection site. Depending on which product is used, dosing may or may not be independent of meal-times (see Table 1 for GLP-1 dose timing), which should be factored into decisions about the chosen regimen.

Reducing GI side effects
With exenatide twice daily, liraglutide and lixisenatide, in order to reduce the risk of GI side effects following addition of the GLP-1 RA to basal insulin, treatment should be initiated at a reduced dose of the GLP-1 RA (see Table 1) and then gradually increased to the recommended dose (electronic Medicines Compendium [eMC], 2014a; 2014b; 2015c; 2015e). Additionally, in our experience, avoiding large or high-fat meals after injection can also help reduce nausea, especially early in treatment.

The future of combination therapy
Two once-daily, single-injection products that combine a GLP-1 RA and basal insulin at a fixed ratio have been developed. IDegLira (Xultophy®), which has a ratio of 1 unit of insulin degludec to 0.036 mg of liraglutide, is now available in the UK (eMC, 2014c). LixiLan, which combines insulin glargine and lixisenatide), is in phase III trials at the time of writing (ClinicalTrials.gov, 2015a; 2015b; Rosenstock et al, 2014b).

IDegLira is administered once daily at any time (preferably at the same time of the day) based on dose steps, with each step consisting of 1 unit of insulin and 0.036 mg of liraglutide. The recommended starting dose is 10 dose steps (10 units of insulin degludec and 0.36 mg of liraglutide) if added to oral antidiabetes therapy, or 16 dose steps if people were previously receiving a basal insulin (eMC, 2014c).

The dose is adjusted using a dial on the injection pen and is based on fasting self-measured blood glucose readings. We recommend increasing or decreasing the dose by two steps twice a week, with the aim of achieving individualised glycaemic targets, to a maximum of 50 dose steps (50 units insulin degludec and 1.8 mg of liraglutide).

Four phase III studies of IDegLira have been completed, two of which have been published in full (Buse et al, 2014; Gough et al, 2014). When added to oral antidiabetes therapy, these two studies have found reductions in HbA1c (mean reduction of 21 mmol/mol [1.9%] in both trials) with IDegLira that were non-inferior to (Gough et al, 2014), or significantly greater than (Buse et al, 2014), that with insulin degludec, and that were significantly greater than that with liraglutide (Gough et al, 2014). Gough et al (2014) also reported that fewer participants in the IDegLira group reported gastrointestinal adverse events than in the liraglutide group (nausea, 8.8% versus 19.7%), which was probably attributable to the slower titration of the liraglutide component in IDegLira. The studies also found that IDegLira was weight neutral (reduction of 0.5 kg) when used in insulin-naïve people (Gough et al, 2014) and resulted in weight loss (reduction of 2.7 kg) in those previously treated with a basal insulin (Buse et al, 2014).

Further developments in basal insulins and GLP-1 RAs may also impact the way the combination is used in future.

Conclusions
The combination of a GLP-1 RA and a basal insulin is an efficacious treatment for people with type 2 diabetes. Co-use of these offers complementary effects on glycaemic control with potential advantages in terms of hypoglycaemia risk. The combination is also beneficial in terms of body weight, resulting in weight loss with the addition of a GLP-1 RA to basal insulin.

When initiating the combination, minor adjustments in prior treatment regimen can help reduce the risk of hypoglycaemia. While GI side effects are possible in the early stages of GLP-1 RA treatment, there are a number of ways to help minimise these effects, and these should be discussed with individuals.

Furthermore, once-daily, single-injection combinations of a basal insulin and a GLP-1 RA have been developed, with one of these already having been launched in the UK.

Acknowledgements
The authors identified the need for this topic and had editorial control over both the design and the content of this manuscript. They wish to thank Leah Pears and Gabrielle Parker at Watermeadow Medical for editorial assistance (funded by Novo Nordisk). The authors did not receive payment in relation to the article’s preparation or publication.

REFERENCES:

Ahmann AJ, Rodbard HW, Rosenstock J et al (2014) Efficacy and safety of liraglutide versus placebo when added to basal insulin analogues in patients with type 2 diabetes (LIRA-ADD2BASAL). Diabetes 63(Suppl 1): A87
Aroda VR, Bailey T, Cariou B et al (2014) The effect of insulin degludec in combination with liraglutide and metformin in patients with type 2 diabetes requiring treatment intensification. Diabetologia 57(Suppl 1): A145
Baggio LL, Drucker DJ (2007) Biology of incretins: GLP-1 and GIP. Gastroenterology 132: 2131–57
Blak BT, Smith HT, Hards M et al (2012a) A retrospective database of insulin initiation in patients with type 2 diabetes in UK primary care. Diabet Med 29: e191–8
Blak BT, Smith HT, Hards M et al (2012b) Optimization of insulin therapy in patients with type 2 diabetes mellitus: beyond insulin therapy. Diabet Med 29: e13–20
Buse JB, Bergenstal RM, Glass LC et al (2011) Use of twice-daily exenatide in basal insulin-treated patients with type 2 diabetes: a randomized, controlled trial. Ann Intern Med 154: 103–12
Buse JB, Vilsbøll T, Thurman J et al (2014) Contribution of liraglutide in the fixed-ratio combination of insulin degludec and liraglutide (IDegLira). Diabetes Care 37: 2926–33
ClinicalTrials.gov (2015a) Efficacy and Safety of Insulin Glargine/ Lixisenatide Fixed Ratio Combination Compared to Insulin Glargine Alone and Lixisenatide Alone on Top of Metformin in Patients With T2DM (LixiLan-O). National Institutes of Health, Bethesda, MD, USA. Available at: https://www.clinicaltrials.gov/ct2/show/NCT02058147 (accessed 25.03.15)
ClinicalTrials.gov (2015b) Efficacy and Safety of the Insulin Glargine/Lixisenatide Fixed Ratio Combination Versus Insulin Glargine in Patients With Type 2 Diabetes (LixiLan-L). National Institutes of Health, Bethesda, MD, USA. Available at: https://www.clinicaltrials.gov/ct2/show/NCT02058160 (accessed 25.03.15)
Cuddihy RM, Philis-Tsimikas A, Nazeri A (2011) Type 2 diabetes care and insulin intensification: is a more multidisciplinary approach needed? Results from the MODIFY survey. Diabetes Educ 37: 111–23
Dalal MR, Xie L, Baser O, DiGenio A (2015) Adding rapid-acting insulin or GLP-1 receptor agonist to basal insulin: outcomes in a community setting. Endocr Pract 21: 68–76
Dale J, Martin S, Gadsby R (2010) Insulin initiation in primary care for patients with type 2 diabetes: 3-year follow-up study. Prim Care Diabetes 4: 85–9
DeVries JH, Bain SC, Rodbard HW et al (2012) Sequential intensification of metformin treatment in type 2 diabetes with liraglutide followed by randomized addition of basal insulin prompted by A1C targets. Diabetes Care 35: 1446–54
Drucker DJ, Buse JB, Taylor K et al (2008) Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. Lancet 372: 1240–50
electronic Medicines Compendium (2014a) Lyxumia 10 micrograms solution for injection. eMC, Leatherhead. Available at: http://www.medicines.org.uk/emc/medicine/27405 (accessed 25.03.15)
electronic Medicines Compendium (2014b) Lyxumia 20 micrograms solution for injection. eMC, Leatherhead. Available at: http://www.medicines.org.uk/emc/medicine/27406 (accessed 25.03.15)
electronic Medicines Compendium (2014c) Xultophy 100 units/ml insulin degludec + 3.6 mg/mL liraglutide solution for injection in a pre-filled pen. eMC, Leatherhead. Available at: http://www.medicines.org.uk/emc/medicine/29493 (accessed 25.03.15)
electronic Medicines Compendium (2015a) BYDUREON 2 mg powder and solvent for prolonged-release suspension for injection. eMC, Leatherhead. Available at: http://www.medicines.org.uk/EMC/medicine/24665 (accessed 25.03.15)
electronic Medicines Compendium (2015b) Bydureon 2 mg powder and solvent for prolonged-release suspension for injection in pre-filled pen. eMC, Leatherhead. Available at: http://www.medicines.org.uk/EMC/medicine/29798 (accessed 25.03.15)
electronic Medicines Compendium (2015c) Byetta 5 micrograms solution for injection, prefilled pen. Byetta 10 micrograms solution for injection, prefilled pen. eMC, Leatherhead. Available at: http://www.medicines.org.uk/EMC/medicine/19257 (accessed 25.03.15)
electronic Medicines Compendium (2015d) TRULICITY 1.5mg & 0.75mg Solution for injection. eMC, Leatherhead. Available at: http://www.medicines.org.uk/emc/medicine/29747 (accessed 25.03.15)
electronic Medicines Compendium (2015e) Victoza 6 mg/ml solution for injection in pre-filled pen. eMC, Leatherhead. Available at: http://www.medicines.org.uk/emc/medicine/21986 (accessed 25.03.15)
Eng C, Kramer CK, Zinman B, Retnakaran R (2014) Glucagon-like peptide-1 receptor agonist and basal insulin combination treatment for the management of type 2 diabetes: a systematic review and meta-analysis. Lancet 384: 2228–34
Gough S, Bode B, Woo V et al (2014) Efficacy and safety of a fixed-ratio combination of insulin degludec and liraglutide 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 2: 885–93
Hicks D, Hill J, James J et al (2014) Glucagon-like peptide-1 receptor agonists: Are they all the same? Diabetes & Primary Care 16: 254–8
Inzucchi SE, Bergenstal RM, Buse JB et al (2012) Management of hyperglycemia in type 2 diabetes: a patient-centred approach. Diabetes Care 35: 1364–79
Inzucchi S, Bergenstal RM, Buse JB et al (2015) Management of hyperglycemia in Type 2 diabetes, 2015: A patient-centered approach. Diabetes Care 38: 140–9
Khunti K, Wolden ML, Thorsted BL et al (2013) Clinical inertia in people with type 2 diabetes: a retrospective cohort study of more than 80,000 people. Diabetes Care 36: 3411–7
MacConell L, Brown C, Gurney K, Han J (2012) Safety and tolerability of exenatide twice daily in patients with type 2 diabetes: integrated analysis of 5594 patients from 19 placebo-controlled and comparator-controlled clinical trials. Diabetes Metab Syndr Obes 5: 29–41
Marre M, Shaw J, Brändle M et al (2009) Liraglutide, a once-daily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater improvements in glycemic and weight control compared with adding rosiglitazone or placebo in subjects with type 2 diabetes (LEAD-1 SU). Diabet Med 26: 268–78
Mathieu C, Rodbard HW, Cariou B et al (2014) 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 16: 636–44
Monnier L, Lapinski H, Colette C (2003) Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycaemia of type 2 diabetic patients: variations with increasing levels of HbA1c. Diabetes Care 26: 881–5
Nauck M, Frid A, Hermansen K et al (2009) Efficacy and safety comparison of liraglutide, glimepiride and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (Liraglutide Effect and Action in Diabetes)-2 study. Diabetes Care 32: 84–90
NICE (2009) Type 2 diabetes: The management of type 2 diabetes (CG87). NICE, London. Available at: http://www.nice.org.uk/guidance/cg87 (accessed 25.03.15)
Riddle MC, Forst T, Aronson R et al (2013a) 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 study (GetGoal-Duo 1). Diabetes Care 36: 2497–503
Riddle MC, Aronson R, Home P et al (2013b) 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 36: 2489–96
Rosenstock J, Fonseca VS, Gross JL et al (2014a) 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 37: 2317–25
Rosenstock J, Diamant M, Sivestre L et al (2014b) Benefits of a fixed-ratio formulation of once-daily insulin glargine/lixisenatide (LixiLan) vs. glargine in type 2 diabetes (T2DM) inadequately controlled on metformin. Diabetes 63(Suppl 1): A87
Ryder B, Thong K, on behalf of the ABCD nationwide exenatide and nationwide liraglutide audit contributors (2012) Findings from the Association of British Clinical Endocrinologists (ABCD) nationwide exenatide and liraglutide audits. Available at: http://bit.ly/1y7o9Ui (accessed 25.03.15)
SIGN (2010) Management of diabetes: Quick Reference Guide. SIGN, Edinburgh. Available at: http://www.sign.ac.uk/pdf/qrg116.pdf (accessed 25.03.15)
Vilsbøll T, Christensen M, Junker AE et al (2012) Effect of glucagon-like peptide-1 receptor agonists on weight loss: systematic review and meta-analyses of randomised controlled trials. Br Med J 344: d7771
Viswanathan P, Chaudhuri A, Bhatia R et al (2007) Exenatide therapy in obese patients with type 2 diabetes mellitus treated with insulin. Endocr Pract 13: 444–50

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