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Intensifying T2DM treatment with IDegLira lowers risk of weight gain or hypoglycaemia

Dr. Rose Ting
Specialist in Endocrinology, Diabetes & Metabolism
Hong Kong
07 Aug 2020
Many patients with type 2 diabetes mellitus (T2DM) fail to achieve guideline-recommended HbA1c level and remain at risk of complications. Existing treatment intensification regimens are complex and often associated with weight gain and hypoglycaemia. In an interview with MIMS Doctor, Dr Rose Ting, Specialist in Endocrinology, Diabetes & Metabolism in Hong Kong, discussed the use of the once-daily fixed-ratio combination (FRC) of insulin degludec (IDeg) plus liraglutide (IDegLira [Xultophy®, Novo Nordisk]) as a simple and effective alternative for basal insulin treatment intensification in patients with T2DM.

Need for basal insulin intensification in T2DM

Over 60 percent of T2DM patients treated with basal insulin fail to meet the recommended HbA1c goal of <7 percent. [Diabetes Obes Metab 2012;14:228-233] Reluctance to switch insulin regimens or to intensify treatment is not uncommon among patients with HbA1c well above target levels. [Diabet Med 2012;29:e13-e20]

“Exposure to prolonged periods of poor glycaemic control is associated with the development of macro- and microvascular complications, particularly retinopathy, neuropathy and nephropathy,” noted Ting.

“The progressive decline in β-cell function in T2DM will eventually necessitate intensification of basal insulin therapy with the addition of prandial [bolus] insulin,” she explained. “Administering multiple daily injections is effective for achieving postprandial glycaemic control, but it requires patient compliance and is associated with increased risks of hypoglycaemia and weight gain.”

Concerns over these side effects can lead to reduced treatment adherence and reluctance to intensify therapy by both the patient and the healthcare provider, resulting in poor glycaemic control. [Am J Med 2013;126(9 Suppl 1):S38-S48] The complexity of insulin intensification regimens is also a barrier to achieving and maintaining target HbA1c levels. [Diabet Med 2012;29:682-689]

Hence, there is a need for more convenient options for intensifying basal insulin therapy, with minimal or no risk of hypoglycaemia and weight gain, to maintain durable glycaemic control and to prevent long-term complications.

Complementary modes of action of IDeg and liraglutide in T2DM

IDegLira is a FRC of the basal insulin IDeg (100 units/mL) and the glucagon-like peptide-1 receptor agonist (GLP-1 RA) liraglutide (3.6 mg/mL) administered as a once-daily injection from a 3 mL prefilled pen. [Xultophy Hong Kong Prescribing Information, Jan 2019]

The complementary actions of IDeg and liraglutide provide several benefits to patients with T2DM. Basal insulin effectively lowers fasting plasma glucose (FPG) levels. The incretin mimetic, liraglutide, lowers both FPG and postprandial glucose by enhancing endogenous insulin release and suppressing endogenous glucagon secretion, both in a glucose-dependent manner. Hence, it can counterbalance the risk of hypoglycaemia associated with increasing doses of insulin. Liraglutide also delays gastric emptying and reduces appetite, thus promoting weight loss. (Figure 1) [Expert Rev Endocrinol Metab 2015;11:7-19]

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DUAL clinical trial programme

The clinical efficacy and tolerability of IDegLira vs traditional insulin therapies was demonstrated in three phase III, randomized, open-label controlled trials in patients with T2DM.

DUAL I: IDegLira vs IDeg or liraglutide

This 26-week trial, conducted in 1,663 T2DM patients with uncontrolled HbA1c  on oral antidiabetic drugs (OADs; insulin-naïve), showed that IDegLira was superior to IDeg and liraglutide in reducing HbA1c levels, with lower rates of gastrointestinal (GI) symptoms (ie, nausea, 8.8 percent vs 19.7 percent for liraglutide) and hypoglycaemia (events per patient-year, 1.8 vs 2.6 for IDeg), and less weight gain (treatment difference vs IDeg, -2.22 kg; p<0.0001). [Lancet Diabetes Endocrinol 2014;2:885-893] A 26-week extension study (n=1,311) further confirmed the sustained efficacy and safety of IDegLira. [Diabetes Obes Metab 2015;17:965-973]

“Remarkably, the insulin dosage plateaued at 39 units from about 20 weeks onwards in the IDegLira group, while it continued to increase to 62 units by 52 weeks in the IDeg group. This insulin-sparing effect of IDegLira can potentially minimize side effects, making it a good alternative for patients with OAD failure,” pointed out Ting. [Diabetes Obes Metab 2015;17:965-973]

DUAL V: IDegLira vs IGlar uptitration

Among 557 T2DM patients with insufficient glycaemic control on insulin glargine (IGlar) and metformin, 26 weeks of IDegLira treatment resulted in greater HbA1c reduction (estimated treatment difference [ETD], -0.59 percent; p<0.001), weight loss (ETD, -3.2 kg; p<0.001), and fewer episodes of hypoglycaemia (estimated rate ratio [ERR], 0.43; p<0.001) (ERR for nocturnal hypoglycaemia, 0.17; p<0.001) vs IGlar uptitration. Notably, 50 percent and 54.3 percent of IDegLira recipients achieved HbA1c target (<7 percent) without weight gain or hypoglycaemia, respectively, vs 19.7 percent and 29.4 percent of those on IGlar uptitration (p<0.001). [JAMA 2016;315:898-907]

DUAL VII: IDegLira vs basal-bolus insulin

In this 26-week trial involving 506 patients with T2DM uncontrolled with IGlar U100 and metformin, similar reductions in HbA1c were observed in the IDegLira and basal-bolus insulin arms. However, patients on IDegLira had fewer hypoglycaemic episodes (RR, 0.11) and demonstrated weight loss vs weight gain in those receiving basal-bolus insulin (ETD, -3.6 kg). (Figure 2) [Diabetes Care 2018;41:1009-1016]

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Switching patients to IDegLira

“In clinical practice, IDegLira can be considered as the first injectable therapy in T2DM patients who have failed OADs, particularly when a GLP-1 RA – with the drawback of having a maximum tolerated dose – is unlikely to bring glucose levels to target or when significant weight reduction is not a treatment goal. In addition, IDegLira can be initiated in patients who require intensification of insulin therapy, including younger patients in whom tight glucose control is desirable,” said Ting.

The dose of IDegLira is titrated twice weekly, in increments of 2 dose steps, based on self-measured pre-breakfast plasma glucose. (Table) [Xultophy Hong Kong Prescribing Information, Jan 2019]

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“In my practice, IDegLira is titrated until FPG is at goal or the patient develops GI symptoms, at which point the uptitration is carried out at a slower pace,” said Ting.

“The convenience of once-daily dosing and the simple titration scheme make IDegLira an attractive treatment option for patients and general practitioners compared with the seven-point glucose profile and multiple daily injections needed for basal-bolus insulin therapy,” noted Ting.

“The use of IDegLira can improve patients’ compliance and quality of life. Since the dosage of each component is less when given in a FRC compared with taking each agent separately, the associated side effects [ie, hypoglycaemia and weight gain with basal insulin, and nausea, diarrhoea and vomiting with GLP-1 RA] are also reduced,” she continued.

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