One‐year safety and efficacy results of insulin treatment simplification with IDegLira in type 2 diabetes

Abstract Introduction This study aimed to investigate the sustained safety and efficacy of insulin treatment simplification with IDegLira in patients with type 2 diabetes and an HbA1c ≤ 7.5% (58 mmol/mol) during a 12‐month follow‐up. Methods Seventy‐two adults with type 2 diabetes and an HbA1c ≤ 7.5% (58 mmol/mol) treated with multiple daily insulin injections (MDI) participated in the trial (age 63.8 ± 9.5 years, HbA1c 6.4 ± 0.7%, [46 ± 8 mmol/mol] body weight 92.95 ± 18.83 kg, total daily insulin dose: 43.21 ± 10.80 units; mean ± SD). Previous insulins were stopped, and once daily IDegLira was started. IDegLira was titrated by the patients to achieve a self‐measured prebreakfast plasma glucose concentration of ≥5 mmol/L to ≤6 mmol/L. Results After 12 months, good glycaemic control was maintained, while body weight decreased significantly. Mean HbA1c changed to 6.2 ± 0.8% (44 ± 9 mmol/mol) (p = .109) and body weight changed by −3.89 kg to 89.06 ± 18.61 kg (p < .0001). The simplified treatment was safe and well‐tolerated. Percentage of patients experiencing at least one episode of hypoglycaemia was 49% during the month before simplification and 17% during the last 3 months of the follow‐up. Conclusions Insulin treatment simplification with IDegLira in selected patients with type 2 diabetes is safe, maintains adequate glycaemic control and is associated with weight loss over 12 months.


| Participants
Recruitment was carried out among subjects presenting on scheduled ambulatory visits for type 2 diabetes at the Diabetes Center of the Békés County Central Hospital in Békéscsaba, Hungary.
Outpatients with type 2 diabetes aged ≥ 18 years were enrolled.
At BV, low TDD was defined as TDD ≤70 IU/day and TDD ≤0.6 IU/kg/ day at the same time. Patients reporting severe or repeated symptomatic hypoglycaemia during the month before BV using TDD ≤70 IU/ day and >0.6 but <0.8 IU/kg/day could also be recruited into the study. In spite of the 70% health insurance coverage IDegLira is still a relatively costly medicine in Hungary. Only those patients who accepted the additional expenses of the treatment were enrolled.
The main exclusion criteria were type 1 diabetes, applying glucose-lowering agents other than insulin or metformin during 90 days before BV, active cancer, anaemia (haemoglobin <100 g/L) and acute or chronic kidney disease with an estimated glomerular filtration rate < 30 ml/min/1.73 m 2 .

| Procedures
At BV, previous insulin treatment was discontinued and once daily IDegLira was started at any time, independent of meals, repeated approximately at the same time each day. The vast majority of the patients administered IDegLira in the morning, before breakfast.
The starting dose of IDegLira was 16 dosage units (each dosage unit contains 1 unit of insulin degludec and 0.036 mg of liraglutide).
Patients were advised to titrate IDegLira every 3 days with 2 units to achieve a prebreakfast self-measured blood glucose (SMBG) range of 5-6 mmol/L. 15 The maximum daily dose of IDegLira was 50 units.
Metformin was initiated or continued and titrated up with 500 mg weekly to 3000 mg or to the maximal tolerated dose.
Patients were instructed to test blood glucose daily (at least once before breakfast and at any time when symptoms of hypoglycaemia occurred) with their own glucometer and to record their readings into their diary.

What has this study found?
• Simplification of insulin regimens is suitable for a lot of people with type 2 diabetes, but it is rarely carried out.
• Overtreatment is present when HbA1c is low and hypoglycaemia risk is high and when HbA1c is optimal, but the patient is using unnecessarily complex treatment instead of simpler alternatives.
• Once daily IDegLira is a potential tool for insulin treatment simplification.
• We demonstrated that switching from complex insulin regimens to IDegLira in selected overtreated patients is safe, induces weight loss and results in similar or better glycaemic control in the long term.
An early control (Visit 0) was performed 14 days after BV to check self-titration and adverse events. Patients were followed during the routine diabetes care. Data were collected by the study staff at baseline and during the scheduled clinical visits performed 3, 7 and 12 months (Visits 1, 2 and 3, respectively) after BV.

| Outcome measures
The primary endpoint was the change in HbA1c from baseline to 12 months. Secondary outcomes included change in body weight, BMI and TDD from baseline to Visit 3. The change in HbA1c was also analysed in the subgroups of patients with a baseline HbA1c ≥ 6.5% and <6.5% (48 mmol/mol). Percentage of patients experiencing at least one episode of documented (SMBG < 3.9 mmol/L) or symptomatic hypoglycaemia was assessed, and the hypoglycaemia data for the month before BV and the last 3 months of the 12-month follow-up were compared.
Severe hypglycaemia requiring external assistance and occurrence of clinically meaningful adverse events were also recorded. Proportion of patients reaching different prespecified glycaemic targets (HbA1c < 7% and <6.5% [53 and 48 mmol/mol]) at Visit 3 were evaluated.

| Statistical analysis
Statistical analysis was performed using GraphPad Prism 9 software (GraphPad Software). Data are presented as mean ± SD or median with interquartile range (IQR) for continuous variables in case of normal and non-normal distribution, respectively, and as n (%) for frequency data. Clinical and demographic variables measured at baseline and at 3, 7 and 12 months after insulin treatment simplification were compared using repeated measures ANOVA with Fisher's LSD post hoc test for normal distributed data and Friedman test with Dunn's post hoc test for non-normal distributed data. p Values < .05 were considered statistically significant.

| RE SULTS
Between February 2016 and December 2019, 93 MDI-treated people were enrolled and switched to IDegLira. Soon after BV 4 persons withdrew consent (ceased therapy due to financial reasons) and 4 patients gradually reduced and finally stopped IDegLira due to repeated low SMBG values before Visit 1, and remained well-controlled on non-insulin treatment. Three patients discontinued IDegLira in a few days due to moderate gastrointestinal adverse effects, 1 patient had to be converted to MDI due to acute illness, 6 participants did not return to the scheduled visits, and 3 patients died during the follow-up. Finally, 72 patients (baseline age 63.8 ± 9.5 years, HbA1c 6.4 ± 0.7% [46 ± 8 mmol/mol], BMI 33.01 ± 6.47 kg/m2, body weight 92.92 ± 18.83 kg, TDD 43.21 ± 10.80 IU/day, insulin requirement 0.48 ± 0.13 IU/kg, duration of diabetes 9.7 ± 7.5 years; mean ± SD) completed the 12-month trial ( Table 1).
At baseline, 62 (86%) patients were on a basal-bolus regimen using one dose of basal and 3 doses of prandial insulins (46 used human and 16 used analogue insulins), and 10 (14%) patients were treated with 2 or 3 doses of human or analogue premix insulins.
In this potentially overtreated group, HbA1c did not change significantly, but the risk of hypoglycaemia decreased. The percentage of patients experiencing at least one episode of hypoglycaemia was 62.2% (n = 23) during the month before BV and 24.3% (n = 9) during the last 3 months of the follow-up.
In the subgroup with a baseline HbA1c ≥ 6.5% to ≤7.5% (48 and 58 mmol/mol) (n = 35), HbA1c decreased significantly (p = .021) from 7.0 ± 0.3% (53 ± 3 mmol/mol) at BV to 6.6 ± 0.9% (49 ± 10 mmol/mol) at Visit 3 ( Figure 3B). In this group of relatively well-controlled sub- options which could ensure the same efficacy with less risk and burden. It is clear that overtreated patients are among those who can benefit the most from treatment simplification. We examined prospectively the safety and efficacy of switching from MDI to once daily IDegLira in subjects with type 2 diabetes using low TDD who were considered to be overtreated (either overcontrolled or wellcontrolled). Our preliminary 3-month follow-up data were promising but we wanted to confirm our results in a larger group of patients with a longer follow-up. 8 We used IDegLira for de-escalation because beside its marked effect on fasting glucose it also has a clinically relevant impact on postprandial glucose. Moreover, the GLP-1RA component of the drug has an insulin-sparing effect as it enhances endogenous insulin secretion in a glucose-dependent way. It also generates weight loss which is associated with improved insulin sensitivity and lower insulin requirement. Furthermore, the LEADER and DEVOTE trials proved the cardiovascular benefits and safety of liraglutide and degludec. 16,17 The DUAL VII trial confirmed that IDegLira has comparable glycaemic effects to MDI in patients with type 2 diabetes uncontrolled on basal insulin, but with less hypoglycaemia and a more beneficial effect on body weight. In this trial, the mean dose of IDegLira and MDI was 40 and 84 units at the end of the follow-up. As the maximal daily dose of IDegLira is 50 units, we enrolled patients only with a TDD ≤ 70 IU/day at BV to be able to fully and securely cover the effect of the previous insulin regimen. 14 Endogenous insulin secretion is a major criterion for the glucose-lowering effect of liraglutide and supplements the effects of IDegLira on postprandial glucose control; therefore, we enrolled only adults who had at least partially preserved beta-cell function. Average daily insulin production in healthy men is about 0.7-0.8 IU/kg, and the mean TDD in Caucasian men and women with type 2 diabetes treated with MDI is usually between 0.9 and 1.4 IU/kg. 14,18,19 It was assumed that a normal or near normal HbA1c achieved with low TDD may refer to a partially preserved beta-cell function. We defined low insulin need as an average TDD ≤ 70 IU/day and an insulin requirement ≤ 0.6 IU/kg/day at the same time and used these parameters together with C-peptide to identify our potential candidates.
Our objective was to assess the sustained efficacy and safety of the simplified treatment during a 12-month follow-up in a larger group of overtreated patients. Our results clearly confirmed that the glycaemic control achieved with the previously used complex insulin regimes can be maintained in the longer term with IDegLira, since mean HbA1c actually remained unchanged during the follow-up.
In the subgroup of overtreated subjects who had an HbA1c < 6.5% (48 mmol/mol) at baseline, mean HbA1c did not change significantly during the trial, but the risk of hypoglycaemia decreased markedly.
In the subgroup of relatively well-controlled patients with a baseline HbA1c ≥ 6.5% to ≤7.5% (48 and 58 mmol/mol), replacing MDI with IDegLira resulted in clinically significant decrease in mean HbA1c without increasing hypoglycaemia risk. Actually in this subgroup, the percentage of patients experiencing hypoglycaemia was substantially lower during the last 3 months of the follow-up than during the month before BV.
Besides the beneficial glycaemic effects, insulin treatment simplification with IDegLira resulted in clinically meaningful weight loss, a reduction of insulin requirement of nearly 50% and a decrease of treatment burden. In addition, there are data which support that among older patients with type 2 diabetes taking multiple glucose-lowering agents deprescribing with IDegLira may also improve quality of life. 20 The observed benefits are emphasized by the fact that at Visit 3, 86.1% of our patients had an HbA1c ≤ 7% (53 mmol/mol) and 55.6% reached this goal without weight gain and hypoglycaemia.
According to our observations, IDegLira + metformin combination therapy was safe and generally well tolerated. The most frequent adverse events were gastrointestinal, transient and nonserious, and the incidence and severity of these digestive symptoms were similar to those described in the literature. 14 Serious adverse events were rare, and none of them was considered to be related to the antidiabetic therapy.
In our trial, we focused on overtreated patients with HbA1c ≤ 7.5% (58 mmol/mol), but insulin treatment simplification with the fixed F I G U R E 3 Change in HbA1c levels (means ± SEM) during the 12-month follow-up in the subgroup of patients (A), and with a baseline HbA1c ≥ 6.5% to ≤7.5% (n = 35) (B). ***p < .0001, **p < .005, *p < .05 compared to the baseline visit