Insulin naive patients
In the DUAL-1 trial [
19], 1663 insulin-naive patients with T2DM in use of metformin and/or pioglitazone were randomized to receive IDeglira, insulin degludec or liraglutide for 26 weeks. The primary endpoint was to prove non-inferiority of the combination compared to degludec and superiority compared to liraglutide. All patients randomized to IDegLira started with 10 U daily. Non-inferiority was proven for IDegLira compared to degludec (ΔA1c − 0.47%; CI − 0.58 to − 0.36%; p < 0.0001) and superiority was proven for IdegLira compared to liraglutide alone (ΔA1c − 0.64%; CI − 0.75 to − 0.53%; p < 0.0001). It is important to notice that there was no limit for degludec dose in this study. The mean dose achieved during titration of IDeglira combination was 38 Units (equivalent of 1.4 mg of liraglutide and 38 IU of degludec) compared to 1.8 mg of liraglutide alone and 53 IU of degludec alone. The IDegLira group used a 28% smaller insulin dose than the degludec group. Also, patients randomized to liraglutide (7%) and to IDegLira (32%) presented significant lower rates of confirmed hypoglycemia than patients randomized to degludec (39%; p < 0.001 vs liraglutida and p = 0.023 vs IDegLira). The main results are summarized in Table
1.
Table 1
Studies evaluating the efficacy of IDegLira and IGlarLixi in patients with diabetes mellitus type 2 inadequately controlled with oral medication and insulin naive
Duration | 26 weeks | 30 weeks |
Population | 1663 T2DM adults, A1c 8.3 ± 0.9; BMI 31.2 ± 4.8 kg/m2, metformin ± pioglitazone | 1170 T2DM adults, A1c 8.2 ± 0.7; BMI 31.7 ± 4.4 kg/m2; metformin ± pioglitazone |
Mean insulin dose (final) | 38 ± 13 | 53 ± 28 | | 39 ± 14 | 40 ± 14 | |
ΔA1c | − 1.9 ± 1.1 | − 1.4 ± 1.0 | − 1.3 ± 1.1 | − 1.6 ± 0.1 | − 1.3 ± 0.1 | − 0.8 ± 0.1 |
Final A1c (week 30) | 6.4 ± 1.0 | 6.9 ± 1.1 | 7.0 ± 1.2 | 6.5 ± 0.8 | 6.8 ± 0.8 | 7.3 ± 0.9 |
Δ body weight (kg) | − 0.5 ± 3.5 | + 1.6 ± 4.0 | − 3.0 ± 3.5 | − 0.3 ± 0.2 | + 1.1 ± 0.2 | − 2.3 ± 0.3 |
% A1c < 7% | 81 | 65 | 60 | 74 | 59 | 33 |
%A1c < 7% without weight gain | 46 | 21 | 54 | 43 | 25 | 28 |
%A1c < 7% without hypoglycemia | 60 | 41 | 58 | 53 | 44 | 30 |
%A1c < 7% without weight gain or hypoglycemia | 36 | 14 | 52 | 32 | 19 | 26 |
Hypoglycemia (%)a | 32 | 39 | 7 | 26 | 24 | 6 |
Patients of DUAL-1 were followed-up for a 26-week extension period [
20]. Overall, at week 52, 56.5% of the patients reached the dose of 50 dose-steps (50 IU of insulin degludec plus 1.8 mg of liraglutide) compared to 44% at week 26 in DUAL-1. The mean insulin dose was 37% lower in the IDeglira compared to degludec arm.
A subgroup of the DUAL-1 population (n = 260) was evaluated for parameters of glycemic control measured by CGMS over 72 h and hormonal and beta cell function during a standardized meal test (‘Ensure Plus’—675 kcal, 15% of protein, 57% of carbohydrates, 28% of lipids) [
21]. At week 26, the mean dose of liraglutide and insulin degludec was, respectively, 1.5 and 1.8 mg in the IDegLira and liraglutide arms and 43 and 60 IU in the IDegLira and degludec arms. There was a reduction in the increment of post-prandial glycemia (AUC 0–4 h) during the meal test from baseline to week 26 of 21.6% in the IDegLira compared to 4% in the degludec arm (p = 0.0023) and 18.4% in the liraglutide arm (p = 0.7). The insulin secretion ratio (p = 0.048) and static index (p = 0.006) were greater in breakfast and supper for IDegLira compared to degludec but similar to liraglutide (p = 0.45 and 0.895, respectively).
Three other studies were performed with IDegLira in insulin-naïve patients. The DUAL-III study evaluated the efficacy of IDegLira in patients receiving GLP-1 RA and the DUAL-IV study in patients receiving sulphonylurea alone or combined to insulin. The DUAL VI study was designed to evaluate different titration strategies. Different from the DUAL-I study, there are no studies with IGlarLixi in these populations.
In the DUAL-III trial [
22], 438 patients with T2DM receiving GLP-1 RA were randomized to receive IDegLira ou to continue with GLP-1 RA therapy. The primary objective was to prove superiority of IDegLira in comparison to continuing with GLP-1 RA therapy. All patients randomized to IDegLira started with 16 dose-steps daily (16 UI of degludec + 0.6 mg of liraglutide). After 26 weeks of treatment, superiority of IDegLira was demonstrated. Patients randomized to IDegLira presented a significant reduction of A1c in comparison to placebo (ΔA1c − 0.94%; p < 0.0001). As expected, the mean chance in weight was + 2.0 kg with IDegLira versus − 0.8 kg with placebo. Also, patients randomized to IDegLira experienced significantly higher rates of hypoglycaemia and nocturnal hypoglycaemia.
In the DUAL IV trial [
23], 435 insulin-naïve patients uncontrolled on sulphonylureas with or without metformin were randomized to IDegLira or Placebo. As in DUAL-I study, patients randomized to IDegLira started with 10 dose-steps daily (10 UI of degludec + 0.36 mg of liraglutide). After 26 weeks, patients randomized to IDegLira presented a significant improvement in glucose control in comparison to placebo (mean A1c change: − 0.46% for placebo and − 1.45% for IDegLira (estimated treatment difference = 1.02%) − 1.02% [CI − 1.18 to − 0.87]; p < 0.001). Interestingly, at the end of the trial, the mean dose of IDegLira was 28 dose-steps (28 UI of degludec + 1.0 mg of liraglutide). There was an increase in body weight in patients randomized to IDegLira (+ 0.5 kg) in comparison to a reduction in the placebo group (1.0 kg). As expected, confirmed hypoglycaemia occurred more frequently in IDegLira group (41.7% vs 17.1% in the placebo group).
The DUAL VI trial [
24] was designed to compare the safety and efficacy of 02 titration strategies of IDegLira for uncontrolled T2DM patients receiving either metformin or metformin + pioglitazone. Patients were then randomized to once-weekly titration group (based on the mean of 2 fasting SMPG values measured pre-breakfast in the morning of 2 consecutive days) or the twice-weekly titration group (every 3–4 days). No difference was found in A1c reduction, weigh chance or hypoglycaemia rates between the two groups.
Insulin treated patients
The DUAL-2 trial [
25] was a 26-week, double-blind phase 3 trial, designed to confirm the superiority of IDegLira compared to insulin degludec alone. T2DM adults treated with basal insulin (20–40 IU) and metformin ± sulphonylureas or glinides with A1c between 7.5 and 10% and BMI ≥ 27 kg/m
2 were included. After randomization, sulphonylureas and glinides were stopped and patients were randomized to receive IDegLira plus metformin or degludec plus metformin. Doses were titrated until a fasting glycemia between 72–90 mg/dL was achieved. As in DUAL-1 study, there was no upper limit for degludec dose. The initial dose of IDegLira was 16 IU (equivalent of liraglutide 0.6 mg and degludec 16 UI). Maximum dose was 50 units of degludec or 50 dose steps IDegLira (50 units degludec plus 1.8 mg liraglutide). Summarized results are presented in Table
2.
Table 2
Studies evaluating the efficacy of IDegLira and IGlarLixi in patients with diabetes mellitus type 2 inadequately controlled with basal insulin
Duration | 26 weeks | 26 weeks | 30 weeks |
Population | 413 T2DM adults, A1c 8.7 ± 0.7%, basal insulin and metformin ± sulphonylureas or glinides; mean basal insulin dose at baseline 29 ± 8 | 557 T2DM, A1c 8.4/8.2 ± 0.9%, basal insulin (glargine) and metformin; mean basal insulin dose at baseline 31 ± 10 | 736 T2DM adults, A1c 8.1 ± 0.7%, basal insulin and metformin ± OAD; mean basal insulin dose at baseline 35 ± 9 |
Mean insulin dose (final) | 45 | 45 | 41 | 66 | 47 | 47 |
ΔA1c | − 1.9 | − 0.9 | − 1.8 | − 1.1 | − 1.1 | − 0.6 |
Final A1c (week 30) | 6.9 | 8.0 | 6.6 | 7.1 | 6.9 | 7.5 |
Δ body weight (kg) | − 2.7 | 0.0 | − 1.4 | + 1.8 | − 0.7 | 0.7 |
% A1c < 7% | 60 | 23 | 72 | 47 | 34 | 13 |
A1c < 7% without weight gain (%) | NA | NA | 50 | 20 | 34 | 13 |
A1c < 7% without hypoglycemia (%) | NA | NA | 54 | 29 | 32 | 19 |
A1c < 7% without weight gain or hypoglycemia (%) | 40 | 8 | 39 | 12 | 20 | 9 |
Hypoglycemia (%)a | 24 | 25 | 28 | 49 | 40 | 42 |
In the DUAL-V trial [
26], the combination IDegLira was compared to insulin glargine up-titration in patients with uncontrolled T2DM. The main objective was to prove non-inferiority of IDegLira on A1c levels. The studied population included 557 patients treated with insulin glargine (20–50 IU) and metformin (≥ 1500 mg/day), with A1c levels between 7 and 10% and BMI ≤ 40 kg/m
2. This was a phase 3 multicenter open-label, treat-to-target trial of 26 weeks of duration. The 278 patients randomized to receive IDegLira stopped glargine use and initiated IDegLira with an initial dose of 16 IU, increasing steps of titration according to fasting glycemia levels. The maximum dose of IDegLira was 50 IU. Patients in the glargine group (n = 279) maintained the insulin glargine once daily and the dose was also titrated (without any upper limit). The titration was performed to achieve a fasting glycemia between 72 and 90 mg/dL (mean of 3 consecutive days). The primary outcome was change in A1c from baseline to week 26 (ΔA1c). The results are summarized in Table
2.
In the DUAL VII trial [
27], patients with uncontrolled T2DM receiving insulin were randomized to IDegLira or basal Insulin + Insulin Aspart (basal–bolus therapy). As in DUAL II and V trials, IDegLira was started with 16 dose-steps daily (16 UI of degludec + 0.6 mg of liraglutide). The main finding of the study was that no difference was observed in A1c reduction in IDegLira in comparison to basal–bolus group. On the other hand, significant differences were observed regarding weight chance and hypoglycaemia rates. During treatment period (26 weeks), significant more patients randomized to basal–bolus experienced a symptomatic hypoglycemic event (52.6%) in comparison to IDegLira (19.8%). In general, there was a 89% reduction in severe or confirmed hypoglycaemia compared to basal–bolus. Mean basal insulin dose with basal–bolus increased from 34 units in week 1–52 units at 26 weeks compared to a mean dose of 40 units with IDegLira (corresponding to 40 units degludec/1.44 mg liraglutide). Finally, the mean body weight decreased by 0.9 kg with IDegLira and increased with basal–bolus by 2.6 kg.
Additional analysis with IDegLira
A post hoc analysis [
28] was performed to investigate if IDegLira was consistently effective in T2DM patients independently of their baseline A1c levels and duration of diabetes. This analysis included data from DUAL-1 extension (52 weeks) and DUAL-2 (26 weeks). Four categories of A1c were created: ≤ 7.5%; 7.5 to ≤ 8.5%; 8.5 to ≤ 9 and > 9%. Across all categories, A1c reductions were significantly greater with IDeglira compared with the degludec or liraglutide alone in DUAL-1.
Reductions in A1c levels were similar in any duration of diabetes in DUAL-1 and 2. In DUAL-1 the A1c reduction from baseline with IDegLira was somewhat higher (estimated difference of 0.21%) in patients in use of pioglitazone and metformin compared to those with metformin alone (ΔA1c for IDegLira − 1.8% in the metformin subgroup and − 2.1% in the metformin plus pioglitazone subgroup; p = 0.002). For degludec and liraglutide alone groups, the differences of the A1c reductions were not significant between baseline oral drugs subgroups. In DUAL-2, the A1c reductions were significantly different across the subgroups of baseline treatment. However, no difference was observed according to pre-study insulin dose.
IDegLira was also indirectly compared to alternative strategies of glycemic control intensification in patients with T2DM treated with basal insulin [
29]. This was an analysis of 5 trials: 199 patients with IDegLira, 225 patients with basal insulin plus liraglutide, 56 patients with basal–bolus insulin, 329 patients with glargine. Results are presented in Table
2. The mean differences in A1c and body weight between IDegLira and basal–bolus therapy and IDeglira and basal glargine were − 0.3% and − 6.89 kg and − 0.65% and − 4.04 kg respectively. The OR of achieving an A1c < 7% was 2.06 for IDegLira compared to basal insulin plus liraglutide and 3.91 for IDegLira compared to basal glargine. The OR of achieving an A1c < 7% without hypoglycemia was 16.05 for IDegLira versus basal–bolus therapy and 4.53 for IDegLira versus basal glargine but there was no difference between IDeglira compared to basal insulin plus liraglutide.