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TRAJENTA DUO®

Efficacy

The coadministration of linagliptin and metformin has been studied in patients with type 2 diabetes mellitus inadequately controlled on diet and exercise and in combination with sulfonylurea.1

There have been no clinical efficacy studies conducted with TRAJENTA DUO®; however, bioequivalence of TRAJENTA DUO® to linagliptin and metformin coadministered as individual tablets was demonstrated in healthy subjects.1

Initial combination therapy with linagliptin and metformin1

A total of 791 patients with type 2 diabetes mellitus and inadequate glycemic control on diet and exercise participated in the 24-week, randomized, double-blind, portion of this placebo-controlled factorial study designed to assess the efficacy of linagliptin as initial therapy with metformin. Patients on an antihyperglycemic agent (52%) underwent a drug washout period of 4 weeks’ duration. After the washout period and after completing a 2-week single-blind placebo run-in period, patients with inadequate glycemic control (HbA1c ≥7.0% to ≤10.5%) were randomized. Patients with inadequate glycemic control (HbA1c ≥7.5% to <11.0%) not on antihyperglycemic agents at study entry (48%) immediately entered the 2-week single-blind placebo run-in period and then were randomized. Randomization was stratified by baseline HbA1c (<8.5% vs ≥8.5%) and use of a prior oral antidiabetic drug (none vs monotherapy). Patients were randomized in a 1:2:2:2:2:2 ratio to either placebo or one of 5 active-treatment arms. Approximately equal numbers of patients were randomized to receive initial therapy with 5 mg of linagliptin once daily, 500 mg or 1,000 mg of metformin twice daily, or 2.5 mg of linagliptin twice daily in combination with 500 mg or 1,000 mg of metformin twice daily. Patients who failed to meet specific glycemic goals during the study were treated with sulfonylurea, thiazolidinedione, or insulin rescue therapy.1

Initial therapy with the combination of linagliptin and metformin provided significant improvements in HbA1c, and fasting plasma glucose (FPG) compared to placebo, to metformin alone, and to linagliptin alone. The adjusted mean treatment difference in HbA1c from baseline to week 24 (LOCF) was -0.5% (95% CI -0.7, -0.3; p<0.0001) for linagliptin 2.5 mg/metformin 1,000 mg twice daily compared to metformin 1,000 mg twice daily; -1.1% (95% CI -1.4, -0.9; p<0.0001) for linagliptin 2.5 mg/metformin 1,000 mg twice daily compared to linagliptin 5 mg once daily; -0.6% (95% CI -0.8, -0.4; p<0.0001) for linagliptin 2.5 mg/metformin 500 mg twice daily compared to metformin 500 mg twice daily; and -0.8% (95% CI -1.0, -0.6; p<0.0001) for linagliptin 2.5 mg/metformin 500 mg twice daily compared to linagliptin 5 mg once daily.1

Lipid effects were generally neutral. No meaningful change in body weight was noted in any of the 6 treatment groups.1

Table 1. Glycemic parameters at final visit (24-week study) for linagliptin and metformin, alone and in combination in randomized patients with type 2 diabetes mellitus inadequately controlled on diet and exercise*1

  Placebo Linagliptin
5 mg once daily†		 Metformin
500 mg twice daily		 Linagliptin 2.5 mg
twice daily† + metformin
500 mg twice daily		 Metformin 1,000 mg twice daily Linagliptin 2.5 mg
twice daily† + metformin
1,000 mg twice daily
HbA1c(%)            
Number of patients n=65 n=135 n=141 n=137 n=138 n=140
Baseline (mean) 8.7 8.7 8.7 8.7 8.5 8.7
Change from baseline (adjusted mean‡) 0.1 -0.5 -0.6 -1.2 -1.1 -1.6
Difference from placebo (adjusted mean) (95% CI) - -0.6 (-0.9, -0.3) -0.8 (-1.0, -0.5) -1.3 (-1.6, -1.1) -1.2 (-1.5, -0.9) -1.7 (-2.0, -1.4)
Patients [n (%)] achieving HbA1c <7%§ 7 (10.8) 14 (10.4) 26 (18.6) 41 (30.1) 42 (30.7) 74 (53.6)
Patients (%) receiving rescue medication 29.2 11.1 13.5 7.3 8.0 4.3
FPG (mg/dL)            
Number of patients n=61 n=134 n=136 n=135 n=132 n=136
Baseline (mean) 203 195 191 199 191 196
Change from baseline (adjusted mean‡) 10 -9 -16 -33 -32 -49
Difference from placebo (adjusted mean) (95% CI) - -19 (-31, -6) -26 (-38, -14) -43 (-56, -31) -42 (-55, -30) -60 (-72, -47)

Treatment-naive patients had a significantly stronger response to initial combination therapy than pretreated patients, with the largest decrease in HbA1c occurring during the first 12 weeks of treatment

Given that treatment-naive patients typically have a shorter duration of disease than pretreated patients, this finding was consistent with analyses indicating that HbA1c change from baseline was negatively associated (p=0.03) with time since diagnosis of diabetes2 (Figure 1).

Therefore, initial combination therapy with linagliptin plus metformin was superior to metformin monotherapy in improving glycemic control, with a similar safety and tolerability profile, no weight gain and a low risk of hypoglycemia. The potential clinical significance of this finding has been highlighted by evidence that early, aggressive lowering of hyperglycemia in newly diagnosed patients can elicit sustained disease remission.2

Efficacy_Figure-1

Figure 1. Adjusted mean change in hemoglobin A1c (HbA1c) over time by prior OAD status in randomized patients. (A) Treatment-naive. (B) Prior OAD treatment.2

Combination of linagliptin and metformin provides even more powerful efficacy in Asian T2D patient2,3

Based on the study results of “Initial combination of linagliptin and metformin improves glycemic control in type 2 diabetes: a randomized, double-blind, placebo-controlled study”, at week 24, adjusted mean change from baseline in HbA1c was: linagliptin 5 mg qd, -0.6%; linagliptin 2.5 mg/metformin 1,000 mg bid, -1.7%.2

According to the study results of “Efficacy and safety of linagliptin/metformin single-pill combination as initial therapy in drug-naive Asian patients with type 2 diabetes”, at week 24, adjusted mean change from baseline in HbA1c (main group, n=733) was: linagliptin 5 mg qd, -1.3%; linagliptin 2.5 mg/metformin 1,000 mg bid, -2.3%.3

Taken the above results together, the combination of linagliptin and metformin treatments showed better efficacy in Asia population.2,3

Efficacy_Figure-2

Figure 2. Adjusted mean change in hemoglobin A1c (HbA1c) at week 24 by HbA1c category at baseline in randomized patients of two different studies.2,3

Initial combination therapy with linagliptin and metformin vs linagliptin in treatment-naïve patients1

A total of 316 patients with type 2 diabetes diagnosed within the previous 12 months and treatment-naïve (no antidiabetic therapy for 12 weeks prior to randomization) and inadequate glycemic control (HbA1c ≥8.5% to ≤12.0%) participated in a 24-week, randomized, double-blind, study designed to assess the efficacy of linagliptin in combination with metformin vs linagliptin. Patients were randomized (1:1), after a 2-week run-in period, to either linagliptin 5 mg plus metformin (1,500 to 2,000 mg per day, n=159) or linagliptin 5 mg plus placebo, (n=157) administered once daily. Patients in the linagliptin and metformin treatment group were up-titrated to a maximum tolerated dose of metformin (1,000 to 2,000 mg per day) over a three-week period. Initial therapy with the combination of linagliptin and metformin provided statistically significant improvements in HbA1c compared to linagliptin. The mean difference between groups in HbA1c change from baseline was -0.8% with 2-sided 95% confidence interval (-1.23%, -0.45%).1

Table 2. Glycemic parameters at 24 weeks in study comparing linagliptin in combination with metformin to linagliptin in treatment-naïve patients††1

  Linagliptin 5 mg
+ metformin		 Linagliptin 5 mg
+ placebo
HbA1c(%)††    
Number of patients n=153 n=150
Baseline (mean) 9.8 9.9
Change from baseline (adjusted mean) -2.9 -2
Difference from linagliptin (adjusted mean‡‡) (95% CI) -0.84 (-1.23, -0.45) -
Patients [n (%)] achieving HbA1c >7%†† 82 (53.6) 45 (30)
FPG (mg/dL)††    
Number of patients n=153 n=150
Baseline (mean) 196 198
Change from baseline (adjusted mean) -54 -35
Difference from linagliptin (adjusted mean‡‡) (95% CI) -18** (-31, -5.5) -

The adjusted mean changes for HbA1c (%) from baseline over time for linagliptin and metformin as compared to linagliptin alone were maintained throughout the 24-week treatment period. Using the completers analysis the respective adjusted means for HbA1c (%) changes from baseline for linagliptin and metformin as compared to linagliptin alone were -1.9 and -1.3 at week 6, -2.6 and -1.8 at week 12, -2.7 and -1.9 at week 18, and -2.7 and -1.9 at week 24.1

Changes in body weight from baseline were not clinically significant in either treatment group.1

Add-on combination therapy with metformin1

A total of 701 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of linagliptin in combination with metformin. Patients already on metformin (n=491) at a dose of at least 1,500 mg per day were randomized after completing a 2-week, open-label, placebo run-in period. Patients on metformin and another antihyperglycemic agent (n=207) were randomized after a run-in period of approximately 6 weeks on metformin (at a dose of at least 1,500 mg per day) in monotherapy. Patients were randomized to the addition of either linagliptin 5 mg or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the studies were treated with glimepiride rescue.1

In combination with metformin, linagliptin provided statistically significant improvements in HbA1c, FPG, and 2-hour PPG compared with placebo. Rescue glycemic therapy was used in 7.8% of patients treated with linagliptin 5 mg and in 18.9% of patients treated with placebo. A similar decrease in body weight was observed for both treatment groups.1

Table 3. Glycemic parameters in placebo-controlled study for linagliptin in combination with metformin*1

  Linagliptin 5 mg + metformin Placebo + metformin
HbA1c(%)    
Number of patients n=513 n=175
Baseline (mean) 8.1 8.0
Change from baseline (adjusted mean¶¶) -0.5 0.15
Difference from placebo + metformin (adjusted mean) (95% CI) -0.6 (-0.8, -0.5) -
Patients [n (%)] achieving HbA1c <7%§§ 127 (26.2) 15 (9.2)
FPG (mg/dL)    
Number of patients n=495 n=159
Baseline (mean) 169 164
Change from baseline (adjusted mean¶¶) -11 11
Difference from placebo + metformin (adjusted mean) (95% CI) -21 (-27, -15) -
2-hour PPG (mg/dL)    
Number of patients n=78 n=21
Baseline (mean) 270 274
Change from baseline (adjusted mean¶¶) -49 18
Difference from placebo + metformin (adjusted mean) (95% CI) -67 (-95, -40) -

Active-controlled study vs glimepiride in combination with metformin1

The efficacy of linagliptin was evaluated in a 104-week, double-blind, glimepiride-controlled non-inferiority study in type 2 diabetic patients with insufficient glycemic control despite metformin therapy. Patients being treated with metformin only entered a run-in period of 2 weeks’ duration, whereas patients pretreated with metformin and one additional antihyperglycemic agent entered a run-in treatment period of 6 weeks’ duration with metformin monotherapy (dose of ≥1,500 mg per day) and washout of the other agent. After an additional 2-week placebo run-in period, those with inadequate glycemic control (HbA1c 6.5% to 10%) were randomized 1:1 to the addition of linagliptin 5 mg once daily or glimepiride. Randomization was stratified by baseline HbA1c (<8.5% vs ≥8.5%), and the previous use of antidiabetic drugs (metformin alone vs metformin plus one other OAD). Patients receiving glimepiride were given an initial dose of 1 mg/day and then electively titrated over the next 12 weeks to a maximum dose of 4 mg/day as needed to optimize glycemic control. Thereafter, the glimepiride dose was to be kept constant, except for down-titration to prevent hypoglycemia.1

After 52 weeks and 104 weeks, linagliptin and glimepiride both had reductions from baseline in HbA1c (52 weeks: -0.4% for linagliptin, -0.6% for glimepiride; 104 weeks: -0.2% for linagliptin, -0.4% for glimepiride) from a baseline mean of 7.7%. The mean difference between groups in HbA1c change from baseline was 0.2% with 2-sided 97.5% confidence interval (0.1%, 0.3%) for the intent-to-treat population using last observation carried forward. These results were consistent with the completers analysis.1

Table 4. Glycemic parameters at 52 and 104 weeks in study comparing linagliptin to glimepiride as add-on therapy in patients inadequately controlled on metformin*1

  Week 52 Week 104
  Linagliptin 5 mg
+ metformin		 Glimepiride +
metformin (mean
glimepiride dose 3 mg)		 Linagliptin 5 mg
+ metformin 		Glimepiride +
metformin (mean
glimepiride dose 3 mg)
HbA1c (%)        
Number of patients n=764 n=755 n=764 n=755
Baseline (mean) 7.7 7.7 7.7 7.7
Change from baseline (adjusted mean‖‖) -0.4 -0.6 -0.2 -0.4
Difference from glimepiride (adjusted mean) (97.5% CI) 0.2 (0.1, 0.3) - 0.2 (0.1, 0.3) -
FPG (mg/dL)        
Number of patients n=733 n=725 n=733 n=725
Baseline (mean) 164 166 164 166
Change from baseline (adjusted mean‖‖) -8*** -15 -2††† -9

Patients treated with linagliptin had a mean baseline body weight of 86 kg and were observed to have an adjusted mean decrease in body weight of 1.1 kg at 52 weeks and 1.4 kg at 104 weeks. Patients on glimepiride had a mean baseline body weight of 87 kg and were observed to have an adjusted mean increase from baseline in body weight of 1.4 kg at 52 weeks and 1.3 kg at 104 weeks (treatment difference p <0.0001 for both timepoints).1

Add-on combination therapy with metformin and a sulfonylurea1

A total of 1,058 patients with type 2 diabetes mellitus participated in a 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of linagliptin in combination with a sulfonylurea and metformin. The most common sulfonylureas used by patients in the study were glimepiride (31%), glibenclamide (26%), and gliclazide (26% [not available in the United States]). Patients on a sulfonylurea and metformin were randomized to receive linagliptin 5 mg or placebo, each administered once daily. Patients who failed to meet specific glycemic goals during the study were treated with pioglitazone rescue. Glycemic end points measured included HbA1c and FPG.1

In combination with a sulfonylurea and metformin, linagliptin provided statistically significant improvements in HbA1c and FPG compared with placebo. In the entire study population (patients on linagliptin in combination with a sulfonylurea and metformin), a mean reduction from baseline relative to placebo in HbA1c of -0.6% and in FPG of -13 mg/dL was seen. Rescue therapy was used in 5.4% of patients treated with linagliptin 5 mg and in 13% of patients treated with placebo. Change from baseline in body weight did not differ significantly between the groups.1

Table 5. Glycemic parameters at final visit (24-week study) for linagliptin in combination with metformin and sulfonylurea*1

  Linagliptin 5 mg + metformin + SU Placebo + metformin + SU
HbA1c (%)    
Number of patients n=778 n=262
Baseline (mean) 8.2 8.1
Change from baseline (adjusted mean‡) -0.7 -0.1
Difference from placebo (adjusted mean) (95% CI) -0.6 (-0.7, -0.5) -
Patients [n (%)] achieving HbA1c >7%‡‡‡ 217 (29.2) 20 (8.1)
FPG (mg/dL)    
Number of patients n=739 n=248
Baseline (mean) 159 163
Change from baseline (adjusted mean‡) -5 8
Difference from placebo (adjusted mean) (95% CI) -13 (-18, -7) -

Footnotes:

  • * Full analysis population using last observation on study.
  • † Total daily dose of linagliptin is equal to 5 mg.
  • ‡ HbA1c: ANCOVA model included treatment and number of prior OADs as class-effects, as well as baseline HbA1c as continuous covariates. FPG: ANCOVA model included treatment and number of prior OADs as class-effects, as well as baseline HbA1c and baseline FPG as continuous covariates.
  • § Metformin 500 mg twice daily, n=140; linagliptin 2.5 mg twice daily + metformin 500 mg twice daily, n=136.
  • Metformin 1000 mg twice daily, n=137; linagliptin 2.5 mg twice daily + metformin 1000 mg twice daily, n=138.
  • ¶ Variables used in adjustment: baseline HbA1c and prior use of OADs.
  • || p<0.0001 compared to linagliptin.
  •  
    ** p=0.0054 compared to linagliptin.
  • †† Full analysis set population.
  • ‡‡ HbA1c: MMRM model included treatment, continuous baseline HbA1c, baseline HbA1c by visit interaction, visit by treatment interaction, baseline renal impairment by treatment interaction and baseline renal impairment by treatment by visit interaction. FPG: MMRM model included treatment, continuous baseline HbA1c, continuous baseline FPG, baseline FPG by visit interaction, visit by treatment interaction, baseline renal impairment by treatment interaction and baseline renal impairment by treatment by visit interaction.
  • §§ Linagliptin 5 mg + metformin, n=485; placebo + metformin, n=163.
  •  
    ¶¶ HbA1c: ANCOVA model included treatment and number of prior oral OADs as class-effects, as well as baseline HbA1c as continuous covariates. FPG: ANCOVA model included treatment and number of prior OADs as class-effects, as well as baseline HbA1c and baseline FPG as continuous covariates. PPG: ANCOVA model included treatment and number of prior OADs as class-effects, as well as baseline HbA1c and baseline postprandial glucose after two hours as covariate.
  • |||| HbA1c: ANCOVA model included treatment and number of prior OADs as class-effects, as well as baseline HbA1c as continuous covariates. FPG: ANCOVA model included treatment and number of prior OADs as class-effects, as well as baseline HbA1c and baseline FPG as continuous covariates.
  • *** p<0.0001 vs glimepiride.
  •  
    ††† p=0.0012 vs glimepiride.
  • ‡‡‡ Linagliptin 5 mg + metformin + SU, n=742;placebo + metformin + SU, n=247.
  • ANCOVA, analysis of covariance; bid, twice daily; CI, confidence interval; FAS, full analysis set; FPG, fasting plasma glucose; HbA1c, glycated hemoglobin; LIN, linagliptin; LOCF, last observation carried forward; MET, metformin; OADs, oral antidiabetic drugs; PPG, Post-prandial glucose; qd, once daily; s.e., standard error; SU, sulfonylurea. 

References:

  1. TRAJENTA DUO® approved package insert. Updated in December 2020 and approved in February 2021.

  2. Haak T, et al. Diabetes Obes Metab. 2012;14:565–574.

  3. Mu Y, et al. Diabetes Res Clin Pract. 2017 Feb;124:48-56.

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