Efficacy

STATISTICALLY SIGNIFICANT HbA_1c REDUCTIONS AS MONOTHERAPY AND ADD-ON THERAPY

As monotherapy and as add-on therapy to metformin, metformin and a sulfonylurea (SU), and basal insulin

Primary endpoint: placebo-adjusted mean difference in HbA_1c at 24 weeks.^1-4*

TRAJENTA® Monotherapy

A randomized, multicenter, double-blind, placebo-controlled study of treatment-naïve and treatment-experienced adult patients with type 2 diabetes aged 18 to 80 years. Participants were randomized to TRAJENTA® 5 mg/day (n=336) or placebo (n=167) for 24 weeks. Primary endpoint was change from baseline HbA_1cat 24 weeks. Secondary endpoints included change in fasting plasma glucose (FPG) and 2-hour postprandial glucose (2hPPG).¹

TRAJENTA® Add-on to Metformin

(Metformin + TRAJENTA® vs Metformin + placebo) A randomized, double-blind, placebo-controlled, parallel-group study of TRAJENTA® in adult patients with type 2 diabetes and insufficient glycemic control despite metformin therapy. Participants were randomized to TRAJENTA® 5 mg/day (n=524) or placebo (n=177) in combination with metformin ≥1,500 mg/day for 24 weeks. Primary endpoint was change from baseline HbA_1cat 24 weeks. Secondary endpoints included change from baseline in FPG and 2h-PPG.²

TRAJENTA® Add-on to Metformin + Sulfonylurea (SU)

(Metformin + SU + TRAJENTA® vs Metformin + SU + placebo)
A randomized, double-blind, placebo-controlled, parallel-group study of TRAJENTA® vs placebo in adult patients with type 2 diabetes and insufficient glycemic control despite treatment with metformin in combination with an SU. Participants were randomized to TRAJENTA® 5 mg/day (n=793) or placebo (n=265) as an add-on to existing metformin + SU therapy. Primary endpoint was change from baseline HbA_1c at 24 weeks. Secondary endpoint included the change from baseline in FPG.³

TRAJENTA® Add-on to Basal Insulin

(Basal insulin + TRAJENTA® vs basal insulin + placebo)
A 52-week, randomized, double-blind, placebo-controlled, parallel-group study of TRAJENTA® vs placebo in adult patients with type 2 diabetes and insufficient glycemic control despite treatment with basal insulin therapy. Participants were randomized to TRAJENTA® 5 mg/day (n=631) or placebo (n=630) as an add-on to existing basal insulin therapy with or without metformin ± pioglitazone. Primary endpoint was change from baseline HbA_1c at 24 weeks. Secondary endpoints included change from baseline in FPG.⁴

COMPARABLE DURABILITY WITH A SIMPLE DOSE

Durable and comparable efficacy with a sulfonylurea for 6.3 years was demonstrated in CAROLINA trial

CAROLINA trial is a multicenter, randomized, double-blind, active-controlled clinical trial examining the effect of treatment with TRAJENTA® versus glimepiride on cardiovascular safety in adult patients with relatively early type 2 diabetes and cardiovascular risk factors or established atherosclerotic cardiovascular disease. Six thousand and thirty-three patients were randomized and received at least 1 dose of 5 mg of once-daily linagliptin (n=3,023) or 1 to 4 mg of once-daily glimepiride (n=3,010). Glimepiride was started at 1 mg/day and up-titrated to a potential maximum dose of 4 mg/day every 4 weeks during the first 16 weeks. The primary endpoint was time to first occurrence of cardiovascular death, nonfatal myocardial infarction (MI), or nonfatal stroke (3-point major cardiovascular event [3P-MACE] composite).⁵

Median follow-up was 6.3 years in both groups. The overall adjusted mean change in HbA_1c until week 256 was not significantly different between the groups (weighted mean difference in adjusted means was 0% [95% CI -0.05% to 0.05%]). In the glimepiride group, 49% of the participants at week 16 and 61% of the participants at week 256 were using the highest 4-mg dose.⁵

SIGNIFICANT IMPROVEMENT IN GLUCOSE FLUCTUATION AS ADD-ON THERAPY

Glycemic variability and control were improved when TRAJENTA® was added to glimepiride therapy

In a randomized, double-blinded, crossover trial, patients with hepatocyte nuclear factor 1-alpha diabetes (n = 19) were randomly assigned to treatment with glimepiride + TRAJENTA® (16 weeks), wash-out (4 weeks) and treatment with glimepiride + placebo (16 weeks) (or vice versa). Treatments were evaluated by continuous glucose monitoring (CGM), HbA_1cand a meal test. Compared with placebo, TRAJENTA® add-on therapy showed significant improvements in glycemic variability (mean difference in coefficient variation -3.5%, p=0.0337) and in HbA_1c (mean difference -0.5%, p=0.0048). Incidence of hypoglycemia (assessed by patient-reported episodes and CGM) was similar between treatments.⁶

CONSISTENT EFFECTS IN VARIOUS PATIEN GROUPS

TRAJENTA® provided consistent glucose-lowering effect across all age groups

A retrospective analysis pooled data from three previously reported trials evaluating the safety and efficacy of TRAJENTA® 5 mg once daily given as monotherapy, as add-on therapy in patients with inadequate glycemic control with metformin, and as add-on therapy in patients with inadequate glycemic control with metformin plus a sulfonylurea to explore what extent baseline characteristics could be associated with variances in glucose-lowering treatment response. Patients were grouped into pre-defined baseline categories according to age of ≤ 50, 51 to <65, 65 to <75 and ≥ 75 years old.⁷ The effect of TRAJENTA® on decreasing HbA_1cwas similar across all age groups.⁷

TRAJENTA® demonstrated consistent efficacy across all stages of kidney function

CKD stages 1 + 2 (eGFR ≥ 60 ml/min/1.73 m²), stage 3a (60 ml/min/1.73 m² > eGFR ≥ 45 ml/min/1.73 m²) and stages 3b + 4 + 5 (45 ml/min/1.73 m² > eGFR).

A retrospective observational study investigating the clinical course over 6 months after the initiation of TRAJENTA® in Japanese patients with type 2 diabetes mellitus divided into groups according to the renal function: CKD stages 1 + 2 were those with eGFR ≥ 60 ml/min/1.73 m², stage 3a were those with eGFR less than 60 ml/min/1.73 m² and ≥ 45 ml/min/1.73 m², and stages 3b + 4 + 5 were those with eGFR less than 45 ml/min/1.73 m². Total of 73 patients received 5 mg once daily of TRAJENTA® as monotherapy and the change in HbA_1cafter 6 months of treatment was not significantly different among the patients with different renal function.⁸

Footnotes:

* Prespecified primary analysis of primary endpoint. Full analysis set. (FAS; defined as all randomized patients treated with at least 1 dose of the study drug, with a baseline HbA_1c value, and at least 1 on-treatment HbA_1c value.) The FAS is the basis for the intention-to-treat (ITT) analysis.^1-4
† ANCOVA model included treatment and number of prior oral antihyperglycemic drugs (OADs) as class effects, as well as baseline HbA_1c as continuous covariates.^1,2
‡ 0.3% adjusted mean increases from baseline HbA_1c 8.0% with placebo (n=163). 20.9% of patients in the placebo group required use of rescue therapy vs 10.2% of patients in the TRAJENTA® group.¹
§ P 0.15% adjusted mean increase from baseline HbA_1c 8.0% with placebo plus metformin (n=175). 19% of patients in the placebo group required use of rescue therapy vs 8% of patients in the TRAJENTA® group.²
¶ ANCOVA model included treatment as factor and baseline HbA_1c as continuous covariates.3 || 0.1% adjusted mean decrease from baseline HbA_1c 8.1% with placebo plus metformin and an SU (n=262). 13% of patients in the placebo group required the use of rescue therapy vs 5.4% in the TRAJENTA® group.³
** ANCOVA model included treatment, categorical renal function impairment status, and concomitant OADs as class effects, as well as baseline HbA_1c as continuous covariates.⁴
†† 0.1% adjusted mean increases from baseline HbA_1c 8.3% with placebo plus basal insulin (n=617). 50.4% of patients in the placebo group required use of rescue therapy vs 38.2% of patients in the TRAJENTA® group at 52 weeks.⁴
‡‡ Based on MMRM including treatment, week repeated within participants, week by treatment interaction, continuous baseline HbA_1c and baseline HbA_1c by week interaction.
§§ Pre-specified subgroup analysis on pooled data from 3 pivotal Phase III, randomized, placebo-controlled trials: treatment in monotherapy, add-on to metformin, and add-on to metformin plus sulfonylurea. p-values for between-group differences (vs. placebo).
¶¶ ANCOVA-adjusted for continuous baseline HbA_1c, washout, treatment, study, subgroup, and treatment by subgroup interaction.
ANOVA, analysis of variance; BL, baseline; CGM, continuous glucose monitoring; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; HbA_1c, glycated hemoglobin; ITT, intention-to-treat; Lina, linagliptin; MI, myocardial infarction; MMRM, mixed-model repeated measures; OADs, oral antihyperglycemic drugs; Pbo, placebo; FPG, fasting plasma glucose; QD, once-daily; SU, sulfonylurea; 2h-PPG, 2-h postprandial plasma glucose; 3P-MACE, 3-point major cardiovascular event.

References:

Del Prato S, Barnett AH, Huisman H, et al. Diabetes Obes Metab. 2011;13(3):258‑267.
Taskinen M-R, Rosenstock J, Tamminen I, et al. Diabetes Obes Metab. 2011;13(1):65‑74.
Owens DR, Swallow R, Dugi KA, et al. Diabet Med. 2011;28(11):1352‑1361. Erratum in: Diabet Med. 2012;29(1):158.
Yki‑Järvinen H, Rosenstock J, Durán‑Garcia S, et al. Diabetes Care. 2013;36(12):3875‑3881.
Rosenstock J, Kahn SE, Johansen OE, et al. JAMA. 2019 Sep 24;322(12):1155-1166.
Christensen AS, Haedesdal S, Støys J, et al. American Diabetes Association 2020 ePoster 923-P.
Del Prato S, Patel S, Crowe S, et al. Nutr Metab Cardiovasc Dis. 2016 Oct;26(10):886-92.
Ito H, Abe M, Antoku S, et al. Expert Opin Pharmacother. 2015 Feb;16(3):289-96.

TRAJENTA®

Efficacy

STATISTICALLY SIGNIFICANT HbA_1c REDUCTIONS AS MONOTHERAPY AND ADD-ON THERAPY