Jisoo Lee

Empagliflozin and Cardiovascular Outcomes in Asian Patients With Type 2 Diabetes and Established Cardiovascular Disease ― Results From EMPA-REG OUTCOME® ―

BACKGROUND In the EMPA-REG OUTCOME®trial, empagliflozin added to standard of care reduced the risk of 3-point major adverse cardiovascular (CV) events (3-point MACE: composite of CV death, non-fatal myocardial infarction, or non-fatal stroke) by 14%, CV death by 38%, hospitalization for heart failure by 35%, and all-cause mortality by 32% in patients with type 2 diabetes (T2DM) and established CV disease. We investigated the effects of empagliflozin in patients of Asian race.Methods and Results:Patients were randomized to receive empagliflozin 10 mg, empagliflozin 25 mg, or placebo. Of 7,020 patients treated, 1,517 (21.6%) were of Asian race. The reduction in 3-point MACE in Asian patients was consistent with the overall population: 3-point MACE occurred in 79/1,006 patients (7.9%) in the pooled empagliflozin group vs. 58/511 patients (11.4%) in the placebo group (hazard ratio: 0.68 [95% confidence interval: 0.48-0.95], P-value for treatment by race interaction (Asian, White, Black/African-American): 0.0872). The effects of empagliflozin on the components of MACE, all-cause mortality, and heart failure outcomes in Asian patients were consistent with the overall population (P-values for interaction by race >0.05). The adverse event profile of empagliflozin in Asian patients was similar to the overall trial population. CONCLUSIONS Reductions in the risk of CV outcomes and mortality with empagliflozin in Asian patients with T2DM and established CV disease were consistent with the overall trial population.

Efficacy and safety of empagliflozin in patients with type 2 diabetes from Asian countries: pooled data from four phase III trials.

We investigated the efficacy and safety of empagliflozin over 24 weeks in Asian patients with type 2 diabetes (T2DM) using pooled data from four phase III trials. In these trials, patients were randomized to receive empagliflozin 10 mg, empagliflozin 25 mg or placebo as monotherapy or add‐on to metformin, metformin plus sulphonylurea or pioglitazone ± metformin. In total, 1326 patients from Asia received ≥1 dose of study drug. At week 24, adjusted mean differences versus placebo in change from baseline in glycated haemoglobin (HbA1c) were −0.66% [95% confidence interval (CI) −0.76, −0.56] and −0.73% (95% CI −0.83, −0.64) and in weight were −1.6 kg (95% CI −1.9, −1.3) and −1.8 kg (95% CI −2.1, −1.5) with empagliflozin 10 and 25 mg, respectively (all p < 0.001). Empagliflozin significantly reduced systolic and diastolic blood pressure. The proportion of patients reporting ≥1 adverse event was similar across treatment groups, but events consistent with genital infection were more common in patients treated with empagliflozin 10 mg (3.4%) or 25 mg (2.3%) than placebo (0.9%). Thus in Asian patients with T2DM, empagliflozin reduced HbA1c, weight and blood pressure, and was well tolerated.

Oral glucose lowering with linagliptin and metformin compared with linagliptin alone as initial treatment in Asian patients with newly diagnosed type 2 diabetes and marked hyperglycemia: Subgroup analysis of a randomized clinical trial

Type 2 diabetes mellitus is an epidemic in Asia, yet clinical trials of glucose‐lowering therapies often enroll predominantly Western populations. We explored the initial combination of metformin and linagliptin, a dipeptidyl peptidase‐4 inhibitor, in newly diagnosed type 2 diabetes mellitus patients in Asia with marked hyperglycemia.

Bladder cancer in the EMPA-REG OUTCOME trial

To the Editor: We read with interest the recently published article in Diabetologia by Tang et al on the risk of cancer in patients with type 2 diabetes treated with sodium–glucose cotransporter 2 (SGLT2) inhibitors [1]. We agree with their conclusion that treatment with SGLT2 inhibitors is not associated with a significantly increased risk of cancer. In their analysis of specific cancer types, the authors suggest that SGLT2 inhibitors may be associated with an increased risk of bladder cancer. With respect to empagliflozin, the authors report that the cardiovascular outcomes trial, EMPA-REG OUTCOME, conducted in individuals with type 2 diabetes and established cardiovascular disease, contributed over 50% of individuals and events to their analysis of bladder cancer. We would like to draw attention to data from this trial that were not considered by the authors, which (except for the data on the events reported up to 7 days after the last intake of study drug) were included in documents submitted to the US Food and Drug Administration [2]. In the EMPA-REG OUTCOME trial, cases of bladder cancer were identified from adverse events coded using the following preferred terms in the Medical Dictionary for Regulatory Activities (MedDRA): ‘bladder cancer’; ‘bladder cancer recurrent’; ‘bladder cancer transitional cell carcinoma’; and ‘transitional cell carcinoma’. Transitional cell carcinoma accounts for over 90% of all bladder cancers [3]. Documentation relating to events coded as transitional cell carcinoma was medically reviewed and cases confirmed. In an on-treatment analysis based on events reported from the first intake of study drug up to 7 days after the last intake, four transitional cell carcinoma cases were located in the bladder (three in the placebo group, one in the empagliflozin 10 mg group) and one was located in the ureter (in the empagliflozin 25 mg group). In an intent-to-treat analysis (based on events reported from the first intake of study drug up to trial termination in patients treated with ≥ 1 dose of study drug), bladder cancer was reported in 5/2333 patients (0.2%) in the placebo group, 3/2345 patients (0.1%) in the empagliflozin 10 mg group and 9/2342 patients (0.4%) in the empagliflozin 25 mg group (Table 1). To elucidate the potential association between a substance and carcinogenesis, length of exposure needs to be considered. We undertook an additional analysis of patients with at least 6 months’ drug exposure. Bladder cancer with an onset after 6 months’ cumulative exposure to study drug was reported in 4/2187 patients (0.2%) in the placebo group, 3/2216 patients (0.1%) in the empagliflozin 10 mg group, and 7/2190 patients (0.3%) in the empagliflozin 25 mg group (Table 1). With the number of events being so small, a few additional cases can make a difference to the conclusions drawn. Based * Sven Kohler sven.kohler@boehringer-ingelheim.com

Empagliflozin as add‐on to linagliptin in a fixed‐dose combination in Japanese patients with type 2 diabetes: Glycaemic efficacy and safety profile in a 52‐week, randomized, placebo‐controlled trial

This double‐blind, randomized, placebo‐controlled trial (ClinicalTrials.gov NCT02453555) evaluated the efficacy and safety of empagliflozin (Empa) 10 or 25 mg as add‐on to linagliptin (Lina) 5 mg (fixed‐dose combination, Empa/Lina 10/5 or 25/5) in insufficiently controlled Japanese type 2 diabetes patients.

Safety and tolerability of empagliflozin in East Asian patients with type 2 diabetes: Pooled analysis of phase I-III clinical trials

We investigated the safety and tolerability of empagliflozin (EMPA) in East Asian patients with type 2 diabetes.

Linagliptin as add-on to empagliflozin in a fixed-dose combination in Japanese patients with type 2 diabetes: Glycaemic efficacy and safety profile in a two-part, randomized, placebo-controlled trial

This two‐part, double‐blind, double‐dummy, randomized, placebo‐controlled trial (83 sites) evaluated the efficacy and safety of empagliflozin (Empa) 10 or 25 mg and linagliptin (Lina) 5 mg fixed‐dose combinations (FDCs) in Japanese patients with type 2 diabetes mellitus (T2DM) who were poorly controlled with Empa.