Elsevier

Journal of Diabetes and its Complications

Volume 30, Issue 8, November–December 2016, Pages 1571-1576
Journal of Diabetes and its Complications

Empagliflozin in combination with oral agents in young and overweight/obese Type 2 diabetes mellitus patients: A pooled analysis of three randomized trials

https://doi.org/10.1016/j.jdiacomp.2016.07.016Get rights and content

Abstract

Aims

This analysis aimed to evaluate efficacy and safety of empagliflozin in combination therapy in < 65 y.o. patients, overweight/obese, and with uncontrolled T2DM.

Methods

Pooled analysis from three phase-III trials, in < 65 y.o. patients, with BMI 25–35 kg/m2, and HbA1c 8% at baseline. Patients (N = 439) were randomized to placebo (n = 138), empagliflozin 10 mg (n = 160), or empagliflozin 25 mg (n = 141) once daily (24 weeks) as add-on to metformin, to metformin plus sulfonylurea, or to pioglitazone ± metformin.

Results

At week 24, adjusted mean (SE) changes from baseline in HbA1c were − 0.19% (0.07) for placebo vs. − 1.10% (0.07) and − 1.10% (0.07) for empagliflozin 10 and 25 mg, respectively (both p < 0.001). Adjusted mean (SE) changes from baseline in weight were − 0.33 kg (0.21) for placebo vs. -1.94 kg (0.19) and − 2.14 kg (0.20) for empagliflozin 10 and 25 mg, respectively (both p < 0.001). Adverse events were reported in 57.2% on placebo, 64.4% on empagliflozin 10 mg and 59.6% on empagliflozin 25 mg. Genital infection AEs were reported in 1.4% on placebo, 3.8% on empagliflozin 10 mg, and 5.0% on empagliflozin 25 mg.

Conclusions

In this specific population, empagliflozin in combination with other oral agents, significantly reduced HbA1c and body weight and was well tolerated.

Introduction

The rise in the prevalence of type 2 diabetes mellitus (T2DM) observed over the last few decades has been accompanied by an increasingly frequent occurrence of this condition in younger adults (Hillier and Pedula, 2001, Hillier and Pedula, 2003, Pettitt et al., 2014). Moreover, studies have found that T2DM patients under 65 have poorer blood glucose control than older patients (Berkowitz et al., 2013, Vinagre et al., 2012). As a consequence of the earlier onset of the condition, they may be more exposed to hyperglycaemic states (Constantino et al., 2013) and proper control through early diagnosis and treatment is, therefore, crucial in reducing potential long-term complications (Holman, Paul, Bethel, Matthews, & Neil, 2008).

Obesity is a risk factor that plays an important role in the development of T2DM (ADA, 2015). In a study evaluating the prevalence of overweight/obesity in patients with T2DM, over 85% had a body mass index (BMI) greater than 25 kg/m2. These patients also had poorer blood glucose control (Daousi et al., 2006). In view of the benefits of modest weight reductions on the control of T2DM, it is essential to focus the treatment of T2DM and obesity under the same premise (Klein et al., 2004), although reducing weight can be difficult in these patients because of comorbidities, the difficulty of making lifestyle changes or even the glucose-lowering treatment itself; which is frequently associated with weight gain (Pi-Sunyer, 2005). Similarly, an inverse linear relationship has been reported between BMI and the age at T2DM diagnosis (Hillier and Pedula, 2001, Hillier and Pedula, 2003, Pettitt et al., 2014), indicating the importance of weight control in younger patients.

Empagliflozin and other sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new therapeutic option for T2DM treatment, particularly in overweight/obese patients. Their unique mechanism of action, independent of beta-cell function and insulin resistance, inhibits renal glucose reabsorption, thus, eliminating excess glucose in the urine, resulting in significant HbA1c reductions (DeFronzo, Davidson, & Del Prato, 2012). Moreover, treatment with empagliflozin is associated with moderate and sustained reductions in body weight and systolic blood pressure (SBP), possibly due to osmotic diuresis caused by glucose and loss of calories resulting from its elimination (Kovacs et al., 2014).

This analysis was carried out in response to the increasingly early onset of T2DM and its strong relationship with overweight and obesity (Hillier and Pedula, 2001, Hillier and Pedula, 2003, Pettitt et al., 2014). The objective was to study the efficacy and safety of empagliflozin in participants younger than 65 years, with overweight or class I obesity (BMI 25–35 kg/m2), and with poorly controlled T2DM (HbA1c ≥ 64 mmol/mol (8%)) at baseline.

Section snippets

Subjects

The patients included in this analysis met all the inclusion and exclusion criteria previously reported in the respective clinical trials (Haring et al., 2013, Haring et al., 2014, Kovacs et al., 2014). In general terms, the inclusion criteria stipulated patients aged 18 or over, with uncontrolled T2DM (HbA1c 7–10% (53–86 mmol/mol)); despite diet, exercise, and a stable regimen (more than 12 weeks) of anti-diabetes treatment, and a BMI of 45 kg/m2 or less. The main exclusion criteria were the

Design

This is a pooled post hoc analysis of three multicentre, phase III, randomized, double-blind, placebo-controlled clinical trials [EMPA-REG PIO (NCT01289990), EMPA-REG MET (NCT01159600), EMPA-REG METSU (NCT01159600)]. Studies for empagliflozin registration that evaluated empagliflozin co-treatment with other oral antidiabetic compounds were considered for this analysis. Monotherapy studies were not included. Patients enrolled in the three trials had been treated with a stable regimen of 1)

Patients characteristics

In this analysis, a total of 439 patients were included (empagliflozin 10 mg, n = 160 (148 completed); empagliflozin 25 mg, n = 141 (135 completed); placebo n = 138 (122 completed), with overall completion of 405 participants (92.3%)). The number of patients included from each study was balanced and their demographic characteristics and baseline condition were similar across treatment groups (Table 1). The mean age ± SD (range) of the population was 52.5 ± 7.7 (27–64) years and 56.3% were men. Mean HbA1c ± 

Discussion

This post hoc analysis of three randomized trials shows that empagliflozin is associated with a clinically and statistically significant reduction in HbA1c in overweight or obese patients under the age of 65 with poorly controlled T2DM. Empagliflozin also produces a consistent decrease in body weight and has demonstrated a good safety and tolerability profile.

When comparing HbA1c reductions in this patient profile to the general population of the parent studies, empagliflozin was found to have

Funding sources

This study was funded by Boehringer Ingelheim and Eli Lilly.

Submission declaration and verification

The work described here has not been published previously nor it is under consideration for publication elsewhere. This manuscript is approved by all authors and, if accepted, it will not be published elsewhere without the consent of the copyright-holder.

Acknowledgements

We thank the participants who contributed in the trials and BCNscience for their assistance in medical writing.

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Conflict of interest: Irene Romera, Sanja Giljanovic Kis and Ebrahim Naderali are full-time employees of Eli Lilly. Arantxa García is a full-time employee of Boehringer Ingelheim. Susanne Crowe and Unai Aranda were employees of Boehringer Ingelheim during the development of the manuscript. Pedro de Pablos-Velasco has received speaker and consulting fees from AstraZeneca, Boehringer Ingelheim, Lilly, Novo Nordisk, and Sanofi-aventis. All remaining authors have none declared.

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