Abstract
BackgroundThe most recent treatment guidelines for type 2 diabetes (T2D) recommend sodium-glucose cotransporter 2 (SGLT2) inhibitors should be considered preferentially in patients with T2D with either a high cardiovascular risk or with cardiovascular disease (CVD), regardless of their diabetes status and prior use of conventional metformin therapy. Whether the therapeutic impact of SGLT2 inhibitors on clinical parameters differs according to the use of metformin therapy however remains unclear.MethodsThe study was a post hoc analysis of the EMBLEM trial (UMIN000024502). All participants (n = 105; women 31.4%; mean age 64.8 years) had both T2D and CVD and were randomized to either 24 weeks of empagliflozin 10 mg daily or placebo. Analysis of the data assessed the effect of empagliflozin on changes from baseline to 24 weeks in glycemic and non-glycemic clinical parameters, according to the baseline use of metformin.ResultsOverall, 53 (50.5%) patients received baseline metformin. In the 52 patients treated with empagliflozin (48.1% with baseline metformin), the decrease in systolic blood pressure from baseline levels was greater in patients receiving metformin, compared to that observed in metformin-naïve patients (group difference − 8.5 [95% confidence interval (CI) − 17.7 to 0.6 mmHg], p = 0.066). Reduction in body mass index (BMI) was significantly greater in patients receiving baseline metformin, relative to nonusers (− 0.54 [95% CI − 1.07 to − 0.01] kg/m2, p = 0.047). The group ratio (baseline metformin users vs. nonusers) of proportional changes in the geometric mean of high-sensitivity Troponin-I (hs-TnI) was 0.74 (95% CI 0.59 to 0.92, p = 0.009). No obvious differences were observed in glycemic parameters (fasting plasma glucose, glycohemoglobin, and glycoalbumin) between the baseline metformin users and nonusers.ConclusionOur findings suggest 24 weeks of empagliflozin treatment was associated with an improvement in glycemic control, irrespective of the baseline use of metformin therapy. The effects of empagliflozin on reductions in BMI and hs-TnI were more apparent in patients who received baseline metformin therapy, compared to that observed in metformin-naïve patients.Trial registration University Medical Information Network Clinical Trial Registry, number 000024502
Highlights
Based on accumulated clinical evidence and demonstration of safety and efficacy, metformin has become recognized as an established glucose-lowering agent for the initial treatment of type 2 diabetes (T2D) [1]
body mass index (BMI) and high-sensitivity Troponin-I (hs-TnI) were more apparent in patients who received baseline metformin therapy, compared to that observed in metformin-naïve patients
In the latest European Society of Cardiology (ESC) Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the European Association for the Study of Diabetes (EASD), it was recommended that metformin should be considered as first-line therapy in patients with T2D, especially in overweight patients without cardiovascular disease (CVD) and those with a moderate cardiovascular risk [2]
Summary
Based on accumulated clinical evidence and demonstration of safety and efficacy, metformin has become recognized as an established glucose-lowering agent for the initial treatment of type 2 diabetes (T2D) [1]. In the CVOTs completed before the development of such a paradigm shift, almost all participants (i.e., more than two-thirds) received baseline metformin therapy in accordance with conventional treatment strategy for diabetes care and had the agents investigated in this study added to metformin therapy [3,4,5,6,7,8,9,10,11,12] This raised the clinical question as to whether or not the cardiovascular benefits of the agents would be expected even in patients with T2D at high cardiovascular risk or those with CVD, independent of the effects of baseline metformin. Whether the therapeutic impact of SGLT2 inhibitors on clinical parameters differs according to the use of metformin therapy remains unclear
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